http://www.mdpi.com/journal/cancers Latest open access articles published in Cancers at http://www.mdpi.com/journal/cancers http://www.mdpi.com/2072-6694/4/2/523 Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor’s molecular biology and pathophysiology, which unfortunately has so far failed to translate into a meaningful clinical benefit. Dysregulation and a resulting prominent pathophysiological role of the epidermal growth factor receptor (EGFR) have been identified in several different malignant tumor entities, GBM among them. The EGFR is overexpressed in about 40% of GBM cases, and half of these coexpress a mutant, constitutively activated subtype, EGFRvIII. Unfortunately, recent trials studying with therapeutic approaches targeted against the EGFR and EGFRvIII have failed to meet expectations, with only a minority of patients responding despite evidence of good in vitro and rodent model activity. Having potentially high relevance within this context, epithelial to mesenchymal transition (EMT) is a phenomenon associated with early stages of carcinogenesis, cancer invasion and recurrence. During EMT, epithelial cells lose many of their epithelial characteristics, prominently E-cadherin expression, and acquire properties that are typical for mesenchymal cells such as the expression of vimentin. Epithelial to mesenchymal transition has been specifically demonstrated in GBM. In this review, we summarize the evidence that EMT may precipitate GBM resistance to EGFR-targeted therapy, and may thus be among the principal factors contributing to the clinical failure of targeted therapy against EGFR and EGFRvIII. http://www.mdpi.com/2072-6694/4/2/523 Tue, 08 May 2012 00:00:00 CEST Cancers 2012-05-08 4 2 Review 523 530 2072-6694 Epidermal to Mesenchymal Transition and Failure of EGFR-Targeted Therapy in Glioblastoma 2012-05-08 doi: 10.3390/cancers4020523 Andrej Pala Georg Karpel-Massler Richard Eric Kast Christian Rainer Wirtz Marc-Eric Halatsch http://www.mdpi.com/2072-6694/4/2/504 We reviewed the literature about entero-pancreatic neuroendocrine tumors in Multiple Endocrine Neoplasia type 1 syndrome (MEN1) to clarify their demographic features, localization imaging, practice, and appropriate therapeutical strategies, analyzing the current approach to entero-pancreatic neuroendocrine tumors in MEN1. Despite the fact that hyperparathyroidism is usually the first manifestation of MEN1, the penetrance of these tumors is similar. They are characterized by multiplicity of lesions, variable expression of the tumors, and propensity for malignant degeneration. Both the histological type and the size of MEN1 neuroendocrine tumors correlate with malignancy. Monitoring of pancreatic peptides and use of imaging exams allow early diagnosis and prompt surgical treatment, resulting in prevention of metastatic disease and improvement of long-term survival. Surgery is often the treatment of choice for MEN1-neuroendocrine tumors. The rationale for surgical approach is to curtail malignant progression of the disease, and to cure the associated biochemical syndrome, should it be present. http://www.mdpi.com/2072-6694/4/2/504 Mon, 07 May 2012 00:00:00 CEST Cancers 2012-05-07 4 2 Review 504 522 2072-6694 Gastroenteropancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1 2012-05-07 doi: 10.3390/cancers4020504 Francesco Tonelli Francesco Giudici Francesca Giusti Maria Luisa Brandi http://www.mdpi.com/2072-6694/4/2/490 Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy. http://www.mdpi.com/2072-6694/4/2/490 Thu, 26 Apr 2012 00:00:00 CEST Cancers 2012-04-26 4 2 Article 490 503 2072-6694 T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma 2012-04-26 doi: 10.3390/cancers4020490 Oliver Abschuetz Wolfram Osen Kathrin Frank Masashi Kato Dirk Schadendorf Viktor Umansky http://www.mdpi.com/2072-6694/4/2/475 Rho GTPases are overexpressed and hyperactivated in many cancers, including breast cancer. Rho proteins, as well as their regulators and effectors, have been implicated in mitosis, and their altered expression promotes mitotic defects and aneuploidy. Previously, we demonstrated that p190B Rho GTPase activating protein (RhoGAP) deficiency inhibits ErbB2-induced mammary tumor formation in mice. Here we describe a novel role for p190B as a regulator of mitosis. We found that p190B localized to centrosomes during interphase and mitosis, and that it is differentially phosphorylated during mitosis. Knockdown of p190B expression in MCF-7 and Hela cells increased the incidence of aberrant microtubule-kinetochore attachments at metaphase, lagging chromosomes at anaphase, and micronucleation, all of which are indicative of aneuploidy. Cell cycle analysis of p190B deficient MCF-7 cells revealed a significant increase in apoptotic cells with a concomitant decrease in cells in G1 and S phase, suggesting that p190B deficient cells die at the G1 to S transition. Chemical inhibition of the Rac GTPase during mitosis reduced the incidence of lagging chromosomes in p190B knockdown cells to levels detected in control cells, suggesting that aberrant Rac activity in the absence of p190B promotes chromosome segregation defects. Taken together, these data suggest that p190B regulates chromosome segregation and apoptosis in cancer cells. We propose that disruption of mitosis may be one mechanism by which p190B deficiency inhibits tumorigenesis. http://www.mdpi.com/2072-6694/4/2/475 Wed, 25 Apr 2012 00:00:00 CEST Cancers 2012-04-25 4 2 Article 475 489 2072-6694 P190B RhoGAP Regulates Chromosome Segregation in Cancer Cells 2012-04-25 doi: 10.3390/cancers4020475 Melissa Hwang Sirisha Peddibhotla Peter McHenry Peggy Chang Zachary Yochum Ko Un Park James Cooper Sears Tracy Vargo-Gogola http://www.mdpi.com/2072-6694/4/2/442 Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed that free radicals play a further complex role in cancer. Low levels of free radicals and steady state levels of antioxidant enzymes are responsible for the fine tuning of redox status inside cells. A change in redox state is a way to modify the physiological status of the cell, in fact, a more reduced status is found in resting cells while a more oxidative status is associated with proliferative cells. The mechanisms by which redox status can change the proliferative activity of cancer cells are related to transcriptional and posttranscriptional modifications of proteins that play a critical role in cell cycle control. Since cancer cells show higher levels of free radicals compared with their normal counterparts, it is believed that the anti-oxidative stress mechanism is also increased in cancer cells. In fact, the levels of some of the most important antioxidant enzymes are elevated in advanced status of some types of tumors. Anti-cancer treatment is compromised by survival mechanisms in cancer cells and collateral damage in normal non-pathological tissues. Though some resistance mechanisms have been described, they do not yet explain why treatment of cancer fails in several tumors. Given that some antitumoral treatments are based on the generation of free radicals, we will discuss in this review the possible role of antioxidant enzymes in the survival mechanism in cancer cells and then, its participation in the failure of cancer treatments. http://www.mdpi.com/2072-6694/4/2/442 Wed, 25 Apr 2012 00:00:00 CEST Cancers 2012-04-25 4 2 Review 442 474 2072-6694 Radical Decisions in Cancer: Redox Control of Cell Growth and Death 2012-04-25 doi: 10.3390/cancers4020442 Rosa M. Sainz Felipe Lombo Juan C. Mayo http://www.mdpi.com/2072-6694/4/2/420 Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for immunotherapy, patient selection and best sequencing with other prostate cancer therapies remain to be determined. A better understanding of immune response may help address these issues. http://www.mdpi.com/2072-6694/4/2/420 Wed, 18 Apr 2012 00:00:00 CEST Cancers 2012-04-18 4 2 Review 420 441 2072-6694 Immune Response to Sipuleucel-T in Prostate Cancer 2012-04-18 doi: 10.3390/cancers4020420 Eddie Thara Tanya B. Dorff Monica Averia-Suboc Michael Luther Mary E. Reed Jacek K. Pinski David I. Quinn http://www.mdpi.com/2072-6694/4/2/400 The blood vasculature in cancers has been the subject of intense interest during the past four decades. Since the original ideas of targeting angiogenesis to treat cancer were proposed in the 1970s, it has become evident that more knowledge about the role of vessels in tumor biology is needed to fully take advantage of such strategies. The vasculature serves the surrounding tissue in a multitude of ways that all must be taken into consideration in therapeutic manipulation. Aspects of delivery of conventional cytostatic drugs, induction of hypoxia affecting treatment by radiotherapy, changes in tumor cell metabolism, vascular leak and trafficking of leukocytes are affected by interventions on vascular function. Many tumors constitute a highly interchangeable milieu undergoing proliferation, apoptosis, and necrosis with abundance of growth factors, enzymes and metabolites. These aspects are reflected by the abnormal tortuous, leaky vascular bed with detached mural cells (pericytes). The vascular bed of tumors is known to be unstable and undergoing remodeling, but it is not until recently that this has been dynamically demonstrated at high resolution, facilitated by technical advances in intravital microscopy. In this review we discuss developmental genetic loss-of-function experiments in the light of tumor angiogenesis. We find this a valid comparison since many studies phenocopy the vasculature in development and tumors. http://www.mdpi.com/2072-6694/4/2/400 Wed, 11 Apr 2012 00:00:00 CEST Cancers 2012-04-11 4 2 Review 400 419 2072-6694 The Dynamics of Developmental and Tumor Angiogenesis—A Comparison 2012-04-11 doi: 10.3390/cancers4020400 Yi Jin Lars Jakobsson http://www.mdpi.com/2072-6694/4/2/379 Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis), to obtain information on the tolerance dose and treatment volume of normal human brain tissue. The studies were analyzed using the linear-quadratic model to express the re-irradiation tolerance in cumulative equivalent total doses when applied in 2 Gy fractions (EQD2cumulative). Analysis shows that the EQD2cumulative increases from conventional re-irradiation series to fractionated stereotactic radiotherapy (FSRT) to LINAC-based stereotactic radiosurgery (SRS). The mean time interval between primary radiotherapy and the re-irradiation course was shortened from 30 months for conventional re-irradiation to 17 and 10 months for FSRT and SRS, respectively. Following conventional re-irradiation, radiation-induced normal brain tissue necrosis occurred beyond an EQD2cumulative around 100 Gy. With increasing conformality of therapy, the smaller the treatment volume is, the higher the radiation dose that can be tolerated. Despite the dose escalation, no increase in late normal tissue toxicity was reported. On basis of our analysis, the use of particle therapy in the treatment of recurrent gliomas, because of the optimized physical dose distribution in the tumour and surrounding healthy brain tissue, should be considered for future clinical trials. http://www.mdpi.com/2072-6694/4/2/379 Thu, 05 Apr 2012 00:00:00 CEST Cancers 2012-04-05 4 2 Review 379 399 2072-6694 External Beam Radiotherapy of Recurrent Glioma: Radiation Tolerance of the Human Brain 2012-04-05 doi: 10.3390/cancers4020379 Peter Sminia Ramona Mayer http://www.mdpi.com/2072-6694/4/2/354 Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and often resistant to chemotherapy protocols. In the last years, agonists targeting the Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) death receptor, has been investigated as a valuable promise for cancer therapy, based on their selectivity for malignant cells and low toxicity for healthy cells. However, many cancer models display resistance to death receptor induced apoptosis, pointing to the requirement for the development of combined therapeutic approaches aimed to selectively sensitize cancer cells to TRAIL. Recently, we identified ATM kinase as a novel modulator of the ability of chemotherapeutic agents to enhance TRAIL sensitivity. Here, we review the biological determinants of HCC responsiveness to TRAIL and provide an exhaustive and updated analysis of the molecular mechanisms exploited for combined therapy in this context. The role of ATM kinase as potential novel predictive biomarker for combined therapeutic approaches based on TRAIL and chemotherapeutic drugs will be closely discussed. http://www.mdpi.com/2072-6694/4/2/354 Thu, 05 Apr 2012 00:00:00 CEST Cancers 2012-04-05 4 2 Review 354 378 2072-6694 A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase 2012-04-05 doi: 10.3390/cancers4020354 Venturina Stagni Simonetta Santini Daniela Barilà http://www.mdpi.com/2072-6694/4/2/340 Solid tumors are intrinsically resistant to therapy. Cancer progression occurs when tumor cells orchestrate responses from diverse stromal cell types such as blood vessels and their support cells, inflammatory cells, and fibroblasts; these cells collectively form the tumor microenvironment and provide direct support for tumor growth, but also evasion from cytotoxic, immune and radiation therapies. An indirect result of abnormal and leaky blood vessels in solid tumors is high interstitial fluid pressure, which reduces drug penetration, but also creates a hypoxic environment that further augments tumor cell growth and metastatic spread. Importantly however, studies during the last decade have shown that the tumor stroma, including the vasculature, can be modulated, or re-educated, to allow better delivery of chemotherapeutic drugs or enhance the efficiency of active immune therapy. Such remodeling of the tumor stroma using genetic, pharmacological and other therapeutic approaches not only enhances selective access into tumors but also reduces toxic side effects. This review focuses on recent novel concepts to modulate tumor stroma and thus locally increase therapeutic efficacy. http://www.mdpi.com/2072-6694/4/2/340 Tue, 27 Mar 2012 00:00:00 CEST Cancers 2012-03-27 4 2 Review 340 353 2072-6694 Remodeling of Tumor Stroma and Response to Therapy 2012-03-27 doi: 10.3390/cancers4020340 Anna Johansson Ruth Ganss http://www.mdpi.com/2072-6694/4/2/323 The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression, such as proliferation, invasion and metastasis, and by inducing apoptosis. http://www.mdpi.com/2072-6694/4/2/323 Fri, 23 Mar 2012 00:00:00 CET Cancers 2012-03-23 4 2 Article 323 339 2072-6694 Micronutrient Synergy in the Fight against Hepatocellular Carcinoma 2012-03-23 doi: 10.3390/cancers4020323 M. Waheed Roomi Nusrath W. Roomi Tatiana Kalinovsky Aleksandra Niedzwiecki Matthias Rath http://www.mdpi.com/2072-6694/4/1/307 For many thoracic malignancies, surgery, when feasible, is the preferred upfront modality for local control. However, adjuvant radiation plays an important role in minimizing the risk of locoregional recurrence. Tumors in the thoracic category include certain subgroups of non-small cell lung cancer (NSCLC) as well as thymic malignancies. The indications, radiation doses, and treatment fields vary amongst subtypes of thoracic tumors, as does the level of data supporting the use of radiation. For example, in the setting of NSCLC, postoperative radiation is typically reserved for close/positive margins or N2/N3 disease, although such diseases as superior sulcus tumors present unique cases in which the role of neoadjuvant vs. adjuvant treatment is still being elucidated. In contrast, for thymic malignancies, postoperative radiation therapy is often used for initially resected Masaoka stage III or higher disease, with its use for stage II disease remaining controversial. This review provides an overview of postoperative radiation therapy for thoracic tumors, with a separate focus on superior sulcus tumors and thymoma, including a discussion of acceptable radiation approaches and an assessment of the current controversies involved in its use. http://www.mdpi.com/2072-6694/4/1/307 Wed, 14 Mar 2012 00:00:00 CET Cancers 2012-03-14 4 1 Review 307 322 2072-6694 Postoperative Radiation Therapy for Non-Small Cell Lung Cancer and Thymic Malignancies 2012-03-14 doi: 10.3390/cancers4010307 Daniel R. Gomez Ritsuko Komaki http://www.mdpi.com/2072-6694/4/1/295 Desmoid tumors are benign soft tissue tumors associated with locally aggressive growth and high rates of morbidity, but they do not metastasize via lymphatic or hematogenous routes. While most of the data on desmoid tumors originates in the adult literature, many of the findings have been applied to the management of pediatric patients. This article discusses the epidemiology, etiology, clinical presentation, pathology, and treatment of this rare tumor in the pediatric population and includes a literature review of the most recent large series of pediatric patients with desmoid tumors. http://www.mdpi.com/2072-6694/4/1/295 Fri, 09 Mar 2012 00:00:00 CET Cancers 2012-03-09 4 1 Review 295 306 2072-6694 Desmoid Tumors in the Pediatric Population 2012-03-09 doi: 10.3390/cancers4010295 Joshua N. Honeyman Michael P. La Quaglia http://www.mdpi.com/2072-6694/4/1/281 The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (PNETs) in vitro, in vivo and human tumor specimen. Expression of EMT markers was analyzed using immunohistochemistry and real-time PCR. For in vitro studies, BON-1 cells were analyzed regarding expression of EMT markers before and after transfection with siRNA against Slug or Snail, and cell aggregation assays were performed. To asses in vivo effects, Rip1Tag2 mice were treated with vehicle or the snail-inhibitor polythlylenglykol from week 5-10 of age. The resected pancreata were evaluated by weight, tumor cell proliferation and apoptosis. Snail and Twist was expressed in 61 % and 64% of PNETs. This was associated with loss of E-cadherin. RT-PCR revealed conservation of the EMT markers Slug and Snail in BON-1 cells. Transfection with siRNA against Slug was associated with upregulation of E-cadherin, enhanced cell-cell adhesion and inhibition of cell proliferation. Snail-inhibition in vivo by PEG was associated with increased apoptosis, decreased tumor cell proliferation and dramatic reduced tumor volume in Rip1Tag2 mice. The presented data show that EMT plays a key role in tumorgenesis of PNETs. The activation of Snail in a considerable subset of human PNETs and the successful effect of Snail inhibition by PEG in islet cell tumors of transgenic mice provides first evidence of Snail as a drug target in PNETs. http://www.mdpi.com/2072-6694/4/1/281 Thu, 08 Mar 2012 00:00:00 CET Cancers 2012-03-08 4 1 Article 281 294 2072-6694 Epithelial-Mesenchymal Transition Is a Critical Step in Tumorgenesis of Pancreatic Neuroendocrine Tumors 2012-03-08 doi: 10.3390/cancers4010281 Volker Fendrich Katja Maschuw Jens Waldmann Malte Buchholz Johannes Rehm Thomas M. Gress Detlef K. Bartsch Alexander König http://www.mdpi.com/2072-6694/4/1/257 Despite the therapeutic advances in neuro-oncology, most patients with glioblastoma ultimately experience local progression/relapse. Re-irradiation has been poorly viewed in the past, mainly due to the overestimated risk of side effects using conventional radiotherapy. To date, thanks to the improvement of several delivery techniques, together with improved imaging capabilities, re-irradiation is a viable salvage treatment option to manage such clinical scenario. A literature overview on the feasibility and efficacy of the different irradiation modalities for recurrent glioblastoma along with considerations on areas of improvement are provided. http://www.mdpi.com/2072-6694/4/1/257 Wed, 07 Mar 2012 00:00:00 CET Cancers 2012-03-07 4 1 Review 257 280 2072-6694 Radiation Therapy for the Treatment of Recurrent Glioblastoma: An Overview 2012-03-07 doi: 10.3390/cancers4010257 Dante Amelio Maurizio Amichetti http://www.mdpi.com/2072-6694/4/1/244 We retrospectively evaluated the usefulness of combined measurement of L-methyl-[11C]methionine (MET) and 3'-deoxy-3'-[18F]fluorothymidine (FLT) positron emission tomography (PET) in the differential diagnosis between recurrent gliomas and necrotic lesions. Twenty-one patients with high-grade glioma, previously treated with surgery and radiotherapy with chemotherapy and first radiological suspicion of recurrence were enrolled. The uptake was assessed by the maximum standardized uptake value (SUVmax) and lesion-to-normal tissue count density ratio (L/N ratio). Of the 21 lesions, 15 were diagnosed recurrent gliomas and six were necrotic lesions. The average SUVmax was not significantly different between recurrent gliomas and necrotic lesions on either MET-PET or FLT-PET. The average L/N ratio of recurrent gliomas (3.36 ± 1.06) was significantly higher than that of necrotic lesions (2.18 ± 0.66) on MET-PET (p < 0.01) and the average L/N ratio of recurrent gliomas (7.01 ± 2.26) was also significantly higher than that of necrotic lesions (4.60 ± 1.23) on FLT-PET (p < 0.01). ROC curve analysis showed that the areas under the curves were high but not different between MET- and FLT-PET. PET studies using MET and FLT are useful in the differentiation of recurrent glioma from treatment-induced necrotic lesion. However, there is no complementary information in the differentiation with simultaneous measurements of MET- and FLT-PET. http://www.mdpi.com/2072-6694/4/1/244 Thu, 01 Mar 2012 00:00:00 CET Cancers 2012-03-01 4 1 Article 244 256 2072-6694 Diagnostic Value of 11C-Methionine (MET) and 18F-Fluorothymidine (FLT) Positron Emission Tomography in Recurrent High-Grade Gliomas; Differentiation from Treatment-Induced Tissue Necrosis 2012-03-01 doi: 10.3390/cancers4010244 Hajime Shishido Nobuyuki Kawai Keisuke Miyake Yuka Yamamoto Yoshihiro Nishiyama Takashi Tamiya http://www.mdpi.com/2072-6694/4/1/218 In addition to malignant cancer cells, tumors contain a variety of different stromal cells that constitute the tumor microenvironment. Some of these cell types provide crucial support for tumor growth, while others have been suggested to actually inhibit tumor progression. The composition of tumor microenvironment varies depending on the tumor site. The brain in particular consists of numerous specialized cell types such as microglia, astrocytes, and brain endothelial cells. In addition to these brain-resident cells, primary and metastatic brain tumors have also been shown to be infiltrated by different populations of bone marrow-derived cells. The role of different cell types that constitute tumor microenvironment in the progression of brain malignancies is only poorly understood. Tumor microenvironment has been shown to be a promising therapeutic target and diagnostic marker in extracranial malignancies. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context. http://www.mdpi.com/2072-6694/4/1/218 Wed, 22 Feb 2012 00:00:00 CET Cancers 2012-02-22 4 1 Review 218 243 2072-6694 Tumor Microenvironment in the Brain 2012-02-22 doi: 10.3390/cancers4010218 Mihaela Lorger http://www.mdpi.com/2072-6694/4/1/193 Prostate cancer (PCa) is the most common noncutaneous cancer diagnosis and the second leading cause of cancer-related deaths among men in the United States. Effective treatment modalities for advanced metastatic PCa are limited. Immunotherapeutic strategies based on T cells and antibodies represent interesting approaches to prevent progression from localized to advanced PCa and to improve survival outcomes for patients with advanced disease. CD8+ cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4+ T cells augment the antigen-presenting capacity of dendritic cells and promote the expansion of tumor-reactive CTLs. Antibodies mediate their antitumor effects via antibody-dependent cellular cytotoxicity, activation of the complement system, improving the uptake of coated tumor cells by phagocytes, and the functional interference of biological pathways essential for tumor growth. Consequently, several tumor-associated antigens (TAAs) have been identified that represent promising targets for T cell- or antibody-based immunotherapy. These TAAs comprise proteins preferentially expressed in normal and malignant prostate tissues and molecules which are not predominantly restricted to the prostate, but are overexpressed in various tumor entities including PCa. Clinical trials provide evidence that specific immunotherapeutic strategies using such TAAs represent safe and feasible concepts for the induction of immunological and clinical responses in PCa patients. However, further improvement of the current approaches is required which may be achieved by combining T cell- and/or antibody-based strategies with radio-, hormone-, chemo- or antiangiogenic therapy. http://www.mdpi.com/2072-6694/4/1/193 Wed, 22 Feb 2012 00:00:00 CET Cancers 2012-02-22 4 1 Review 193 217 2072-6694 Tumor-Associated Antigens for Specific Immunotherapy of Prostate Cancer 2012-02-22 doi: 10.3390/cancers4010193 Andrea Kiessling Rebekka Wehner Susanne Füssel Michael Bachmann Manfred P. Wirth Marc Schmitz http://www.mdpi.com/2072-6694/4/1/184 We report here a review of the current medical literature on pregnancy associated desmoids, including 10 cases of our own. The pertinent findings are that a large percentage of desmoids in females arise in and around pregnancy. Most occur in the abdominal muscles, particularly the right rectus abdominus, perhaps related to trauma from abdominal stretching and fetal movement. While these tumors may regress spontaneously after delivery most can be surgically resected with low recurrence rates even with R1 resections and this is clearly the treatment of choice. Subsequent pregnancies do not appear to result in recurrence in either FAP or non FAP patients. It is not clear from currently available data whether pregnancy associated desmoids are molecularly distinct from other desmoids. http://www.mdpi.com/2072-6694/4/1/184 Tue, 21 Feb 2012 00:00:00 CET Cancers 2012-02-21 4 1 Review 184 192 2072-6694 Desmoid Tumors in Pregnant and Postpartum Women 2012-02-21 doi: 10.3390/cancers4010184 William A. Robinson Colette McMillan Amy Kendall Nathan Pearlman http://www.mdpi.com/2072-6694/4/1/165 Transcatheter methods such as transcatheter arterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have an important role in the treatment for advanced hepatocellular carcinoma (HCC). Recently, sorafenib, an inhibitor of tyrosine kinases, has been found to obtain survival benefits in patients with HCC, leading to major advances in the treatment of advanced HCC. However, it is associated with a low tumor response rate, minimal survival advantage, and high rates of adverse events. On the other hand, high rates of objective treatment response with HAIC for advanced HCC have been reported, although convincing evidence of it contributing to overall survival in HAIC has been lacking. In Japan, HAIC still tends to be the preferred method for the treatment of advanced HCC, even in patients with poor liver function. However, the choice of chemotherapeutic agents in TACE/HAIC for HCC varies between institutions. In this review, based on studies reported to date in the literature, we refer to current knowledge regarding the chemotherapeutic agents used for TACE/HAIC for HCC in Japan and consider the future perspectives for HAIC for this cancer. http://www.mdpi.com/2072-6694/4/1/165 Tue, 21 Feb 2012 00:00:00 CET Cancers 2012-02-21 4 1 Review 165 183 2072-6694 Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma in Japan 2012-02-21 doi: 10.3390/cancers4010165 Hiroki Nishikawa Yukio Osaki Ryuichi Kita Toru Kimura http://www.mdpi.com/2072-6694/4/1/156 The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study. Inflammatory breast carcinoma (IBC) is widely recognized as an extremely aggressive malignancy characterized by micrometastasis at the time of diagnosis, with one interesting subgroup defined as secondary IBC where pathologically identifiable IBC appears after surgical treatment of a primary non-inflammatory breast cancer. One possible mechanism can be related to the stimulation of dormant micrometastasis through local angiogenesis occurring as part of posttraumatic healing. In this report, we review cases of secondary IBC and others where localized trauma was followed by the appearance of IBC at the traumatized site that have been identified by our IBC Registry (IBCR) and hypothesize that angiogenesis appearing as part of the healing process could act as an accelerant to an otherwise latent breast malignancy. It is therefore possible that secondary IBC can be used as a model to support local angiogenesis as an important contributor to the development of an aggressive cancer. http://www.mdpi.com/2072-6694/4/1/156 Mon, 20 Feb 2012 00:00:00 CET Cancers 2012-02-20 4 1 Article 156 164 2072-6694 Does Secondary Inflammatory Breast Cancer Represent Post-Surgical Metastatic Disease? 2012-02-20 doi: 10.3390/cancers4010156 Salman Hashmi Ladan Zolfaghari Paul H. Levine http://www.mdpi.com/2072-6694/4/1/141 The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62) and pancreatic (n = 48) NETs. CgA levels were analyzed by a commercially-available immunoradiometric assay (CIS-bio) during routine follow-up in the years 2000–2009. CgA showed a higher sensitivity for midgut (68%) than pancreatic (54%) NETs. A higher CgA sensitivity and significantly higher median CgA values were found in patients with liver metastases than in those without, and in patients with hepatic and additionally extra-hepatic metastases than in those with hepatic and nodal metastases alone, respectively. We found an overall sensitivity for elevated 5HIAA excretion of 69% for midgut NETs and a significant correlation between median CgA and 5-HIAA values. The sensitivity of AP and the correlations of AP/CgA-data-pairs were low in both midgut and pancreatic NETs, although highest for metastatic pancreatic NETs. The sensitivity of CgA measurement depends on the NET primary location and spread of disease. 5-HIAA and CgA showed comparable sensitivity in midgut NETs, while AP does not seem to be useful as a tumor marker in GEP-NETs. http://www.mdpi.com/2072-6694/4/1/141 Wed, 15 Feb 2012 00:00:00 CET Cancers 2012-02-15 4 1 Article 141 155 2072-6694 Chromogranin A as Serum Marker for Gastroenteropancreatic Neuroendocrine Tumors: A Single Center Experience and Literature Review 2012-02-15 doi: 10.3390/cancers4010141 Svenja Nölting Axel Kuttner Michael Lauseker Michael Vogeser Alexander Haug Karin A. Herrmann Johannes N. Hoffmann Christine Spitzweg Burkhard Göke Christoph J. Auernhammer http://www.mdpi.com/2072-6694/4/1/130 The majority of gastrinomas causing Zollinger-Ellison syndrome (ZES) are located in the duodenum or the pancreas. Primary hepatic gastrinomas (PHG) are extremely rare and difficult to diagnose because the liver is the commonest site of metastatic disease and gastrinomas can be very small. Furthermore, gastrinomas are typically slow-growing thus a missed, occult primary tumour may not become evident for many years. The diagnosis of PHG is therefore dependent on a careful search for a primary and long-term biochemical follow-up following curative hepatic resection. We report a case of a 7 cm PHG in a 48 year old man with ZES. Preoperatively, both a basal and stimulated gastrin levels were elevated. Surgical exploration including intraoperative ultrasound and duodenotomy, failed to reveal a primary. Patient underwent a right hepatectomy. Yearly, gastrin and secretin stimulation tests remain normal 6 years following surgery. He remains symptom free off all medication. An additional 26 cases of PHG were found. Including this case, 21 had at least 1 year follow-up, however only eight had greater than 5 years (median 24 months). Post-op gastrin levels were reported in 25, however provocative testing was done in only 10. Persistence and recurrence occurred in one and four, respectively. PHG causing ZES is extremely rare. Although the current literature claims to include 26 additional cases of PHG, without a thorough search for the primary and long-term follow-up data including provocative testing, this diagnosis remains a challenge. http://www.mdpi.com/2072-6694/4/1/130 Tue, 14 Feb 2012 00:00:00 CET Cancers 2012-02-14 4 1 Case Report 130 140 2072-6694 Primary Hepatic Gastrinoma Causing Zollinger-Ellison Syndrome: A Rare and Challenging Diagnosis 2012-02-14 doi: 10.3390/cancers4010130 Adrian Harvey Janice L. Pasieka Hassan Al-Bisher Elijah Dixon http://www.mdpi.com/2072-6694/4/1/113 Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-a, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors. http://www.mdpi.com/2072-6694/4/1/113 Wed, 08 Feb 2012 00:00:00 CET Cancers 2012-02-08 4 1 Review 113 129 2072-6694 Medical Treatment of Gastroenteropancreatic Neuroendocrine Tumors 2012-02-08 doi: 10.3390/cancers4010113 Anja Rinke Patrick Michl Thomas Gress http://www.mdpi.com/2072-6694/4/1/100 Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower. http://www.mdpi.com/2072-6694/4/1/100 Wed, 08 Feb 2012 00:00:00 CET Cancers 2012-02-08 4 1 Article 100 112 2072-6694 PET-Guided Surgery — High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours 2012-02-08 doi: 10.3390/cancers4010100 Håkan Örlefors Anders Sundin Barbro Eriksson Britt Skogseid Kjell Öberg Göran Åkerström Per Hellman http://www.mdpi.com/2072-6694/4/1/88 Treatment modalities for desmoid tumors have been changed because of the high recurrence rate, even after wide resection, and some cases experience spontaneous self-regression during clinical course. The treatment modality in our institutions before 2003 was surgical resection with wide surgical margin, however, meloxicam, which is a NSAID and a selective COX-2 inhibitor has been applied consecutively since 2003. We reviewed the previously reported outcomes of surgical and conservative treatment in our institutions. Among 30 patients receiving surgical treatment, 16 (53%) recurred. Younger age ( p < 0.05) was a significant poor factor. According to RECIST for meloxicam treatment, CR was in one, PR in 10, SD in eight, PD in one evaluated at 2011. Older age ( p < 0.01) was significantly associated with good outcome for meloxicam treatment. Results of the previous study indicated that surgical treatment alone could not control desmoid tumors, even with negative surgical margin. Considering the functional impairment resulting from surgery with negative surgical margin, a conservative and effective treatment modality with fewer complications is desired. Conservative treatment with meloxicam is a promising novel modality for patients with extra-abdominal desmoid tumors. http://www.mdpi.com/2072-6694/4/1/88 Tue, 07 Feb 2012 00:00:00 CET Cancers 2012-02-07 4 1 Review 88 99 2072-6694 Transition of Treatment for Patients with Extra-Abdominal Desmoid Tumors: Nagoya University Modality 2012-02-07 doi: 10.3390/cancers4010088 Yoshihiro Nishida Satoshi Tsukushi Yoji Shido Hiroshi Urakawa Eisuke Arai Naoki Ishiguro http://www.mdpi.com/2072-6694/4/1/77 Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas. http://www.mdpi.com/2072-6694/4/1/77 Wed, 01 Feb 2012 00:00:00 CET Cancers 2012-02-01 4 1 Review 77 87 2072-6694 Fotemustine: A Third-Generation Nitrosourea for the Treatment of Recurrent Malignant Gliomas 2012-02-01 doi: 10.3390/cancers4010077 Patrick Beauchesne http://www.mdpi.com/2072-6694/4/1/55 Here, we investigated the relative contribution of genetic/signaling components versus microenvironmental factors to the malignancy phenotype. In this system, we took advantage of non-transformed fibroblasts that carried defined oncogenic modifications in Ras and/or p53. These cells were exposed to microenvironmental pressures, and the expression of a cancer-related chemokine cluster was used as readout for the malignancy potential (CCL2, CCL5, CXCL8, CXCL10). In cells kept in-culture, synergism between Ras hyper-activation and p53 dysfunction was required to up-regulate the expression of the chemokine cluster. The in vivo passage of RasHigh/p53Low-modified cells has led to tumor formation, accompanied by potentiation of chemokine release, implicating a powerful role for the tumor microenvironment in up-regulating the chemokine cluster. Indeed, we found that inflammatory mediators which are prevalent in tumor sites, such as TNFa and IL-1β, had a predominant impact on the release of the chemokines, which was substantially higher than that obtained by the oncogenic modifications alone, possibly acting through the transcription factors AP-1 and NF-kB. Together, our results propose that in the unbiased model system that we were using, inflammatory mediators of the tumor milieu have dominating roles over oncogenic modifications in dictating the expression of a pro-malignancy chemokine readout. http://www.mdpi.com/2072-6694/4/1/55 Fri, 20 Jan 2012 00:00:00 CET Cancers 2012-01-20 4 1 Article 55 76 2072-6694 Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations 2012-01-20 doi: 10.3390/cancers4010055 Tal Leibovich-Rivkin Yosef Buganim Hilla Solomon Tsipi Meshel Varda Rotter Adit Ben-Baruch http://www.mdpi.com/2072-6694/4/1/39 Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease. It is associated with a broad range of endocrine tumours, most frequently arising in the parathyroid glands, the pituitary and the pancreas. Most neuroendocrine tumours will be diagnosed in the pancreas as non-functioning neuroendocrine tumours or insulinomas. Forty-two percent of the patients will develop a gastrin-secreting neuroendocrine tumour, a gastrinoma. Gastrinomas in MEN-1 tend to be small, multiple and preferentially located in the duodenum. This paper will focus on the specific characteristics of gastrinomas in the setting of MEN-1 compared to sporadic gastrinomas. The developments in understanding the tumorigenesis of these tumours and the consequences for diagnosis and therapy will be discussed. http://www.mdpi.com/2072-6694/4/1/39 Fri, 20 Jan 2012 00:00:00 CET Cancers 2012-01-20 4 1 Review 39 54 2072-6694 Diagnosis and Treatment of Gastrinomas in Multiple Endocrine Neoplasia Type 1 (MEN-1) 2012-01-20 doi: 10.3390/cancers4010039 Ursula Plöckinger http://www.mdpi.com/2072-6694/4/1/31 Advanced intra-abdominal desmoids tumors present with severe symptoms, complications or rapid growth, which lead to adverse outcomes. Our aim was to evaluate the treatment and outcome of patients with advanced intra-abdominal desmoids tumors, and develop guidelines for surgical management of these patients. We reviewed the clinical courses of 21 adult patients with advanced stage intra-abdominal desmoid tumors who presented to an intestinal rehabilitation and transplantation program. Patients with massive intestinal resection presented in two groups. The first group had a short small intestinal remnant after resection ( < 60 cm). These patients were poor rehabilitation candidates and eventually met criteria for transplant. The second had longer intestinal remnants and were more successfully rehabilitated and have not had complications that would lead to transplantation. Advanced intra-abdominal desmoid tumors have outcomes after resection that merit aggressive resection and planned intestinal rehabilitation and intestinal transplantation as indicated. http://www.mdpi.com/2072-6694/4/1/31 Thu, 19 Jan 2012 00:00:00 CET Cancers 2012-01-19 4 1 Article 31 38 2072-6694 Surgical Treatment of Intra-Abdominal Desmoid Tumors Resulting In Short Bowel Syndrome 2012-01-19 doi: 10.3390/cancers4010031 Matthew Wheeler David Mercer Wendy Grant Jean Botha Alan Langnas Jon Thompson http://www.mdpi.com/2072-6694/4/1/11 The systematic application of immunohistochemical techniques to the study of tumors has led to the recognition that neuroendocrine cells occur rather frequently in exocrine neoplasms of the gut. It is now well known that there is a wide spectrum of combinations of exocrine and neuroendocrine components, ranging from adenomas or carcinomas with interspersed neuroendocrine cells at one extreme to classical neuroendocrine tumors with a focal exocrine component at the other. In addition, both exocrine and neuroendocrine components can have different morphological features ranging, for the former, from adenomas to adenocarcinomas with different degrees of differentiation and, for the latter, from well differentiated to poorly differentiated neuroendocrine tumors. However, although this range of combinations of neuroendocrine and exocrine components is frequently observed in routine practice, mixed exocrine-neuroendocrine carcinomas, now renamed as mixed adenoneuroendocrine carcinomas (MANECs), are rare; these are, by definition, neoplasms in which each component represents at least 30% of the lesion. Gastrointestinal MANECs can be stratified in different prognostic categories according to the grade of malignancy of each component. The present paper is an overview of the main clinicopathological, morphological, immunohistochemical and molecular features of this specific rare tumor type. http://www.mdpi.com/2072-6694/4/1/11 Mon, 16 Jan 2012 00:00:00 CET Cancers 2012-01-16 4 1 Review 11 30 2072-6694 Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update 2012-01-16 doi: 10.3390/cancers4010011 Stefano La Rosa Alessandro Marando Fausto Sessa Carlo Capella http://www.mdpi.com/2072-6694/4/1/1 Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response. http://www.mdpi.com/2072-6694/4/1/1 Wed, 28 Dec 2011 00:00:00 CET Cancers 2011-12-28 4 1 Article 1 10 2072-6694 Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer 2011-12-28 doi: 10.3390/cancers4010001 Francesca Bergomas Fabio Grizzi Andrea Doni Samantha Pesce Luigi Laghi Paola Allavena Alberto Mantovani Federica Marchesi http://www.mdpi.com/2072-6694/3/4/4281 Prostate cancer is the most common cancer in men, both in the USA and Europe. Although incurable, metastatic disease can often be controlled for years with anti-androgen therapy. Once the disease becomes castrate resistant, the median survival is 18 months. There is growing evidence that the immune system, and in particular cytokines, play an important role in prostate cancer immunosurveillance and progression. Here, we have undertaken a clinical investigation of the role of two closely related cytokines, IL-4 and IL-13 in prostate cancer. In the largest series studied to date, we show that serum IL-4, but not IL-13 is significantly elevated in castrate resistant, compared to androgen sensitive disease. Notably however, serum IL-4 levels are also raised in patients with benign prostatic disease. Analysis of benign and malignant prostate tissue demonstrates that the source of IL-4 is epithelial cells rather than infiltrating leukocytes. Together, our data are consistent with a dual role for IL-4 in prostate cancer development. In benign disease, our data add to the evidence that IL-4 serves a protective role. By contrast, the data support a direct role for IL-4 in the progression of prostate cancer from androgen responsive, to advanced castrate-resistant disease. http://www.mdpi.com/2072-6694/3/4/4281 Fri, 16 Dec 2011 00:00:00 CET Cancers 2011-12-16 3 4 Article 4281 4293 2072-6694 Clinical Investigation of the Role of Interleukin-4 and Interleukin-13 in the Evolution of Prostate Cancer 2011-12-16 doi: 10.3390/cancers3044281 Robert Goldstein Charles Hanley Jonathan Morris Declan Cahill Ashish Chandra Peter Harper Simon Chowdhury John Maher Sophie Burbridge http://www.mdpi.com/2072-6694/3/4/4269 It is well-established that the actin cytoskeleton plays an important role in tumor development yet the contribution made by nuclear actin is ill-defined. In a recent study, nuclear actin was identified as a key mediator through which laminin type III (LN1) acts to control epithelial cell growth. In the breast, epithelial tumors are surrounded by an environment which lacks LN1. These findings point to actin as a potential mediator of tumor development. Here our current understanding of the roles of cytoplasmic and nuclear actin in normal and tumor cell growth is reviewed, relating these functions to cell phenotype in a tissue context. http://www.mdpi.com/2072-6694/3/4/4269 Wed, 14 Dec 2011 00:00:00 CET Cancers 2011-12-14 3 4 Review 4269 4280 2072-6694 Actin—Towards a Deeper Understanding of the Relationship Between Tissue Context, Cellular Function and Tumorigenesis 2011-12-14 doi: 10.3390/cancers3044269 Virginia A. Spencer http://www.mdpi.com/2072-6694/3/4/4258 The development of lung cancer in humans can be divided into three steps: initiation, promotion and progression. This process is driven by alterations in related signal transduction pathways. These pathways signal the aberrant activation of NF-kappaB, a transcription factor that regulates the expression of genes important for lung tumorigenesis. Our current knowledge about the role of the NF-kappaB signaling pathway in the development of lung cancer has been bolstered by animal models demonstrating the connection between K-ras and tobacco induced lung transformation with NF-kappaB. Activation of downstream genes leads to cell proliferation, inhibition of apoptosis, angiogenesis, inflammation, invasion, and metastasis. http://www.mdpi.com/2072-6694/3/4/4258 Wed, 14 Dec 2011 00:00:00 CET Cancers 2011-12-14 3 4 Review 4258 4268 2072-6694 NF-kappaB in Lung Tumorigenesis 2011-12-14 doi: 10.3390/cancers3044258 Zhenjian Cai Kam-Meng Tchou-Wong William N. Rom http://www.mdpi.com/2072-6694/3/4/4245 Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone, but also by a variety of stromal cells. Tumor stroma contains abundant extracellular matrix and several types of cells, including carcinoma-associated fibroblasts (CAFs), endothelial cells, pericytes and inflammatory cells including macrophages. In gastric cancer tissues, tumor cells express platelet-derived growth factor (PDGF)-B. Stromal cells, including CAFs, pericytes and lymphatic endothelial cells, express PDGF receptor (PDGFR)-β. Administration of PDGFR tyrosine kinase inhibitor significantly decreases stromal reaction, lymphatic vessel area and pericyte coverage of tumor microvessels. Administration of PDGFR tyrosine kinase inhibitor in combination with cytotoxic chemotherapeutic drug(s) impairs the progressive growth and metastasis of gastric cancer. Activated stroma might serve as a novel therapeutic target in cases of gastric cancer. http://www.mdpi.com/2072-6694/3/4/4245 Thu, 08 Dec 2011 00:00:00 CET Cancers 2011-12-08 3 4 Review 4245 4257 2072-6694 Stroma-Directed Molecular Targeted Therapy in Gastric Cancer 2011-12-08 doi: 10.3390/cancers3044245 Yasuhiko Kitadai Michiyo Kodama Kei Shinagawa http://www.mdpi.com/2072-6694/3/4/4228 Hsp90a’s vital role in tumour survival and progression, together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validates it as a therapeutic target for glioma. Hsp90a was downregulated using the post-transcriptional RNAi strategy (sihsp90a) and a post-translational inhibitor, the benzoquinone antibiotic 17-AAG. Glioblastoma U87-MG and normal human astrocyte SVGp12 were treated with sihsp90a, 17-AAG and concurrent sihsp90a/17-AAG (combined treatment). Both Hsp90a gene silencing and the protein inhibitor approaches resulted in a dramatic reduction in cell viability. Results showed that sihsp90a, 17-AAG and a combination of sihsp90a/17-AAG, reduced cell viability by 27%, 75% and 88% (p < 0.001), respectively, after 72 h. hsp90a mRNA copy numbers were downregulated by 65%, 90% and 99% after 72 h treatment with sihsp90a, 17-AAG and sihsp90a/17-AAG, respectively. The relationship between Hsp90a protein expression and its client Akt kinase activity levels were monitored following treatment with sihsp90a, 17-AAG and sihsp90a/17-AAG. Akt kinase activity was downregulated as a direct consequence of Hsp90a inhibition. Both Hsp90a and Akt kinase levels were significantly downregulated after 72 h. Although, 17-AAG when used as a single agent reduces the Hsp90a protein and the Akt kinase levels, the efficacy demonstrated by combinatorial treatment was found to be far more effective. Combination treatment reduced the Hsp90a protein and Akt kinase levels to 4.3% and 43%, respectively, after 72 h. hsp90a mRNA expression detected in SVGp12 was negligible compared to U87-MG, also, the combination treatment did not compromise the normal cell viability. Taking into account the role of Hsp90a in tumour progression and the involvement of Akt kinase in cell signalling and the anti-apoptotic pathways in tumours, this double targets treatment infers a novel therapeutic strategy. http://www.mdpi.com/2072-6694/3/4/4228 Thu, 08 Dec 2011 00:00:00 CET Cancers 2011-12-08 3 4 Article 4228 4244 2072-6694 A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90a 2011-12-08 doi: 10.3390/cancers3044228 Adi Mehta Leroy Shervington Chinmay Munje Amal Shervington http://www.mdpi.com/2072-6694/3/4/4212 Abnormal cell division leading to the gain or loss of entire chromosomes and consequent genetic instability is a hallmark of cancer. Centromere protein –A (CENPA) is a centromere-specific histone-H3-like variant gene involved in regulating chromosome segregation during cell division. CENPA is one of the genes included in some of the commercially available RNA based prognostic assays for breast cancer (BCa)—the 70 gene signature MammaPrint® and the five gene Molecular Grade Index (MGISM). Our aim was to assess the immunohistochemical (IHC) expression of CENPA in normal and malignant breast tissue. Clinically annotated triplicate core tissue microarrays of 63 invasive BCa and 20 normal breast samples were stained with a monoclonal antibody against CENPA and scored for percentage of visibly stained nuclei. Survival analyses with Kaplan–Meier (KM) estimate and Cox proportional hazards regression models were applied to assess the associations between CENPA expression and disease free survival (DFS). Average percentage of nuclei visibly stained with CENPA antibody was significantly higher (p = 0.02) in BCa than normal tissue. The 3-year DFS in tumors over-expressing CENPA (>50% stained nuclei) was 79% compared to 85% in low expression tumors ( 60.07; p = 0.06) within our small cohort. To the best of our knowledge, this is the first published report evaluating the implications of increased IHC expression of CENPA in paraffin embedded breast tissue samples. Our finding that increased CENPA expression may be associated with shorter DFS in BCa supports its exploration as a potential prognostic biomarker. http://www.mdpi.com/2072-6694/3/4/4212 Tue, 06 Dec 2011 00:00:00 CET Cancers 2011-12-06 3 4 Article 4212 4227 2072-6694 Immunohistochemical Assessment of Expression of Centromere Protein—A (CENPA) in Human Invasive Breast Cancer 2011-12-06 doi: 10.3390/cancers3044212 Ashish B. Rajput Nianping Hu Sonal Varma Chien-Hung Chen Keyue Ding Paul C. Park Judy-Anne W. Chapman Sandip K. SenGupta Yolanda Madarnas Bruce E. Elliott Harriet E. Feilotter http://www.mdpi.com/2072-6694/3/4/4191 New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines. http://www.mdpi.com/2072-6694/3/4/4191 Fri, 25 Nov 2011 00:00:00 CET Cancers 2011-11-25 3 4 Review 4191 4211 2072-6694 Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines 2011-11-25 doi: 10.3390/cancers3044191 Lijin Li Peter Goedegebuure Elaine R. Mardis Matthew J.C. Ellis Xiuli Zhang John M. Herndon Timothy P. Fleming Beatriz M. Carreno Ted H. Hansen William E. Gillanders http://www.mdpi.com/2072-6694/3/4/4170 During tumorigenesis the transformed cells lose their normal growth control mechanisms and become dependent on oncogenes’ products and pathways for survival. Treatments tailored to block the expression or function of transforming genes have shown efficacy in eliminating neoplastic cells. The mRNAs of many oncogenes, as well as regulators of other key processes such as cell proliferation, angiogenesis, and apoptosis, typically have shorter half-lives. Agents that impede mRNA synthesis are expected to selectively hinder the expression of these genes and, therefore, be detrimental to neoplastic cells that are physiologically dependent on them. In addition to exploiting the tumor cells’ dependency on short-lived transcripts, RNA-directed agents also take advantage of the differential sensitivity between transformed and non-transformed cells, as the cytotoxic effects of inhibiting RNA synthesis have not been seen in non-transformed cells. The abrogation of the formation of oncotranscripts provides a new concept in cancer therapeutics and numerous agents have been developed which are able to target transcription. The focus of this review is to give an overview of transcription and the different inhibitory strategies that target various aspects of the transcriptional process. http://www.mdpi.com/2072-6694/3/4/4170 Wed, 23 Nov 2011 00:00:00 CET Cancers 2011-11-23 3 4 Review 4170 4190 2072-6694 Transcription Inhibition as a Therapeutic Target for Cancer 2011-11-23 doi: 10.3390/cancers3044170 Christine M. Stellrecht Lisa S. Chen http://www.mdpi.com/2072-6694/3/4/4151 Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against terminal mono- and disaccharide constituents of TACA raises concerns regarding the balance between “tumor destruction” and “tissue damage”, as mono- and disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia lectin 1 (GS-I), and tissue reactivity of serum antibodies were compared with the tissue staining profile of GS-I. Tissues from CMP immunized mice were analyzed using hematoxylin and eosin stain, and Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum antibodies, and naive serum antibodies. CMP immunization enhanced glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses. http://www.mdpi.com/2072-6694/3/4/4151 Fri, 11 Nov 2011 00:00:00 CET Cancers 2011-11-11 3 4 Article 4151 4169 2072-6694 Carbohydrate Mimetic Peptides Augment Carbohydrate-Reactive Immune Responses in the Absence of Immune Pathology 2011-11-11 doi: 10.3390/cancers3044151 Leah Hennings Cecile Artaud Fariba Jousheghany Behjatolah Monzavi-Karbassi Anastas Pashov Thomas Kieber-Emmons http://www.mdpi.com/2072-6694/3/4/4139 Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis. http://www.mdpi.com/2072-6694/3/4/4139 Thu, 10 Nov 2011 00:00:00 CET Cancers 2011-11-10 3 4 Review 4139 4150 2072-6694 Sarcoma Immunotherapy 2011-11-10 doi: 10.3390/cancers3044139 Launce G. Gouw Kevin B. Jones Sunil Sharma R. Lor Randall http://www.mdpi.com/2072-6694/3/4/4127 Epidemiological and experimental evidence suggests that inflammation plays a role in both prostate cancer (PCa) and benign prostate hyperplasia (BPH). This study evaluates the risk of PC after transurethral resection (TURP) for BPH and estimates the PCa risk related to presence of inflammation in the resected material. The Pathology Department at the University Hospital of Umeå (Umeå, Sweden) identified BPH cases (n = 7,901) that underwent TURP between 1982 and 1997. Using these pathological specimens, we compared the incidence of PCa in the cohort to the population and calculated the standardized incidence and mortality ratios (SIR and SMR). Inflammation, the androgen receptor (AR), and p53 were evaluated in a nested case-control study of 201 cases and controls. Inflammation was graded severe or mild-moderate. In the follow-up period after TURP, cases developed prostate cancer and the controls did not. After TURP, SIR for prostate cancer increased [1.26, CI 95% (1.17–1.35)], whereas SMR decreased [0.59, CI 95% (0.47–0.73)]. Presence of inflammation at the time of TURP did not differ between cases and controls nor were there differences in p53 or AR staining. The data suggest a small increased risk of PCa after TURP and decreased PCa mortality. Inflammation at the time of TURP is not associated with PCa risk in this material. The increased PCa risk may be attributed to increased surveillance and PSA screening. http://www.mdpi.com/2072-6694/3/4/4127 Tue, 08 Nov 2011 00:00:00 CET Cancers 2011-11-08 3 4 Article 4127 4138 2072-6694 Risk of Prostate Cancer after Trans Urethral Resection of BPH: A Cohort and Nested Case-Control Study 2011-11-08 doi: 10.3390/cancers3044127 Camilla T. Karlsson Fredrik Wiklund Henrik Grönberg Anders Bergh Beatrice Melin http://www.mdpi.com/2072-6694/3/4/4114 Purpose: To analyze the distribution of functional liver volume (FLV) in the margin volume (MV) surrounding hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) before radiation therapy (RT) and to verify the safety of single photon emission computed tomography-based three-dimensional conformal radiotherapy (SPECT-B3DCRT) by exploring the relation of FLV in MV to radiation-induced liver disease (RILD). Methods and Materials: Clinical target volume (CTV) included main tumor and PVTT, and planning target volume (PTV) included CTV with a 10 mm margin. MV was defined as PTV–CTV. FLV ratio in MV was calculated as FLV in MV/MV × 100 (%). The two high-dose beams were planned to irradiate FLV as little as possible. Fifty-seven cases of HCC (26/57, 46%; Child–Pugh grade B) with PVTT underwent SPECT-B3DCRT which targeted the CTV to a total dose of 45 Gy/18 fractions. The destructive ratio was defined as radiation induced dysfunctional volume/FLV × 100 (%). Results: We observed a significant negative correlation between FLV ratio in MV and CTV (p < 0.001). Three cases with CTVs of 287, 587 and 1184 cm3 experienced transient RILD. The FLV ratio in MV was highest in patients with RILD: nine patients with CTV of 200–300 cm3, three with CTV of 500–600 cm3, and two with CTV of 1100–1200 cm3. The destructive ratio yielded a mean value of 24.2 ± 1.5%. Conclusions: Radiation planning that takes into account the distribution of FLV appears to result in the least possible RILD. http://www.mdpi.com/2072-6694/3/4/4114 Mon, 31 Oct 2011 00:00:00 CET Cancers 2011-10-31 3 4 Article 4114 4126 2072-6694 Distribution of Functional Liver Volume in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombus in the 1st Branch and Main Trunk Using Single Photon Emission Computed Tomography—Application to Radiation Therapy 2011-10-31 doi: 10.3390/cancers3044114 Shintaro Shirai Morio Sato Yasutaka Noda Kazushi Kishi Nobuyuki Kawai Hiroki Minamiguchi Motoki Nakai Hiroki Sanda Shinya Sahara Akira Ikoma Tetsuo Sonomura http://www.mdpi.com/2072-6694/3/4/4102 Despite the expanded understanding of tumor angiogenesis phenomenon and how it impacts cancer treatment outcomes, we have yet to develop a robust assay that can quickly, easily, and quantitatively measure tumor-induced angiogenesis. Since the zebrafish/tumor xenograft represents an emerging tool in this regard, the present study strives to capitalize on the ease, effectiveness, and the adaptability of this model to quantify tumor angiogenesis. In order to test a range of responses, we chose two different tumorigenic cell lines, the human non-small cell lung carcinoma (H1299) and the mouse lung adenocarcinoma (CL13). Non-tumorigenic 3T3-L1 cells served as negative control. The cells were grafted near to the perivitelline space of the zebrafish embryos and the angiogenic response was analyzed using whole-mount alkaline phosphatase (AP) vessel staining and fluorescence microscopy. Angiogenic activity was scored based on the length and number of the newly formed ectopic vessels and the percentage of embryos with ectopic vessels. At 2 day-post-implantation, we detected a significant increase in the length and number of ectopic vessels with H1299 cell implantation compared to CL13 cell transplantation, both are higher than 3T3-L1 control. We also observed a significantly higher percentage of embryos with ectopic vessels with H1299 and CL13 transplantation compared to the 3T3-L1 control, but this parameter is not as robust and reliable as measuring the length and number of ectopic vessels. Furthermore, the systemic exposure of zebrafish embryos to an anti-angiogenesis drug (PTK 787, inhibitor of vascular endothelial growth factor receptor tyrosine kinase) inhibited tumor-induced angiogenesis, suggesting that the assay can be used to evaluate anti-angiogenic drugs. This study implicates the feasibility of using zebrafish xenotransplantation to perform quantitative measurement of the angiogenic activity of cancer cells which can be further extended to measure cancer cell metastasis. This assay represents not only the useful test for patient diagnosis, but also has the potential for evaluating anti-cancer drugs treatment. http://www.mdpi.com/2072-6694/3/4/4102 Mon, 31 Oct 2011 00:00:00 CET Cancers 2011-10-31 3 4 Article 4102 4113 2072-6694 Discriminating Different Cancer Cells Using a Zebrafish in Vivo Assay 2011-10-31 doi: 10.3390/cancers3044102 Karni S. Moshal Karine F. Ferri-Lagneau Jamil Haider Pooja Pardhanani TinChung Leung http://www.mdpi.com/2072-6694/3/4/4090 The standard of care for the management of locally advanced esophageal cancers in the United States is chemotherapy combined with radiation, either definitively, or for those who could tolerate surgery, preoperatively before esophagectomy. Although the appropriate radiation dose remains somewhat controversial, the quality of the radiation delivery is critical for the treatment of esophageal cancer since the esophagus is positioned close to vital structures, such as the heart and lung. The volume and relative doses to these normal tissues affect acute and late term complications. Advances in radiation delivery from 2D to 3D conformal radiation therapy, to Intensity Modulated Radiation Therapy (IMRT) or charged particle therapy (carbon ion or proton beam therapy (PBT)), allow incremental improvements in the therapeutic ratio. This could have implications in non-cancer related morbidity for long term survivors. This article reviews the evolution in radiation technologies and the use of PBT with chemotherapy in the management of esophageal cancer. http://www.mdpi.com/2072-6694/3/4/4090 Fri, 28 Oct 2011 00:00:00 CEST Cancers 2011-10-28 3 4 Review 4090 4101 2072-6694 The Utility of Proton Beam Therapy with Concurrent Chemotherapy for the Treatment of Esophageal Cancers 2011-10-28 doi: 10.3390/cancers3044090 Steven H. Lin http://www.mdpi.com/2072-6694/3/4/4061 Despite the use of more effective multimodal treatments in high-grade glioma (HGG), the outcome of patients affected by this disease is still dismal and recurrence is a very common event. Many therapeutic approaches, alone or combined (surgery, drugs, targeted agents, immunotherapy, radiotherapy, supportive therapy), are available in the clinical armamentarium so far. The attitude of physicians is increasingly interventionist, but recurrent HGG still remains a very difficult scenario to be treated. Radiotherapy with different re-irradiation techniques is increasingly proposed as a therapeutic option with interesting results, even though the resulting duration of response is usually quite short. Most lesions re-recur locally, with inadequate identification and targeting of viable tumor being the most important cause of failure. Prognosis is affected by many patient-, tumor-, and treatment-associated prognostic factors. Radiotherapy is delivered with many advanced modalities: 3D-CRT, intensity-modulated radiation therapy, stereotactic fractionated radiotherapy, radiosurgery, and brachitherapy with or without chemotherapy administration. In order to evaluate the feasibility and efficacy of re-irradiation in this setting, we reviewed the PubMed and MEDLINE databases restricting the search to original reports published from January 1990 to June 2011. The search resulted in a total of 155 reports: 78 of them covering 2,688 patients treated with different irradiation modalities overall fulfilled the entry criteria. Radiation therapy demonstrated to be an acceptable option in recurrent HGG with good response rates and acceptable toxicity. http://www.mdpi.com/2072-6694/3/4/4061 Fri, 28 Oct 2011 00:00:00 CEST Cancers 2011-10-28 3 4 Review 4061 4089 2072-6694 A Review of the Role of Re-Irradiation in Recurrent High-Grade Glioma (HGG) 2011-10-28 doi: 10.3390/cancers3044061 Maurizio Amichetti Dante Amelio http://www.mdpi.com/2072-6694/3/4/4046 Carbon ion radiotherapy (C-ion RT) offers superior dose conformity in the treatment of deep-seated tumors compared with conventional X-ray therapy. In addition, carbon ion beams have a higher relative biological effectiveness compared with protons or X-ray beams. C-ion RT for the first patient at Gunma University Heavy Ion Medical Center (GHMC) was initiated in March of 2010. The major specifications of the facility were determined based on the experience of clinical treatments at the National Institute of Radiological Sciences (NIRS), with the size and cost being reduced to one-third of those at NIRS. The currently indicated sites of cancer treatment at GHMC are lung, prostate, head and neck, liver, rectum, bone and soft tissue. Between March 2010 and July 2011, a total of 177 patients were treated at GHMC although a total of 100 patients was the design specification during the period in considering the optimal machine performance. In the present article, we introduce the facility set-up of GHMC, including the facility design, treatment planning systems, and clinical preparations. http://www.mdpi.com/2072-6694/3/4/4046 Wed, 26 Oct 2011 00:00:00 CEST Cancers 2011-10-26 3 4 Article 4046 4060 2072-6694 Carbon Ion Radiotherapy at the Gunma University Heavy Ion Medical Center: New Facility Set-up 2011-10-26 doi: 10.3390/cancers3044046 Tatsuya Ohno Tatsuaki Kanai Satoru Yamada Ken Yusa Mutsumi Tashiro Hirofumi Shimada Kota Torikai Yukari Yoshida Yoko Kitada Hiroyuki Katoh Takayoshi Ishii Takashi Nakano http://www.mdpi.com/2072-6694/3/4/4024 The advent of nanotechnology has had a revolutionary impact on many aspects of 21st century life. Nanotechnology has provided an opportunity to explore new avenues that conventional technologies have been unable to make an impact on for diagnosis, prevention, and therapy of different diseases, and of cancer in particular. Entities in nanometer sizes are excellent platforms to incorporate various drugs or active materials that can be delivered effectively to the desired action site without compromising the activity of the incorporated drug or material. In particular, nanotechnology entities can be used to deliver conventional natural products that have poor solubility or a short half life. Conventional natural products used with entities in nanometer sizes enable us to solve many of the inherent problems (stability, solubility, toxicity) associated with natural products, and also provide a platform for targeted delivery to tumor sites. We recently introduced the novel concept of using nanotechnology for enhancing the outcome of chemoprevention, which we called ‘nanochemoprevention’. This idea was subsequently exploited by several laboratories worldwide and has now become an advancing field in chemoprevention research. This review examines some of the applications of nanotechnology for cancer prevention and therapy using natural products. http://www.mdpi.com/2072-6694/3/4/4024 Wed, 26 Oct 2011 00:00:00 CEST Cancers 2011-10-26 3 4 Review 4024 4045 2072-6694 Nanoparticle Delivery of Natural Products in the Prevention and Treatment of Cancers: Current Status and Future Prospects 2011-10-26 doi: 10.3390/cancers3044024 Dhruba J. Bharali Imtiaz A. Siddiqui Vaqar M. Adhami Jean Christopher Chamcheu Abdullah M. Aldahmash Hasan Mukhtar Shaker A. Mousa http://www.mdpi.com/2072-6694/3/4/4010 Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control. http://www.mdpi.com/2072-6694/3/4/4010 Wed, 26 Oct 2011 00:00:00 CEST Cancers 2011-10-26 3 4 Review 4010 4023 2072-6694 Role of Radiation Therapy in the Management of Renal Cell Cancer 2011-10-26 doi: 10.3390/cancers3044010 Angel I. Blanco Bin S. Teh Robert J. Amato http://www.mdpi.com/2072-6694/3/4/3991 Therapeutic cancer vaccines have the potential to generate a long lasting immune response that will destroy tumor cells with specificity and safety, in contrast to many other current cancer therapies. Clinical success to date has been limited by a number of factors including choice of immunogenic cancer rejection antigens, optimization of vaccine platforms and immune adjuvants to effectively polarize the immune response, and incorporation of strategies to reverse cancer mediated immune suppression by utilization of effective adjuvant/immune modulators. WT-1 (Wilms’ tumor gene 1) is a cancer antigen that is required for tumorigenesis, expressed in a high percentage of tumor cells and rarely expressed in adult normal cells. Moreover spontaneous immunity to WT-1 is seen in cancer patients and can be augmented with various therapeutic vaccine approaches. IRX-2 is an immune modulator with demonstrated preclinical and clinical pleiotropic immune activities including enhancement of the immune response to potential tumor antigens. This paper presents the rationale and preclinical data for utilizing the WT-1 tumor antigen in a novel vaccine platform consisting of a synthetic long peptide containing multiple class I and class II epitopes in combination with the IRX-2 immunomodulatory regimen to overcome immuno-suppressive pathways and enhance the anti-tumor response. http://www.mdpi.com/2072-6694/3/4/3991 Tue, 25 Oct 2011 00:00:00 CEST Cancers 2011-10-25 3 4 Article 3991 4009 2072-6694 Peptide Based Vaccine Approaches for Cancer—A Novel Approach Using a WT-1 Synthetic Long Peptide and the IRX-2 Immunomodulatory Regimen 2011-10-25 doi: 10.3390/cancers3043991 Paul H. Naylor James E. Egan Neil L. Berinstein http://www.mdpi.com/2072-6694/3/4/3972 Helical Tomotherapy (HT) is a highly conformal image-guided radiation technique, introduced into clinical routine in 2006 at the Centro di Riferimento Oncologico Aviano (Italy). With this new technology, intensity-modulated radiotherapy (IMRT) is delivered using a helicoidal method. Here we present our dosimetric experiences using HT in 100 children, adolescents and young adults treated from May 2006 to February 2011. The median age of the patients was 13 years (range 1–24). The most common treated site was the central nervous system (50; of these, 24 were craniospinal irradiations), followed by thorax (22), head and neck (10), abdomen and pelvis (11), and limbs (7). The use of HT was calculated in accordance to the target dose conformation, the target size and shape, the dose to critical organs adjacent to the target, simultaneous treatment of multiple targets, and re-irradiation. HT has demonstrated to improve target volume dose homogeneity and the sparing of critical structures, when compared to 3D Linac-based radiotherapy (RT). In standard cases this technique represented a comparable alternative to IMRT delivered with conventional linear accelerator. In certain cases (e.g., craniospinal and pleural treatments) only HT generated adequate treatment plans with good target volume coverage. However, the gain in target conformality should be balanced with the spread of low-doses to distant areas. This remains an open issue for the potential risk of secondary malignancies (SMNs) and longer follow-up is mandatory. http://www.mdpi.com/2072-6694/3/4/3972 Tue, 25 Oct 2011 00:00:00 CEST Cancers 2011-10-25 3 4 Article 3972 3990 2072-6694 Helical Tomotherapy in Children and Adolescents: Dosimetric Comparisons, Opportunities and Issues 2011-10-25 doi: 10.3390/cancers3043972 Maurizio Mascarin Francesca Maria Giugliano Elisa Coassin Annalisa Drigo Paola Chiovati Andrea Dassie Giovanni Franchin Emilio Minatel Mauro Gaetano Trovò http://www.mdpi.com/2072-6694/3/4/3957 Cancer stem cells are defined as a subpopulation of cells within a tumor that are capable of self-renewal and differentiation into the heterogeneous cell lineages that comprise the tumor. Many studies indicate that cancer stem cells may be responsible for treatment failure and relapse in cancer patients. The factors that regulate cancer stem cells are not well defined. MicroRNAs (miRNAs) are small non-coding RNAs that regulate translational repression and transcript degradation. miRNAs play a critical role in embryonic and inducible pluripotent stem cell regulation and emerging evidence supports their role in cancer stem cell evolution. To date, miRNAs have been shown to act either as tumor suppressor genes or oncogenes in driving critical gene expression pathways in cancer stem cells in a wide range of human malignancies, including hematopoietic and epithelial tumors and sarcomas. miRNAs involved in cancer stem cell regulation provide attractive, novel therapeutic targets for cancer treatment. This review attempts to summarize progress to date in defining the role of miRNAs in cancer stem cells. http://www.mdpi.com/2072-6694/3/4/3957 Mon, 24 Oct 2011 00:00:00 CEST Cancers 2011-10-24 3 4 Review 3957 3971 2072-6694 Emerging Evidence for MicroRNAs as Regulators of Cancer Stem Cells 2011-10-24 doi: 10.3390/cancers3043957 Aisha Sethi Lynette M. Sholl http://www.mdpi.com/2072-6694/3/4/3921 Understanding the mechanisms that control stress is central to realize how cells respond to environmental and physiological insults. All the more important is to reveal how tumour cells withstand their harsher growth conditions and cope with drug-induced apoptosis, since resistance to chemotherapy is the foremost complication when curing cancer. Intensive research on tumour biology over the past number of years has provided significant insights into the molecular events that occur during oncogenesis, and resistance to anti-cancer drugs has been shown to often rely on stress response and expression of inducible heat shock proteins (HSPs). However, with respect to the mechanisms guarding cancer cells against proteotoxic stresses and the modulatory effects that allow their survival, much remains to be defined. Heat shock proteins are molecules responsible for folding newly synthesized polypeptides under physiological conditions and misfolded proteins under stress, but their role in maintaining the transformed phenotype often goes beyond their conventional chaperone activity. Expression of inducible HSPs is known to correlate with limited sensitivity to apoptosis induced by diverse cytotoxic agents and dismal prognosis of several tumour types, however whether cancer cells survive because of the constitutive expression of heat shock proteins or the ability to induce them when adapting to the hostile microenvironment remains to be elucidated. Clear is that tumours appear nowadays more “addicted” to heat shock proteins than previously envisaged, and targeting HSPs represents a powerful approach and a future challenge for sensitizing tumours to therapy. This review will focus on the anti-apoptotic role of heat shock 70kDa protein (Hsp70), and how regulatory factors that control inducible Hsp70 synthesis, expression and activity may be relevant for response to stress and survival of cancer cells. http://www.mdpi.com/2072-6694/3/4/3921 Fri, 21 Oct 2011 00:00:00 CEST Cancers 2011-10-21 3 4 Review 3921 3956 2072-6694 Inducible Hsp70 in the Regulation of Cancer Cell Survival: Analysis of Chaperone Induction, Expression and Activity 2011-10-21 doi: 10.3390/cancers3043921 Elisa Zorzi Paolo Bonvini http://www.mdpi.com/2072-6694/3/4/3909 We previously reported that the transcription factor Zinc Finger Protein 143 (ZNF143) regulates the expression of genes associated with cell cycle and cell division, and that downregulation of ZNF143 induces cell cycle arrest at G2/M. To assess the function of ZNF143 expression in the cell cycle, we established two cells with forced expression of ZNF143 derived from PC3 prostate cancer cell lines. These cell lines overexpress genes associated with cell cycle and cell division, such as polo-like kinase 1 (PLK1), aurora kinase B (AURKB) and some minichromosome maintenance complex components (MCM). However, the doubling time of cells with forced expression of ZNF143 was approximately twice as long as its control counterpart cell line. Analysis following serum starvation and re-seeding showed that PC3 cells were synchronized at G1 in the cell cycle. Also, ZNF143 expression fluctuated, and was at its lowest level in G2/M. However, PC3 cells with forced expression of ZNF143 synchronized at G2/M, and showed lack of cell cycle-dependent fluctuation of nuclear expression of MCM proteins. Furthermore, G2/M population of both cisplatin-resistant PCDP6 cells over-expressing ZNF143 (derived from PC3 cells) and cells with forced expression of ZNF143 was significantly higher than that of each counterpart, and the doubling time of PCDP6 cells is about 2.5 times longer than that of PC3 cells. These data suggested that fluctuations in ZNF143 expression are required both for gene expression associated with cell cycle and for cell division. http://www.mdpi.com/2072-6694/3/4/3909 Wed, 19 Oct 2011 00:00:00 CEST Cancers 2011-10-19 3 4 Article 3909 3920 2072-6694 Forced Expression of ZNF143 Restrains Cancer Cell Growth 2011-10-19 doi: 10.3390/cancers3043909 Hiroto Izumi Yoshihiro Yasuniwa Masaki Akiyama Takahiro Yamaguchi Akihiro Kuma Noriaki Kitamura Kimitoshi Kohno http://www.mdpi.com/2072-6694/3/4/3894 Colorectal cancer (CRC) is now the second-leading cause of cancer deaths in the USA. Colorectal cancer progression and metastasis depends on the orchestration of the aberrant signaling pathways that control tumor cell proliferation, survival and migration/invasion. Epidemiological, clinical, and animal studies have demonstrated that prostaglandin-endoperoxide synthase 2 (PTGS2) and epithelial growth factor (EGF) signaling pathways play key roles in promoting colorectal cancer growth and metastasis. In this review, we highlight major advances in our understanding of the roles of PTGS2 and EGF signaling in colorectal cancer. http://www.mdpi.com/2072-6694/3/4/3894 Fri, 14 Oct 2011 00:00:00 CEST Cancers 2011-10-14 3 4 Review 3894 3908 2072-6694 The Crosstalk of PTGS2 and EGF Signaling Pathways in Colorectal Cancer 2011-10-14 doi: 10.3390/cancers3043894 Dingzhi Wang Dianren Xia Raymond N. DuBois http://www.mdpi.com/2072-6694/3/4/3856 Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. The growing interest over the past two decades in harnessing the immune system to eradicate cancer has been accompanied by heightened efforts to characterize cytokines and exploit their vast signaling networks to develop cancer treatments. The goal of this paper is to review the major cytokines involved in cancer immunotherapy and discuss their basic biology and clinical applications. The paper will also describe new cytokines in pre-clinical development, combinations of biological agents, novel delivery mechanisms, and potential directions for future investigation using cytokines. http://www.mdpi.com/2072-6694/3/4/3856 Thu, 13 Oct 2011 00:00:00 CEST Cancers 2011-10-13 3 4 Review 3856 3893 2072-6694 Cytokines in Cancer Immunotherapy 2011-10-13 doi: 10.3390/cancers3043856 Sylvia Lee Kim Margolin http://www.mdpi.com/2072-6694/3/4/3838 Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose. http://www.mdpi.com/2072-6694/3/4/3838 Tue, 11 Oct 2011 00:00:00 CEST Cancers 2011-10-11 3 4 Review 3838 3855 2072-6694 Targeted Radionuclide Therapy 2011-10-11 doi: 10.3390/cancers3043838 Devrim Ersahin Indukala Doddamane David Cheng http://www.mdpi.com/2072-6694/3/4/3824 Angiotensin II (Ang II), the main effector of the renin angiotensin system, acts upon two distinct transmembrane receptors, the Ang II type 1 and the type 2 (AT2-) receptor, to induce promotion and inhibition of ERK2 phosphorylation. The AT2-receptor, through an interaction with its putative signaling partner MTUS1/ATIP (AT2-receptor interacting protein), inhibits the mitogenic effects of EGF in prostate cancer cell lines representing both early and late stage disease. This is the first report on the expression of ATIP in normal and malignant human prostatic biopsies. The expression of ATIP and its major isoforms, ATIP1 and ATIP3, in normal prostatic cells and three prostate cancer cell lines was examined using QPCR and immunohistochemistry. Human biopsies containing benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and well, moderately and poorly differentiated prostate cancer were also examined. Overall, ATIP1 and ATIP3 mRNA expression was increased in malignant compared to normal tissues and cell lines. ATIP immunostaining was low or absent in both the basal and columnar epithelial cell layers surrounding BPH acini; however, it was observed in high concentration in neoplastic epithelial cells of HGPIN and was clearly evident in cytoplasms of malignant cells in all prostate cancer grades. ATIP immunostaining was also identified in the cytoplasms of LNCaP and PC3 prostate cancer cells. As the AT2-receptor/ATIP inhibitory signaling pathway exists in malignant cells in all grades of prostate cancer, enhancement of this pathway may be a therapeutic target even after the development of androgen-independence. http://www.mdpi.com/2072-6694/3/4/3824 Tue, 11 Oct 2011 00:00:00 CEST Cancers 2011-10-11 3 4 Article 3824 3837 2072-6694 The Expression of MTUS1/ATIP and Its Major Isoforms, ATIP1 and ATIP3, in Human Prostate Cancer 2011-10-11 doi: 10.3390/cancers3043824 Simon N.S. Louis Laurie T.C. Chow Naghmeh Varghayee Linda A. Rezmann Albert G. Frauman William J. Louis http://www.mdpi.com/2072-6694/3/4/3799 Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an in­tegral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, car­diac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threat­ening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy. http://www.mdpi.com/2072-6694/3/4/3799 Fri, 30 Sep 2011 00:00:00 CEST Cancers 2011-09-30 3 4 Review 3799 3823 2072-6694 Combined Hyperthermia and Radiotherapy for the Treatment of Cancer 2011-09-30 doi: 10.3390/cancers3043799 Punit Kaur Mark D. Hurwitz Sunil Krishnan Alexzander Asea http://www.mdpi.com/2072-6694/3/4/3773 Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high risk for developing prostate cancer. In cancer epidemiology, epigenetic biomarkers offer advantages over other types of biomarkers because they are expressed against a person’s genetic background and environmental exposure, and because abnormal events occur early in cancer development, which includes several epigenetic alterations in cancer cells. This article describes different biomarkers that have potential use in studying the epidemiology of prostate cancer. We also discuss the characteristics of an ideal biomarker for prostate cancer, and technologies utilized for biomarker assays. Among epigenetic biomarkers, most reports indicate GSTP1 hypermethylation as the diagnostic marker for prostate cancer; however, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS, and NSE1 also have been reported to be regulated by methylation mechanisms in prostate cancer. Current challenges in utilization of biomarkers in prostate cancer diagnosis and epidemiologic studies and potential solutions also are discussed. http://www.mdpi.com/2072-6694/3/4/3773 Fri, 30 Sep 2011 00:00:00 CEST Cancers 2011-09-30 3 4 Review 3773 3798 2072-6694 Biomarkers in Prostate Cancer Epidemiology 2011-09-30 doi: 10.3390/cancers3043773 Mukesh Verma Payal Patel Mudit Verma http://www.mdpi.com/2072-6694/3/4/3762 In the present study, we determined the effects of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on the growth and apoptosis of cultured human prostate cancer LNCaP cells. We also determined the effects of dietary γ-TmT on the formation and growth of LNCaP tumors in immunodeficient mice. In the in vitro study, we found that the activity of γ-TmT was stronger than α-tocopherol for inhibiting the growth and stimulating apoptosis in LNCaP cells. In the animal study, treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT inhibited the formation and growth of LNCaP xenograft tumors in a dose-dependent manner. Mechanistic studies showed that g-TmT administration inhibited proliferation as reflected by decreased mitosis and stimulated apoptosis as reflected by increased caspase-3 (active form) expression in LNCaP tumors. In addition, dietary administration of g-TmT increased the levels of a-, γ- and δ- tocopherol in plasma, and increased levels of γ- and δ- tocopherol were also observed in the prostate and in tumors. The present study demonstrated that g-TmT had strong anticancer activity both in vitro and in vivo. Additional studies are needed to determine the potential preventive effect of g-TmT for prostate cancer in humans. http://www.mdpi.com/2072-6694/3/4/3762 Wed, 28 Sep 2011 00:00:00 CEST Cancers 2011-09-28 3 4 Article 3762 3772 2072-6694 Inhibitory Effect of a γ-Tocopherol-Rich Mixture of Tocopherols on the Formation and Growth of LNCaP Prostate Tumors in Immunodeficient Mice 2011-09-28 doi: 10.3390/cancers3043762 Xi Zheng Xiao-Xing Cui Tin Oo Khor Ying Huang Robert S DiPaola Susan Goodin Mao-Jung Lee Chung S Yang Ah-Ng Kong Allan H. Conney http://www.mdpi.com/2072-6694/3/4/3740 Tumor-Associated Macrophages (TAM) are key components of the reactive stroma of tumors. In most, although not all cancers, their presence is associated with poor patient prognosis. In addition to releasing cytokines and growth factors for tumor and endothelial cells, a distinguished feature of TAM is their high-rate degradation of the extra-cellular matrix. This incessant stroma remodelling favours the release of matrix-bound growth factors and promotes tumor cell motility and invasion. In addition, TAM produce matrix proteins, some of which are typical of the neoplastic tissues. The gene expression profile of TAM isolated from human tumors reveals a matrix-related signature with the up-regulation of genes coding for different matrix proteins, as well as several proteolytic enzymes. Among ECM components are: osteopontin, osteoactivin, collagens and fibronectin, including also a truncated isoform of fibronectin termed migration stimulation factor. In addition to serve as structural proteins, these matrix components have key functions in the regulation of the vessel network, in the inductionof tumor cell motility and degradation of cellular debris. Among proteolytic enzymes are: matrix metalloproteases, cathepsins, lysosomal and ADAM proteases, and the urokinase-type plasminogen activator. The degrading activity of TAM, coupled to the production of bio-active ECM proteins, co-operate to the build-up and maintenance of an inflammatory micro-environment which eventually promotes tumor progression. http://www.mdpi.com/2072-6694/3/4/3740 Wed, 28 Sep 2011 00:00:00 CEST Cancers 2011-09-28 3 4 Review 3740 3761 2072-6694 Tumor-Associated Macrophages as Incessant Builders and Destroyers of the Cancer Stroma 2011-09-28 doi: 10.3390/cancers3043740 Manuela Liguori Graziella Solinas Giovanni Germano Alberto Mantovani Paola Allavena http://www.mdpi.com/2072-6694/3/4/3726 Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment of many solid tumors. The functional competence of TAMs varies depending on the type of tumors and their respective microenvironments. The classically activated M1 macrophages exhibit antitumor functions, whereas the alternatively activated M2 macrophages exhibit protumor functions that contribute to tumor development and progression. Although TAMs have been detected in oral squamous cell carcinoma (OSCC), little is known about their phenotype. In the present study, we performed an immunohistochemical analysis to identify TAMs in surgically resected specimens from 50 patients with OSCC and evaluated the relationship between infiltrated TAMs and the pathological grade of OSCC. Positive staining for CD163, which has been used as a marker for M2 macrophages, was observed in OSCC specimens, and the percentages of CD163+ cells were significantly increased based on the pathological grade. CD163+ cells were detected in the tumor stroma in grade I tumors, whereas an increase in the CD163+ cells in the tumor nest was observed in higher grades of tumors. Although infiltrated CD4+ and CD8+ T cells were detected in all pathological grades of OSCC, no correlation between the infiltrated T cells and the CD163+ TAMs was observed. These results indicate that the infiltrated TAMs in OSCC have an M2 phenotype and that the M2 macrophages may participate in the development of OSCC. http://www.mdpi.com/2072-6694/3/4/3726 Wed, 28 Sep 2011 00:00:00 CEST Cancers 2011-09-28 3 4 Article 3726 3739 2072-6694 Infiltration of M2 Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma Correlates with Tumor Malignancy 2011-09-28 doi: 10.3390/cancers3043726 Kazumasa Mori Miki Hiroi Jun Shimada Yoshihiro Ohmori http://www.mdpi.com/2072-6694/3/4/3714 Overexpression of the classical homeobox transcription factor HOXC6 is frequent in prostate cancers and correlates with adverse clinical parameters. Since surprisingly many HOXC6 target genes are downregulated in prostate cancer, it has been posited that oncogenic effects of HOXC6 in prostate cancer may be unmasked by concurrent epigenetic downregulation of target genes exerting tumor suppressive effects. To test this hypothesis, we have studied the expression of three HOXC6 target genes, CNTN1 (encoding a cell adhesion protein), DKK3 and WIF1 (encoding WNT growth factor antagonists) as well as DNA methylation of DKK3 and WIF1. HOXC6 upregulation and association with poor prognosis were confirmed in our tissue series. The three target genes were each significantly downregulated in cancer tissues and expression of each one correlated inversely with that of HOXC6. Cases with lower WIF1 expression showed significantly earlier recurrence (p = 0.021), whereas no statistical significance was reached for CNTN1 and DKK3. Hypermethylation of DKK3 or WIF1 gene promoters was observed in a subset of cancers with downregulated expression, but was often weak. Our data support the hypothesis that HOXC6 target genes exerting tumor-suppressive effects are epigenetically downregulated in prostate cancer, but DNA methylation appears to follow or bolster rather than to cause their transcriptional inactivation. http://www.mdpi.com/2072-6694/3/4/3714 Tue, 27 Sep 2011 00:00:00 CEST Cancers 2011-09-27 3 4 Article 3714 3725 2072-6694 DNA Methylation and the HOXC6 Paradox in Prostate Cancer 2011-09-27 doi: 10.3390/cancers3043714 Anna Vinarskaja Masanori Yamanaka Marc Ingenwerth Wolfgang A. Schulz http://www.mdpi.com/2072-6694/3/3/3687 Therapeutic vaccination against cancer is an important approach which, when combined with other therapies, can improve long-term control of cancer. In fact, the induction of adaptive immune responses against Tumor Associated Antigens (TAAs) as well as innate immunity are important factors for tumor stabilization/eradication. A variety of immunization technologies have been explored in last decades and are currently under active evaluation, such as cell-based, protein, peptide and heat-shock protein-based cancer vaccines. Genetic vaccines are emerging as promising methodologies to elicit immune responses against a wide variety of antigens, including TAAs. Amongst these, Adenovirus (Ad)-based vectors show excellent immunogenicity profile and have achieved immunological proof of concept in humans. In vivo electroporation of plasmid DNA (DNA-EP) is also a desirable vaccine technology for cancer vaccines, as it is repeatable several times, a parameter required for the long-term maintenance of anti-tumor immunity. Recent findings show that combinations of different modalities of immunization (heterologous prime/boost) are able to induce superior immune reactions as compared to single-modality vaccines. In this review, we will discuss the challenges and requirements of emerging cancer vaccines, particularly focusing on the genetic cancer vaccines currently under active development and the promise shown by Ad and DNA-EP heterologous prime-boost. http://www.mdpi.com/2072-6694/3/3/3687 Thu, 22 Sep 2011 00:00:00 CEST Cancers 2011-09-22 3 3 Review 3687 3713 2072-6694 Emerging Cancer Vaccines: The Promise of Genetic Vectors 2011-09-22 doi: 10.3390/cancers3033687 Luigi Aurisicchio Gennaro Ciliberto http://www.mdpi.com/2072-6694/3/3/3676 Pancreatic ductal adenocarcinoma (PDAC) remains amongst the most lethal human cancers. PDAC is characterized by the tumor mass containing a paucity of malignant cells in association with a large desmoplastic reaction comprised of a variety of stromal components. Sporadic PDAC oncogenesis occurs as a result of the sequential acquisition of genetic aberrations occurring in core genetic pathways. Unfortunately, the average PDAC contains a large number of genetic aberrations that are not uniform between individual cancers. The interplay between the complex genetics and stromal component may represent a significant barrier to the development of effective therapy for this disease and ultimately be an important factor in PDAC lethality. The Wnt pathway has been identified as a one of the common pathways undergoing genetic alterations in PDAC. Wnt is a complex signal transduction pathway utilizing both a b-catenin dependent (canonical) and b-catenin independent (noncanonical) signals to affect a wide array of intracellular events. Wnt signal transduction is an integral component of pancreas organogenesis promoting the expansion and development of the exocrine pancreas. Pancreatic cancer may utilize the Wnt signaling pathway in concert with other signaling pathways such as notch during tumorigenesis. This review will focus on the role of Wnt signal transduction in pancreatic cancer biology. http://www.mdpi.com/2072-6694/3/3/3676 Wed, 21 Sep 2011 00:00:00 CEST Cancers 2011-09-21 3 3 Review 3676 3686 2072-6694 The Many Faces of Wnt and Pancreatic Ductal Adenocarcinoma Oncogenesis 2011-09-21 doi: 10.3390/cancers3033676 Colin D. Weekes Robert A. Winn http://www.mdpi.com/2072-6694/3/3/3661 Natural killer T cells are T lymphocytes with unique activation and effector properties. The majority of NKT cells, termed type-I or iNKT cells, recognize lipid antigens presented on MHC-like CD1d molecules. Type-I NKT cells have the capacity to rapidly secrete various cytokines upon activation, thereby regulate immune responses exerts dominant anti-tumor and anti-microbial effector functions. Specific activation of type-I NKT cells in mouse models boosts immunity and prevents metastasis, which has led to a number of phase I-II clinical trials. Since the discovery of NKT cells other subsets with different specificities and effector functions have been described. This article briefly reviews the physiological functions of NKT cell subsets, their implications in cancer and the attempts that have been made to employ NKT cells for immune therapy of cancer. http://www.mdpi.com/2072-6694/3/3/3661 Tue, 20 Sep 2011 00:00:00 CEST Cancers 2011-09-20 3 3 Review 3661 3675 2072-6694 Natural Killer T Cells Subsets in Cancer, Functional Defects in Prostate Cancer and Implications for Immunotherapy 2011-09-20 doi: 10.3390/cancers3033661 Michael Nowak Ingo G.H. Schmidt-Wolf http://www.mdpi.com/2072-6694/3/3/3632 This article brings mathematical modeling to bear on the reconstruction of the natural history of prostate cancer and assessment of the effects of treatment on metastatic progression. We present a comprehensive, entirely mechanistic mathematical model of cancer progression accounting for primary tumor latency, shedding of metastases, their dormancy and growth at secondary sites. Parameters of the model were estimated from the following data collected from 12 prostate cancer patients: (1) age and volume of the primary tumor at presentation; and (2) volumes of detectable bone metastases surveyed at a later time. This allowed us to estimate, for each patient, the age at cancer onset and inception of the first metastasis, the expected metastasis latency time and the rates of growth of the primary tumor and metastases before and after the start of treatment. We found that for all patients: (1) inception of the first metastasis occurred when the primary tumor was undetectable; (2) inception of all or most of the surveyed metastases occurred before the start of treatment; (3) the rate of metastasis shedding is essentially constant in time regardless of the size of the primary tumor and so it is only marginally affected by treatment; and most importantly, (4) surgery, chemotherapy and possibly radiation bring about a dramatic increase (by dozens or hundred times for most patients) in the average rate of growth of metastases. Our analysis supports the notion of metastasis dormancy and the existence of prostate cancer stem cells. The model is applicable to all metastatic solid cancers, and our conclusions agree well with the results of a similar analysis based on a simpler model applied to a case of metastatic breast cancer. http://www.mdpi.com/2072-6694/3/3/3632 Tue, 20 Sep 2011 00:00:00 CEST Cancers 2011-09-20 3 3 Article 3632 3660 2072-6694 Effects of Surgery and Chemotherapy on Metastatic Progression of Prostate Cancer: Evidence from the Natural History of the Disease Reconstructed through Mathematical Modeling 2011-09-20 doi: 10.3390/cancers3033632 Leonid Hanin Marco Zaider http://www.mdpi.com/2072-6694/3/3/3610 Local tumor recurrence and distant tumor metastasis frequently occur after radiation therapy and result in the death of cancer patients. These problems are caused, at least in part, by a tumor-specific oxygen-poor microenvironment, hypoxia. Oxygen-deprivation is known to inhibit the chemical ionization of both intracellular macro-molecules and water, etc., and thus reduce the cytotoxic effects of radiation. Moreover, DNA damage produced by free radicals is known to be more repairable under hypoxia than normoxia. Hypoxia is also known to induce biological tumor radioresistance through the activation of a transcription factor, hypoxia-inducible factor 1 (HIF-1). Several potential strategies have been devised in radiation therapy to overcome these problems; however, they have not yet achieved a complete remission. It is essential to reveal the intratumoral localization and dynamics of hypoxic/HIF-1-active tumor cells during tumor growth and after radiation therapy, then exploit the information to develop innovative therapeutic strategies, and finally damage radioresistant cells. In this review, we overview problems caused by hypoxia/HIF-1-active cells in radiation therapy for cancer and introduce strategies to assess intratumoral hypoxia/HIF-1 activity. http://www.mdpi.com/2072-6694/3/3/3610 Thu, 15 Sep 2011 00:00:00 CEST Cancers 2011-09-15 3 3 Review 3610 3631 2072-6694 Strategies To Assess Hypoxic/HIF-1-Active Cancer Cells for the Development of Innovative Radiation Therapy 2011-09-15 doi: 10.3390/cancers3033610 Chan Joo Yeom Lihua Zeng Yuxi Zhu Masahiro Hiraoka Hiroshi Harada http://www.mdpi.com/2072-6694/3/3/3601 Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy. http://www.mdpi.com/2072-6694/3/3/3601 Thu, 15 Sep 2011 00:00:00 CEST Cancers 2011-09-15 3 3 Article 3601 3609 2072-6694 Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression 2011-09-15 doi: 10.3390/cancers3033601 Gerhard Hamilton Ulrike Olszewski-Hamilton Gerhard Theyer http://www.mdpi.com/2072-6694/3/3/3585 The purpose of this study was to evaluate the efficacy and safety of high-dose-rate (HDR) brachytherapy of a single implant with two fractions plus external beam radiotherapy (EBRT) for hormone-naïve prostate cancer in comparison with radical prostatectomy. Of 150 patients with localized prostate cancer (T1c–T2c), 59 underwent HDR brachytherapy plus EBRT, and 91 received radical prostatectomy. The median follow-up of patients was 62 months for HDR brachytherapy plus EBRT, and 64 months for radical prostatectomy. In patient backgrounds between the two cohorts, the frequency of T2b plus T2c was greater in HDR brachytherapy cohort than in prostatectomy cohort (27% versus 12%, p = 0.029). Patients in HDR brachytherapy cohort first underwent 3D conformal RT with four beams to the prostate to an isocentric dose of 50 Gy in 25 fractions and then, a total of 15–18 Gy in two fractions at least 5 hours apart. We prescribed 9 Gy/fraction for target (prostate gland plus 3 mm lateral outside margin and seminal vesicle) using CT image method for radiation planning. The total biochemical failure-free control rates (BF-FCR) at 3 and 5 years for the HDR brachytherapy cohort, and for the prostatectomy cohort were 92% and 85%, and 72% and 72%, respectively (significant difference, p = 0.0012). The 3-and 5-year BF-FCR in the HDR brachytherapy cohort and in the prostatectomy cohort by risk group was 100 and 100%, and 80 and 80%, respectively, for the low-risk group (p = 0.1418); 92 and 92%, 73 and 73%, respectively, for the intermediate-risk group (p = 0.0492); and 94 and 72%, 45 and 45%, respectively, for the high-risk group (p = 0.0073). After HDR brachytherapy plus EBRT, no patient experienced Grade 2 or greater genitourinay toxicity. The rate of late Grade 1 and 2 GI toxicity was 6% (n = 4). No patient experienced Grade 3 GI toxicity. HDR brachytherapy plus EBRT is useful for treating patients with hormone-naïve localized prostate cancer, and has low GU and GI toxicities. http://www.mdpi.com/2072-6694/3/3/3585 Wed, 14 Sep 2011 00:00:00 CEST Cancers 2011-09-14 3 3 Article 3585 3600 2072-6694 Efficacy and Safety of High-Dose-Rate Brachytherapy of Single Implant with Two Fractions Combined with External Beam Radiotherapy for Hormone-Naïve Localized Prostate Cancer 2011-09-14 doi: 10.3390/cancers3033585 Yasutaka Noda Morio Sato Shintaro Shirai Kazushi Kishi Takeshi Inagaki Takeshi Mori Isao Hara http://www.mdpi.com/2072-6694/3/3/3557 The effects of several cancer chemotherapeutic drugs and radiation are mediated, at least in part, by oxidative stress. To better understand this process, we analyzed certain biochemical properties affecting reduction-oxidation (redox) balance in normal prostate epithelial cells and several prostate cancer cell lines. Highly aggressive androgen-independent prostate cancer PC3 cells demonstrated significantly higher levels of total antioxidant capacity (AC) and intra- and extracellular glutathione (GSH)/glutathione disulfide (GSSG) ratios when compared with normal prostate epithelial PrEC cells. WPE1-NB26 cells, a prostate cancer cell line derived from immortalized RWPE1 human prostate epithelial cells, demonstrated significantly higher levels of total AC and intra- and extracellular GSH/GSSG ratios, but lower levels of intracellular reactive oxygen/nitrogen species and lipid peroxidation compared with RWPE1 cells. LNCaP-C4-2 cells, a more aggressive prostate cancer derived from less aggressive androgen-responsive LNCaP cells, exhibited higher levels of AC and extracellular GSH/GSSG ratio when compared to LNCaP cells. Specific cell types showed distinct cytotoxic responses to redox-modulating compounds. WPE1-NB26 cells were more sensitive to phenethyl isothiocyanate and tumor necrosis factor (TNF) than RWPE1 cells, while PC3 cells were more sensitive to TNF than PrEC cells. These results are consistent with the hypothesis that cancer cell redox state may modulate responses to redox-modulating therapeutic regimens. http://www.mdpi.com/2072-6694/3/3/3557 Tue, 13 Sep 2011 00:00:00 CEST Cancers 2011-09-13 3 3 Article 3557 3584 2072-6694 Distinct Redox Profiles of Selected Human Prostate Carcinoma Cell Lines: Implications for Rational Design of Redox Therapy 2011-09-13 doi: 10.3390/cancers3033557 Luksana Chaiswing Weixiong Zhong Terry D. Oberley http://www.mdpi.com/2072-6694/3/3/3525 Recent advances have begun to elucidate how epigenetic regulatory mechanisms are responsible for establishing and maintaining cell identity during development and adult life and how the disruption of these processes is, not surprisingly, one of the hallmarks of cancer. In this review, we describe the major epigenetic mechanisms (i.e., DNA methylation, histone and chromatin modification, non-coding RNA deployment, RNA editing, and nuclear reorganization) and discuss the broad spectrum of epigenetic alterations that have been uncovered in pediatric and adult nervous system tumors. We also highlight emerging evidence that suggests epigenetic deregulation is a characteristic feature of so-called cancer stem cells (CSCs), which are thought to be present in a range of nervous system tumors and responsible for tumor maintenance, progression, treatment resistance, and recurrence. We believe that better understanding how epigenetic mechanisms operate in neural cells and identifying the etiologies and consequences of epigenetic deregulation in tumor cells and CSCs, in particular, are likely to promote the development of enhanced molecular diagnostics and more targeted and effective therapeutic agents for treating recalcitrant nervous system tumors. http://www.mdpi.com/2072-6694/3/3/3525 Tue, 13 Sep 2011 00:00:00 CEST Cancers 2011-09-13 3 3 Review 3525 3556 2072-6694 Epigenetics, Nervous System Tumors, and Cancer Stem Cells 2011-09-13 doi: 10.3390/cancers3033525 Irfan A. Qureshi Mark F. Mehler http://www.mdpi.com/2072-6694/3/3/3506 Recent advances in the treatment of non-small cell lung cancer (NSCLC) have led to improvements in patient survival and quality of life. It is unclear whether molecular abnormalities associated with NSCLC cell survival, growth and proliferation are useful in predicting treatment benefit. We conducted a systematic review to establish which biomarkers contribute meaningfully to the management of NSCLC. A team of researchers searched PubMed and conference proceedings (ASCO, ESMO, IASLC, USCAP) using MESH terms for NSCLC and randomized trials (RCT), plus keywords for variables of interest. Evidence from multiple RCTs confirmed that histologic subtype is prognostic for survival and predictive of treatment efficacy and/or toxicity in NSCLC. Likewise, activating mutations of the epidermal growth factor receptor (EGFR) are associated with benefit from EGFR tyrosine kinase inhibitors in patients with advanced non-squamous NSCLC and should be assessed routinely. No biomarkers to date reliably predict response to anti-Vascular Endothelial Growth Factor (VEGF) therapies. There are inconsistent data on the role of ERCC1, BRCA, Beta tubulin III, RRM1, K-RAS, or TP-53 in treatment decisions. These tests should not be routinely used in selecting treatment at this time, whereas EML4/ALK translocations predict responses to specific targeted agents, the optimal assessment of this molecular abnormality has yet to be established. Personalized care of patients with NSCLC based on biomarkers is increasingly important to both clinical practice and research. http://www.mdpi.com/2072-6694/3/3/3506 Tue, 13 Sep 2011 00:00:00 CEST Cancers 2011-09-13 3 3 Review 3506 3524 2072-6694 An Evidence-Based Approach to the Use of Predictive Biomarkers in the Treatment of Non- Small Cell Lung Cancer (NSCLC) 2011-09-13 doi: 10.3390/cancers3033506 Cindy Quinton Peter M. Ellis http://www.mdpi.com/2072-6694/3/3/3496 We introduced non-surgical therapy with a novel enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II) into early stages breast cancer treatment. The purpose of this study was to examine changes in tumor shadows and microcalcifications on mammography (MMG) following KORTUC II for elderly patients with breast cancer. We also sought to determine whether MMG was useful in evaluating the therapeutic effect of KORTUC II. In addition to MMG, positron emission tomography-computed tomography (PET-CT) was performed to detect both metastasis and local recurrence. In all 10 patients, tumor shadows on MMG completely disappeared in several months following the KORTUC II treatment. The concomitant microcalcifications also disappeared or markedly decreased in number. Disappearance of the tumors was also confirmed by the profile curve of tumor density on MMG following KORTUC II treatment; density fell and eventually approached that of the peripheral mammary tissue. These 10 patients have so far have also shown neither local recurrence nor distant metastasis on PET-CT with a mean follow-up period of approximately 27 months at the end of September, 2010. We conclude that breast-conservation treatment using KORTUC II, followed by aromatase inhibitor, is a promising therapeutic method for elderly patients with breast cancer, in terms of avoiding any surgical procedure. Moreover, MMG is considered to be useful for evaluating the efficacy of KORTUC II. http://www.mdpi.com/2072-6694/3/3/3496 Fri, 09 Sep 2011 00:00:00 CEST Cancers 2011-09-09 3 3 Article 3496 3505 2072-6694 Evaluation of Changes in Tumor Shadows and Microcalcifications on Mammography Following KORTUC II, a New Radiosensitization Treatment without any Surgical Procedure for Elderly Patients with Stage I and II Breast Cancer 2011-09-09 doi: 10.3390/cancers3033496 Akira Tsuzuki Yasuhiro Ogawa Kei Kubota Shiho Tokuhiro Ryo Akima Shin Yaogawa Kenji Itoh Yoko Yamada Toshikazu Sasaki Masahide Onogawa Tomoaki Yamanishi Shinji Kariya Munenobu Nogami Akihito Nishioka Mitsuhiko Miyamura http://www.mdpi.com/2072-6694/3/3/3461 Cervical cancer is the second most common cancer of women worldwide and is the first cancer shown to be entirely induced by a virus, the human papillomavirus (HPV, major oncogenic genotypes HPV-16 and -18). Two recently developed prophylactic cervical cancer vaccines, using virus-like particles (VLP) technology, have the potential to prevent a large proportion of cervical cancer associated with HPV infection and to ensure long-term protection. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and do not prevent their progression to HPV-associated malignancy. In animal models, therapeutic vaccines for persisting HPV infection can eliminate transplantable tumors expressing HPV antigens, but are of limited efficacy in inducing rejection of skin grafts expressing the same antigens. In humans, clinical trials have reported successful immunotherapy of HPV lesions, providing hope and further interest. This review discusses possible new approaches to immunotherapy for HPV associated cancer, based on recent advances in our knowledge of the immunobiology of HPV infection, of epithelial immunology and of immunoregulation, with a brief overview on previous and current HPV vaccine clinical trials. http://www.mdpi.com/2072-6694/3/3/3461 Fri, 02 Sep 2011 00:00:00 CEST Cancers 2011-09-02 3 3 Review 3461 3495 2072-6694 New Approaches to Immunotherapy for HPV Associated Cancers 2011-09-02 doi: 10.3390/cancers3033461 Anne-Sophie Bergot Andrew Kassianos Ian H Frazer Deepak Mittal http://www.mdpi.com/2072-6694/3/3/3449 Background: Pomalidomide is a distinct immunomodulatory agent that also displays anti-proliferative and proapoptotic activity. The purpose of this study was to assess the efficacy and safety of pomalidomide for the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). Methods: Pomalidomide was administered orally in doses of 1 or 2 mg/day without interruption. Follow ups were conducted every 4 weeks with evaluation of study outcomes at 12 weeks. The principal study outcomes were PSA response, time to progression (TTP) using RECIST, overall survival (OS), and safety. A total of 32 patients were enrolled: 15 in the 1 mg/day cohort (median baseline PSA level of 12.30 ng/mL [0.8–236.0]), and 17 in the 2 mg/day cohort (median baseline PSA level of 12.50 ng/mL [0.6–191.8]). Results: In the 1 mg cohort disease was stabilized for ≥28 days in eight patients, and median TTP was 2.90 months. In the 2 mg cohort, PSA decreased >50% in three patients, disease was stabilized for ≥28 days in seven patients, and median TTP was 5.87 months. Toxicity in both cohorts was predominantly grade 1 or 2; 2 grade 3 toxicity (fatigue) occurred in the 1 mg cohort, and 5 grade 3 toxicities (chest pain, diarrhea, epigastric pain, impaction, pain) occurred in the 2 mg cohort. One grade 4 toxicity of cardiac ischemia occurred. Conclusions: Pomalidomide shows promising activity in patients with CRPC and has an acceptable safety profile. http://www.mdpi.com/2072-6694/3/3/3449 Fri, 02 Sep 2011 00:00:00 CEST Cancers 2011-09-02 3 3 Article 3449 3460 2072-6694 Phase II Study of Pomalidomide in Patients with Castration-Resistant Prostate Cancer 2011-09-02 doi: 10.3390/cancers3033449 Robert J. Amato L. Michael Glode Jeremy Podolnick Robert Knight David Crawford http://www.mdpi.com/2072-6694/3/3/3432 Treatment options for early-stage (T1-2 N0) non-small cell lung cancer are often limited by the patient’s advanced age, poor performance status, and comorbidities. Despite these challenges, stereotactic ablative radiotherapy (SABR) provides a highly effective and safe therapy for intrathoracic tumors and has become the standard of care for delivering definitive treatment in medically inoperable patients. High-quality treatment, which includes reliable immobilization, accurate tumor targeting, and precise verification of dose delivery, is essential both to achieve successful cure and to avoid debilitating toxicities. Generally, SABR is well tolerated in patients with peripherally located tumors, but even centrally or superiorly located lesions can be treated if there is adequate conformal avoidance of normal structures and/or modified fractionation to meet dose constraints. While several preliminary studies suggest that SABR is as efficacious as surgery in operable patients, results of randomized data will illuminate whether the indications for SABR can be expanded to include patients who are candidates for surgical resection. Herein, we review the rationale for using SABR and its application in treating different patient populations with early-stage lung cancer. http://www.mdpi.com/2072-6694/3/3/3432 Thu, 01 Sep 2011 00:00:00 CEST Cancers 2011-09-01 3 3 Review 3432 3448 2072-6694 Scalpel or SABR for Treatment of Early-Stage Lung Cancer: Clinical Considerations for the Multidisciplinary Team 2011-09-01 doi: 10.3390/cancers3033432 Shervin M. Shirvani Joe Y. Chang http://www.mdpi.com/2072-6694/3/3/3419 Purpose: To report the toxicity and long-term outcomes of dose-escalated intensity-modulated radiation therapy (IMRT) for patients with localised prostate cancer. Methods and Materials: From 2001 to 2005, a total of 125 patients with histologically confirmed T1-3N0M0 prostate cancer were treated with IMRT to 74Gy at the Austin Health Radiation Oncology Centre. The median follow-up was 5.5 years (range 0.5–8.9 years). Biochemical prostate specific antigen (bPSA) failure was defined according to the Phoenix consensus definition (absolute nadir + 2ng/mL). Toxicity was scored according to the RTOG/EORTC criteria. Kaplan-Meier analysis was used to calculate toxicity rates, as well as the risks of bPSA failure, distant metastases, disease-specific and overall survival, at 5 and 8-years post treatment. Results: All patients completed radiotherapy without any treatment breaks. The 8-year risks of ≥ Grade 2 genitourinary (GU) and gastrointestinal (GI) toxicity were 6.4% and 5.8% respectively, and the 8-year risks of ≥ Grade 3 GU and GI toxicity were both < 0.05%. The 5 and 8-year freedom from bPSA failure were 76% and 58% respectively. Disease-specific survival at 5 and 8 years were 95% and 91%, respectively, and overall survival at 5 and 8 years were 90% and 71%, respectively. Conclusions: These results confirm existing international data regarding the safety and efficacy of dose-escalated intensity-modulated radiation therapy for localised prostate cancer within an Australian setting. http://www.mdpi.com/2072-6694/3/3/3419 Thu, 01 Sep 2011 00:00:00 CEST Cancers 2011-09-01 3 3 Article 3419 3431 2072-6694 Toxicity and Long-Term Outcomes of Dose-Escalated Intensity Modulated Radiation Therapy to 74Gy for Localised Prostate Cancer in a Single Australian Centre 2011-09-01 doi: 10.3390/cancers3033419 Joseph Sia Daryl Lim Joon Angela Viotto Carmel Mantle George Quong Aldo Rolfo Morikatsu Wada Nigel Anderson Maureen Rolfo Vincent Khoo http://www.mdpi.com/2072-6694/3/3/3405 Tumor angiogenesis is known to be regulated by growth factors secreted by host and tumor cells. Despite the importance of tumor vasculature and angiogenic heterogeneity in solid tumors, few studies have compared the vasculature in different regions of human cancer. Blood vessels from different regions of carcinomas might have morphofunctional implications in tumor angiogenesis. In the present study, therefore, we have examined the relationship between microvascular density (MVD) and vascular endothelial growth factor (VEGF) expression and alpha smooth muscle actin (α-SMA) expression in the center of the tumor (CT), periphery (P) and metastasis (M) regions from gastrointestinal carcinomas (GITC), as well as the association of MVD with clinicopathological factors. Surgically resected specimens corresponding to the CT, P and M from 27 patients were examined for FVIII, VEGF and α-SMA by immunohistochemistry. The MVD was not significantly different in the CT, P and M regions from GITC. The MVD in the VEGF positive group was significantly higher than in the VEGF negative group (CT, p = 0.034; P, p = 0.030; M, p = 0.032). The MVD as a function of α-SMA expression was also significantly higher in the CT and P region compared to the M region (p = 0.0008). In conclusion, the MVD association with VEGF and α-SMA expression, might indicate an increase of the number of neoformed and preexisting blood vessels uniformly or partially covered by pericytes in different regions of GITC, suggesting that not only MVD and VEGF are important parameters to the tumor vasculature, but also blood vessels maturation is a crucial factor for gastrointestinal tumor angiogenesis regulation and possible target of vascular therapy. http://www.mdpi.com/2072-6694/3/3/3405 Wed, 31 Aug 2011 00:00:00 CEST Cancers 2011-08-31 3 3 Article 3405 3418 2072-6694 Microvessel Density Is Associated with VEGF and α-SMA Expression in Different Regions of Human Gastrointestinal Carcinomas 2011-08-31 doi: 10.3390/cancers3033405 Paola Tonino Carmen Abreu http://www.mdpi.com/2072-6694/3/3/3394 Fibromatosis, or extra-abdominal desmoid tumor, is a benign disease which often has an aggressive clinical course that can be difficult to treat. We performed a retrospective review of 16 patients (12 females and four males) with a mean age of 34.2 years treated with methotrexate and vinblastine for newly diagnosed or recurrent extra-abdominal desmoid tumor. The mean age of our patient cohort was 34.2 years (range 11–70), and the mean tumor size was 11.5 cm (range 2.5–21.2 cm). The mean duration of therapy was 12 months with an average follow-up of 43 months (range 1–149 months). Fourteen of 16 patients demonstrated a clinical response to treatment. Eight of 14 patients demonstrated a radiologic decrease in tumor size. Only one patient progressed on therapy. Six patients developed recurrent symptoms after discontinuation of treatment. Chemotherapy-related symptoms including neutropenia, nausea, and vomiting were common and observed in most patients, however these side effects were mild and transient. Five patients developed peripheral neuropathy that prompted a change from vinblastine to vinorelbine during treatment. One potentially life-threatening complication (pneumocystis pneumonia) occurred which was diagnosed early and successfully treated. The use of methotrexate and vinblastine/vinorelbine in the management of fibromatosis appears to be an effective treatment with minimal treatment-related side effects. http://www.mdpi.com/2072-6694/3/3/3394 Thu, 25 Aug 2011 00:00:00 CEST Cancers 2011-08-25 3 3 Article 3394 3404 2072-6694 Treatment of Extra — Abdominal Desmoid Tumors with Chemotherapy 2011-08-25 doi: 10.3390/cancers3033394 Corey Montgomery Cynthia Emory Sheila Adams Jonathan Cohen John David Pitcher Benjamin Kyle Potter H. Thomas Temple http://www.mdpi.com/2072-6694/3/3/3370 The relative success of monoclonal antibodies in cancer immunotherapy and the vast manipulation potential of recombinant antibody technology have encouraged the development of novel antibody-based antitumor proteins. Many insightful reagents have been produced, mainly guided by studies on the mechanisms of action associated with complete and durable remissions, results from experimental animal models, and our current knowledge of the human immune system. Strikingly, only a small percent of these new reagents has demonstrated clinical value. Tumor burden, immune evasion, physiological resemblance, and cell plasticity are among the challenges that cancer therapy faces, and a number of antibody-based proteins are already available to deal with many of them. Some of these novel reagents have been shown to specifically increase apoptosis/cell death of tumor cells, recruit and activate immune effectors, and reveal synergistic effects not previously envisioned. In this review, we look into different approaches that have been followed during the past few years to produce these biologics and analyze their relative success, mainly in terms of their clinical performance. The use of antibody-based antitumor proteins, in combination with standard or novel therapies, is showing significant improvements in objective responses, suggesting that these reagents will become important components of the antineoplastic protocols of the future. http://www.mdpi.com/2072-6694/3/3/3370 Fri, 19 Aug 2011 00:00:00 CEST Cancers 2011-08-19 3 3 Review 3370 3393 2072-6694 Novel Antibody-Based Proteins for Cancer Immunotherapy 2011-08-19 doi: 10.3390/cancers3033370 Jaheli Fuenmayor Ramon F. Montaño http://www.mdpi.com/2072-6694/3/3/3353 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), a synthetic analog of oleanolic acid, and its C28 methyl ester derivative (CDDO-Me), have shown potent antitumorigenic activity against a wide range of cancer cell lines, including prostate cancer cells in vitro, and inhibited the development of liver and lung cancer in vivo. In the present study, we examined the efficacy of CDDO-Me in preventing the development and progression of prostate cancer in the transgenic adenocarinoma of the mouse prostate (TRAMP) model. CDDO-Me inhibited the growth of murine TRAMPC-1 prostate cancer cells by inducing apoptosis through the inhibition of antiapoptotic p-Akt, p-mTOR and NF-κB. Early intervention with CDDO-Me (7.5 mg/kg) initiated at five weeks of age for 20 wk inhibited the progression of the preneoplastic lesions (low-grade PIN and high-grade-PIN) to adenocarcinoma in the dorsolateral prostate (DLP) and ventral prostate (VP) lobes of TRAMP mice. Even delayed administration of CDDO-Me started at 12 wk of age for 12 wk inhibited the development of adenocarcimona of the prostate. Both early and late treatment with CDDO-Me inhibited the metastasis of tumor to the distant organs. Treatment with CDDO-Me inhibited the expression of prosurvival p-Akt and NF-κB in the prostate and knocking-down Akt in TRAMPC-1 tumor cells sensitized them to CDDO-Me. These findings indicated that Akt is a target for apoptoxicity in TRAMPC-1 cells in vitro and potentially a target of CDDO-Me for inhibition of prostate cancer in vivo. http://www.mdpi.com/2072-6694/3/3/3353 Fri, 19 Aug 2011 00:00:00 CEST Cancers 2011-08-19 3 3 Article 3353 3369 2072-6694 Prevention of Prostate Cancer with Oleanane Synthetic Triterpenoid CDDO-Me in the TRAMP Mouse Model of Prostate Cancer 2011-08-19 doi: 10.3390/cancers3033353 Xiaohua Gao Dorrah Deeb Yongbo Liu Ali S. Arbab George W. Divine Scott A. Dulchavsky Subhash C. Gautam http://www.mdpi.com/2072-6694/3/3/3331 The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC. http://www.mdpi.com/2072-6694/3/3/3331 Mon, 15 Aug 2011 00:00:00 CEST Cancers 2011-08-15 3 3 Review 3331 3352 2072-6694 Therapeutic Approaches to Target Cancer Stem Cells 2011-08-15 doi: 10.3390/cancers3033331 Arlhee Diaz Kalet Leon http://www.mdpi.com/2072-6694/3/3/3279 Cancer therapy has been characterized throughout history by ups and downs, not only due to the ineffectiveness of treatments and side effects, but also by hope and the reality of complete remission and cure in many cases. Within the therapeutic arsenal, alongside surgery in the case of solid tumors, are the antitumor drugs and radiation that have been the treatment of choice in some instances. In recent years, immunotherapy has become an important therapeutic alternative, and is now the first choice in many cases. Nanotechnology has recently arrived on the scene, offering nanostructures as new therapeutic alternatives for controlled drug delivery, for combining imaging and treatment, applying hyperthermia, and providing directed target therapy, among others. These therapies can be applied either alone or in combination with other components (antibodies, peptides, folic acid, etc.). In addition, gene therapy is also offering promising new methods for treatment. Here, we present a review of the evolution of cancer treatments, starting with chemotherapy, surgery, radiation and immunotherapy, and moving on to the most promising cutting-edge therapies (gene therapy and nanomedicine). We offer an historical point of view that covers the arrival of these therapies to clinical practice and the market, and the promises and challenges they present. http://www.mdpi.com/2072-6694/3/3/3279 Fri, 12 Aug 2011 00:00:00 CEST Cancers 2011-08-12 3 3 Review 3279 3330 2072-6694 Assessment of the Evolution of Cancer Treatment Therapies 2011-08-12 doi: 10.3390/cancers3033279 Manuel Arruebo Nuria Vilaboa Berta Sáez-Gutierrez Julio Lambea Alejandro Tres Mónica Valladares África González-Fernández http://www.mdpi.com/2072-6694/3/3/3242 Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies. http://www.mdpi.com/2072-6694/3/3/3242 Wed, 10 Aug 2011 00:00:00 CEST Cancers 2011-08-10 3 3 Review 3242 3278 2072-6694 Aberrant Signaling Pathways in Glioma 2011-08-10 doi: 10.3390/cancers3033242 Mitsutoshi Nakada Daisuke Kita Takuya Watanabe Yutaka Hayashi Lei Teng Ilya V. Pyko Jun-Ichiro Hamada http://www.mdpi.com/2072-6694/3/3/3225 DNA vaccination exploits a relatively simple and flexible technique to generate an immune response against microbial and tumor-associated antigens (TAAs). Its effectiveness is enhanced by the application of an electrical shock in the area of plasmid injection (electroporation). In our studies we exploited a sophisticated electroporation device approved for clinical use (Cliniporator, IGEA, Carpi, Italy). As the target antigen is an additional factor that dramatically modulates the efficacy of a vaccine, we selected ErbB2 receptor as a target since it is an ideal oncoantigen. It is overexpressed on the cell membrane by several carcinomas for which it plays an essential role in driving their progression. Most oncoantigens are self-tolerated molecules. To circumvent immune tolerance we generated two plasmids (RHuT and HuRT) coding for chimeric rat/human ErbB2 proteins. Their immunogenicity was compared in wild type mice naturally tolerant for mouse ErbB2, and in transgenic mice that are also tolerant for rat or human ErbB2. In several of these mice, RHuT and HuRT elicited a stronger anti-tumor response than plasmids coding for fully human or fully rat ErbB2. The ability of heterologous moiety to blunt immune tolerance could be exploited to elicit a significant immune response in patients. A clinical trial to delay the recurrence of ErbB2+ carcinomas of the oral cavity, oropharynx and hypopharynx is awaiting the approval of the Italian authorities. http://www.mdpi.com/2072-6694/3/3/3225 Wed, 10 Aug 2011 00:00:00 CEST Cancers 2011-08-10 3 3 Review 3225 3241 2072-6694 Chimeric DNA Vaccines against ErbB2+ Carcinomas: From Mice to Humans 2011-08-10 doi: 10.3390/cancers3033225 Elena Quaglino Federica Riccardo Marco Macagno Silvio Bandini Rodica Cojoca Elisabetta Ercole Augusto Amici Federica Cavallo http://www.mdpi.com/2072-6694/3/3/3206 Development from chronic inflammation to Barrett’s adenocarcinoma is known as one of the inflammation-related carcinogenesis routes. Gastroesophageal reflux disease induces regurgitant esophagitis, and esophageal mucosa is usually regenerated by squamous epithelium, but sometimes and somewhere replaced with metaplastic columnar epithelium. Specialized columnar epithelium, so-called Barrett’s epithelium (BE), is a risk factor for dysplasia and adenocarcinoma in esophagus. Several experiments using rodent model inducing duodenogastroesophageal reflux or duodenoesophageal reflux revealed that columnar epithelium, first emerging at the proliferative zone, progresses to dysplasia and finally adenocarcinoma, and exogenous carcinogen is not necessary for cancer development. It is demonstrated that duodenal juice rather than gastric juice is essential to develop esophageal adenocarcinoma in not only rodent experiments, but also clinical studies. Antireflux surgery and chemoprevention by proton pump inhibitors, nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, green tea, retinoic acid and thioproline showed preventive effects on the development of Barrett’s adenocarcinoma in rodent models, but it remains controversial whether antireflux surgery could regress BE and prevent esophageal cancer in clinical observation. The Chemoprevention for Barrett's Esophagus Trial (CBET), a phase IIb, multicenter, randomized, double-masked study using celecoxib in patients with Barrett's dysplasia failed to prove to prevent progression of dysplasia to cancer. The AspECT (Aspirin Esomeprazole Chemoprevention Trial), a large multicenter phase III randomized trial to evaluate the effects of esomeprazole and/or aspirin on the rate of progression to high-grade dysplasia or adenocarcinoma in patients with BE is now ongoing. http://www.mdpi.com/2072-6694/3/3/3206 Wed, 10 Aug 2011 00:00:00 CEST Cancers 2011-08-10 3 3 Review 3206 3224 2072-6694 Inflammation-Related Carcinogenesis and Prevention in Esophageal Adenocarcinoma Using Rat Duodenoesophageal Reflux Models 2011-08-10 doi: 10.3390/cancers3033206 Takashi Fujimura Katsunobu Oyama Shozo Sasaki Koji Nishijima Tomoharu Miyashita Tetsuo Ohta Koichi Miwa Takanori Hattori http://www.mdpi.com/2072-6694/3/3/3189 Complex interactions between cancer cells and host stromal cells result in the formation of the “tumor microenvironment”, where inflammatory alterations involve the infiltration of tumor-associated fibroblasts and inflammatory leukocytes that contribute to the acquisition of malignant characteristics, such as increased cancer cell proliferation, invasiveness, metastasis, angiogenesis, and avoidance of adaptive immunity. The microenvironment of a solid tumor is comprised not only of cellular compartments, but also of bioactive substances, including cytokines, growth factors, and extracellular matrix (ECM). ECM can act as a scaffold for cell migration, a reservoir for cytokines and growth factors, and a signal through receptor binding. During inflammation, ECM components and their degraded fragments act directly and indirectly as inflammatory stimuli in certain cases and regulate the functions of inflammatory and immune cells. One such ECM component, hyaluronan, has recently been implicated to modulate innate immune cell function through pattern recognition toll-like receptors and accelerate the recruitment and activation of tumor-associated macrophages in inflamed cancers. Here, we will summarize the molecular mechanism linking inflammation with ECM remodeling in the tumor microenvironment, with a particular emphasis on the role of hyaluronan in controlling the inflammatory response. http://www.mdpi.com/2072-6694/3/3/3189 Tue, 09 Aug 2011 00:00:00 CEST Cancers 2011-08-09 3 3 Review 3189 3205 2072-6694 Inflammatory Alterations of the Extracellular Matrix in the Tumor Microenvironment 2011-08-09 doi: 10.3390/cancers3033189 Junko Iijima Kenjiro Konno Naoki Itano http://www.mdpi.com/2072-6694/3/3/3169 Dendritic cells are key regulators in directing immune responses and therefore are under extensive research for the induction of anti-tumor responses. DCs express a large array of receptors by which they scan their surroundings for recognition and uptake of pathogens. One of the receptor-families is the C-type lectins (CLR), which bind carbohydrate structures and internalize antigens upon recognition. Intracellular routing of antigen through CLR enhances loading and presentation of antigen through MHC class I and II, inducing antigen-specific CD4+ and CD8+ T-cell proliferation and skewing T-helper cells. These characteristics make CLRs very interesting targets for DC-based immunotherapy. Profound research has been done on targeting specific tumor antigens to CLR using either antibodies or the natural ligands such as glycan structures. In this review we will focus on the current data showing the potency of CLR-targeting and discuss improvements that can be achieved to enhance anti-tumor activity in the near future. http://www.mdpi.com/2072-6694/3/3/3169 Mon, 08 Aug 2011 00:00:00 CEST Cancers 2011-08-08 3 3 Review 3169 3188 2072-6694 C-type Lectin Receptors for Tumor Eradication: Future Directions 2011-08-08 doi: 10.3390/cancers3033169 Ingeborg Streng-Ouwehand Wendy W. J. Unger Yvette Van Kooyk http://www.mdpi.com/2072-6694/3/3/3156 Background: Leukotrienes (LT) mediate allergic and inflammatory processes. Previously, we identified significant changes in the expression pattern of LT receptors in the gastric mucosa after eradication of Helicobacter pylori infection. The aim of the present study was to evaluate the expression of 5-lipoxygenase (5-LOX) and LT receptors in gastric cancer (GC). Methods: The expression of 5-LOX and receptors for LTB4 (BLT-1, BLT-2) and cysteinyl-LT (CysLT-1, CysLT-2) were analyzed by immunohistochemistry (IHC) in GC samples of 35 consecutive patients who underwent gastrectomy and in 29 tumor-free tissue specimens from gastric mucosa. Results: Male-to-female ratio was 24:11. The median age was 70 years (range 34–91). Twenty-two patients had GC of intestinal, six of diffuse, six of mixed and one of undifferentiated type. The IHC analysis showed a nearly ubiquitous expression of studied proteins in GC (88–97%) and in tumor-free specimens as well (89–100%). An increase in the immunoreactive score of both BLT receptors and CysLT-1 was observed in GC compared to tumor-free gastric mucosa (p < 0.001 for BLT-1; p < 0.01 for BLT-2 and CysLT-1, Mann-Whitney U-test). No differences in the IHC expression of 5-LOX and CsyLT-2 were observed between GC and tumor-free mucosa. The expression of BLT-2, CysLT-1 and CysLT-2 was increased in GC of intestinal type when compared to the diffuse type (p < 0.05; Mann-Whitney U-test). Conclusions: LTB4 receptors and CysLT-1 are up-regulated in GC tissue implying a role in gastric carcinogenesis. http://www.mdpi.com/2072-6694/3/3/3156 Mon, 08 Aug 2011 00:00:00 CEST Cancers 2011-08-08 3 3 Article 3156 3168 2072-6694 Upregulation of Leukotriene Receptors in Gastric Cancer 2011-08-08 doi: 10.3390/cancers3033156 Marino Venerito Doerthe Kuester Caroline Harms Daniel Schubert Thomas Wex Peter Malfertheiner http://www.mdpi.com/2072-6694/3/3/3143 Desmoid tumors are a rare group of locally aggressive, non malignant tumors of fibroblastic origin that can lead to significant morbidity due to local invasion. Despite advances in the understanding of these tumors, their natural history is incompletely understood and the optimal treatment is still a matter of debate. Local control is the main goal of treatment and there has been a change in philosophy regarding the management of these tumors from aggressive surgical resection to function preservation. A multidisciplinary approach is essential to plan local control with acceptable morbidity. The current Mayo Clinic algorithm for the treatment of these tumors is based on institutional experience and the available evidence in the literature: asymptomatic/non progressive lesions away from vital structures are managed with observation and regular imaging; primary or recurrent desmoid tumors which are symptomatic or progressive or near vital structures are managed with wide surgical resection when wide surgical margins are possible with minimal functional and cosmetic loss. When positive or close surgical margins are likely, surgical resection with adjuvant radiotherapy or definitive radiotherapy is preferred. If likely functional or cosmetic deficit is unacceptable, radiotherapy is the treatment of choice. Unresectable lesions are considered for radiotherapy, chemotherapy or newer modalities however an unresectable lesion associated with a painful, functionless, infected extremity is managed with an amputation. http://www.mdpi.com/2072-6694/3/3/3143 Mon, 08 Aug 2011 00:00:00 CEST Cancers 2011-08-08 3 3 Review 3143 3155 2072-6694 Current Perspectives on Desmoid Tumors: The Mayo Clinic Approach 2011-08-08 doi: 10.3390/cancers3033143 Siddharth B. Joglekar Peter S. Rose Franklin Sim Scott Okuno Ivy Petersen http://www.mdpi.com/2072-6694/3/3/3114 Chemotherapy has been a mainstay in cancer treatment for many years. Despite some success, the cure rate with chemotherapy remains unsatisfactory in some types of cancers, and severe side effects from these treatments are a concern. Recently, understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies, including cancer vaccines. Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity. Many developments have increased their potency in pre-clinical models, but cancer vaccines continue to have a poor clinical track record. In part, this could be due to an inability to effectively overcome tumor-induced immune suppression. It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma. Chemotherapies could be used to condition the immune system and tumor to create an environment where cancer vaccines have a better chance of success. Other types of immunotherapies could also be used to modulate the immune system. This review will discuss how immune modulation by chemotherapy or immunotherapy could be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments. http://www.mdpi.com/2072-6694/3/3/3114 Fri, 05 Aug 2011 00:00:00 CEST Cancers 2011-08-05 3 3 Review 3114 3142 2072-6694 Immune Modulation by Chemotherapy or Immunotherapy to Enhance Cancer Vaccines 2011-08-05 doi: 10.3390/cancers3033114 Genevieve M. Weir Robert S. Liwski Marc Mansour http://www.mdpi.com/2072-6694/3/3/3104 Chronic inflammation has long been implicated as a predisposition for cancer, but the underlying mechanism for how this occurs has remained obscure. Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine which is known to be highly linked to colorectal cancer. During chronic inflammation the intestinal mucosa is in a constant cycle of injury and repair resulting in aberrant epithelial proliferation, a process that increases the risk of neoplastic transformation. In particular, the coexistence of commensal flora in the intestine plays an important role in the regulation of mucosal restitution after epithelial injury. It has become apparent that signaling through toll-like receptors (TLRs), the receptor family recognizing pathogen-associated molecular patterns, is crucial to intestinal epithelial proliferation and mucosal restitution. We have recently described two important downstream pathways underlying TLR4-mediated epithelial proliferation in a mouse model of colitis-associated cancer; i.e., cyclooxygenase 2 (COX-2)-mediated production of prostaglandin E2 (PGE2), and induction of specific ligands for epidermal growth factor receptor (EGFR). These two pathways are closely involved with mucosal levels of PGE2 and other prostanoids such as 15-deoxy-delta 12,14-prostaglandin-J2 (15d-PGJ2). Understanding the fine interplay between the TLR signaling and intestinal tumorigenesis in the setting of chronic inflammation can contribute to establishing a novel treatment strategy for inflammation-associated cancers. http://www.mdpi.com/2072-6694/3/3/3104 Tue, 02 Aug 2011 00:00:00 CEST Cancers 2011-08-02 3 3 Review 3104 3113 2072-6694 Toll-Like Receptor 4 Signaling Integrates Intestinal Inflammation with Tumorigenesis: Lessons from the Murine Model of Colitis-Associated Cancer 2011-08-02 doi: 10.3390/cancers3033104 Yasmin Hernandez John Sotolongo Masayuki Fukata http://www.mdpi.com/2072-6694/3/3/3073 MUC1 is a membrane-tethered mucin expressed on the ductal cell surface of glandular epithelial cells. Loss of polarization, overexpression and aberrant glycosylation of MUC1 in mucosal inflammation and in adenocarcinomas induces humoral immune responses to the mucin. MUC1 IgG responses have been associated with a benefit in survival in patients with breast, lung, pancreatic, ovarian and gastric carcinomas. Antibodies bound to the mucin may curb tumor progression by restoring cell-cell interactions altered by tumor-associated MUC1, thus preventing metastatic dissemination, as well as counteracting the immune suppression exerted by the molecule. Furthermore, anti-MUC1 antibodies are capable of effecting tumor cell killing by antibody-dependent cell-mediated cytotoxicity. Although cytotoxic T cells are indispensable to achieve anti-tumor responses in advanced disease, abs to tumor-associated antigens are ideally suited to address minimal residual disease and may be sufficient to exert adequate immune surveillance in an adjuvant setting, destroying tumor cells as they arise or maintaining occult disease in an equilibrium state. Initial evaluation of MUC1 peptide/glycopeptide mono and polyvalent vaccines has shown them to be immunogenic and safe; anti-tumor responses are scarce. Progress in carbohydrate synthesis has yielded a number of sophisticated substrates that include MUC1 glycopeptide epitopes that are at present in preclinical testing. Adjuvant vaccination with MUC1 glycopeptide polyvalent vaccines that induce strong humoral responses may prevent recurrence of disease in patients with early stage carcinomas. Furthermore, prophylactic immunotherapy targeting MUC1 may be a strategy to strengthen immune surveillance and prevent disease in subjects at hereditary high risk of breast, ovarian and colon cancer. http://www.mdpi.com/2072-6694/3/3/3073 Fri, 29 Jul 2011 00:00:00 CEST Cancers 2011-07-29 3 3 Review 3073 3103 2072-6694 Natural and Induced Humoral Responses to MUC1 2011-07-29 doi: 10.3390/cancers3033073 Silvia Von Mensdorff-Pouilly Maria Moreno René H. M. Verheijen http://www.mdpi.com/2072-6694/3/3/3055 Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8+ T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules. http://www.mdpi.com/2072-6694/3/3/3055 Fri, 29 Jul 2011 00:00:00 CEST Cancers 2011-07-29 3 3 Review 3055 3072 2072-6694 Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives 2011-07-29 doi: 10.3390/cancers3033055 Hiroshi Kitamura Taiji Tsukamoto http://www.mdpi.com/2072-6694/3/3/3029 The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas. http://www.mdpi.com/2072-6694/3/3/3029 Tue, 26 Jul 2011 00:00:00 CEST Cancers 2011-07-26 3 3 Review 3029 3054 2072-6694 Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance 2011-07-26 doi: 10.3390/cancers3033029 Joseph A. Ludwig Salah-Eddine Lamhamedi-Cherradi Ho-Young Lee Aung Naing Robert Benjamin http://www.mdpi.com/2072-6694/3/3/3018 Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis. http://www.mdpi.com/2072-6694/3/3/3018 Mon, 25 Jul 2011 00:00:00 CEST Cancers 2011-07-25 3 3 Review 3018 3028 2072-6694 Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis 2011-07-25 doi: 10.3390/cancers3033018 Eun-Hee Kim Kyung-Sook Hong Hua Hong Ki Baik Hahm http://www.mdpi.com/2072-6694/3/3/3002 Carcinogenesis occurs through a series of steps from normal into benign and finally malignant phenotype. This cancer evolutionary trajectory has been accompanied by similar metabolic transformation from normal metabolism into Pasteur and/or Crabtree-Effects into Warburg-Effect and finally Cannibalism and/or Lactate-Symbiosis. Due to lactate production as an end-product of glycolysis, tumor colonies acquire new phenotypes that rely on lactate as energetic fuel. Presence of Warburg-Effect indicates that some tumor cells undergo partial (if not complete) de-endosymbiosis and so cancer cells have been become unicellular microorganism (anti-Dollo’s Law) specially when they evolve to develop cannibalism as way of metabolism while oxidative types of cells that rely on lactate, as their energetic fuel, might represent extra-endosymbiosis. Thus, at the end, the cancer colony could be considered as integrated metabolic ecosystem. Proper understanding of tumor metabolism will contribute to discover potential anticancer agents besides conventional chemotherapy. http://www.mdpi.com/2072-6694/3/3/3002 Fri, 22 Jul 2011 00:00:00 CEST Cancers 2011-07-22 3 3 Opinion 3002 3017 2072-6694 Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity) 2011-07-22 doi: 10.3390/cancers3033002 Khalid O. Alfarouk Mohammed E.A. Shayoub Abdel Khalig Muddathir Gamal O. Elhassan Adil H.H. Bashir