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Cancers, Volume 3, Issue 2 (June 2011) , Pages 1480-2810

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Open AccessReview
Review of Histopathological and Molecular Prognostic Features in Colorectal Cancer
Cancers 2011, 3(2), 2767-2810; https://doi.org/10.3390/cancers3022767
Received: 10 March 2011 / Revised: 14 June 2011 / Accepted: 15 June 2011 / Published: 23 June 2011
Cited by 15 | Viewed by 4871 | PDF Full-text (575 KB) | HTML Full-text | XML Full-text
Abstract
Prediction of prognosis in colorectal cancer is vital for the choice of therapeutic options. Histopathological factors remain paramount in this respect. Factors such as tumor size, histological type and subtype, presence of signet ring morphology and the degree of differentiation as well as [...] Read more.
Prediction of prognosis in colorectal cancer is vital for the choice of therapeutic options. Histopathological factors remain paramount in this respect. Factors such as tumor size, histological type and subtype, presence of signet ring morphology and the degree of differentiation as well as the presence of lymphovascular invasion and lymph node involvement are well known factors that influence outcome. Our understanding of these factors has improved in the past few years with factors such as tumor budding, lymphocytic infiltration being recognized as important. Likewise the prognostic significance of resection margins, particularly circumferential margins has been appreciated in the last two decades. A number of molecular and genetic markers such as KRAS, BRAF and microsatellite instability are also important and correlate with histological features in some patients. This review summarizes our current understanding of the main histopathological factors that affect prognosis of colorectal cancer. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessArticle
Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis
Cancers 2011, 3(2), 2750-2766; https://doi.org/10.3390/cancers3022750
Received: 13 May 2011 / Revised: 9 June 2011 / Accepted: 14 June 2011 / Published: 22 June 2011
Cited by 4 | Viewed by 3926 | PDF Full-text (297 KB) | HTML Full-text | XML Full-text
Abstract
Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is [...] Read more.
Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
Open AccessReview
TRAF4, at the Crossroad between Morphogenesis and Cancer
Cancers 2011, 3(2), 2734-2749; https://doi.org/10.3390/cancers3022734
Received: 12 May 2011 / Revised: 16 June 2011 / Accepted: 17 June 2011 / Published: 21 June 2011
Cited by 10 | Viewed by 3738 | PDF Full-text (482 KB) | HTML Full-text | XML Full-text
Abstract
Tumor Necrosis Factor Receptor-Associated Factor 4 (TRAF4) is a gene whose expression is altered in cancers. It is overexpressed in a variety of carcinomas of different origins, often as a consequence of amplification. TRAF4 encodes an adaptor protein that belongs to the TRAF [...] Read more.
Tumor Necrosis Factor Receptor-Associated Factor 4 (TRAF4) is a gene whose expression is altered in cancers. It is overexpressed in a variety of carcinomas of different origins, often as a consequence of amplification. TRAF4 encodes an adaptor protein that belongs to the TRAF protein family. While most TRAF proteins influence immune and inflammation processes, TRAF4 is mainly involved in developmental and morphogenic processes. Interestingly, this protein has been shown to be linked to crucial cellular functions such as cell polarity and the regulation of reactive oxygen species production. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Graphical abstract

Open AccessReview
Mechanism of Cancer Growth Suppression of Alpha-Fetoprotein Derived Growth Inhibitory Peptides (GIP): Comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects
Cancers 2011, 3(2), 2709-2733; https://doi.org/10.3390/cancers3022709
Received: 6 April 2011 / Revised: 2 June 2011 / Accepted: 14 June 2011 / Published: 20 June 2011
Cited by 6 | Viewed by 4283 | PDF Full-text (678 KB) | HTML Full-text | XML Full-text
Abstract
The Alpha-fetoprotein (AFP) derived Growth Inhibitory Peptide (GIP) is a 34-amino acid segment of the full-length human AFP molecule that inhibits tumor growth and metastasis. The GIP-34 and its carboxy-terminal 8-mer segment, termed GIP-8, were found to be effective as anti-cancer therapeutic peptides [...] Read more.
The Alpha-fetoprotein (AFP) derived Growth Inhibitory Peptide (GIP) is a 34-amino acid segment of the full-length human AFP molecule that inhibits tumor growth and metastasis. The GIP-34 and its carboxy-terminal 8-mer segment, termed GIP-8, were found to be effective as anti-cancer therapeutic peptides against nine different human cancer types. Following the uptake of GIP-34 and GIP-8 into the cell cytoplasm, each follows slightly different signal transduction cascades en route to inhibitory pathways of tumor cell growth and proliferation. The parallel mechanisms of action of GIP-34 versus GIP-8 are demonstrated to involve interference of signaling transduction cascades that ultimately result in: (1) cell cycle S-phase/G2-phase arrest; (2) prevention of cyclin inhibitor degradation; (3) protection of p53 from inactivation by phosphorylation; and (4) blockage of K+ ion channels opened by estradiol and epidermal growth factor (EGF). The overall mechanisms of action of both peptides are discussed in light of their differing modes of cell attachment and uptake fortified by RNA microarray analysis and electrophysiologic measurements of cell membrane conductance and resistance. As a chemotherapeutic adjunct, the GIPs could potentially aid in alleviating the negative side effects of: (1) tamoxifen resistance, uterine hyperplasia/cancer, and blood clotting; (2) Herceptin antibody resistance and cardiac (arrest) arrhythmias; and (3) doxorubicin’s bystander cell toxicity. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
Open AccessReview
Clinical Trial Design for Testing the Stem Cell Model for the Prevention and Treatment of Cancer
Cancers 2011, 3(2), 2696-2708; https://doi.org/10.3390/cancers3022696
Received: 27 April 2011 / Revised: 7 June 2011 / Accepted: 8 June 2011 / Published: 20 June 2011
Cited by 3 | Viewed by 4526 | PDF Full-text (179 KB) | HTML Full-text | XML Full-text
Abstract
The cancer stem cell model introduces new strategies for the prevention and treatment of cancers. In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs [...] Read more.
The cancer stem cell model introduces new strategies for the prevention and treatment of cancers. In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs to reduce the risk of initiation of new tumors. Disease progression of established tumors could also potentially be inhibited by targeting the tumorigenic stem cells alone, rather than aiming to reduce overall tumor size. These new approaches mandate a change in the design of clinical trials and biomarkers chosen for efficacy assessment for preventative, neoadjuvant, adjuvant, and palliative treatments. Cancer treatments could be evaluated by assessing stem cell markers before and after treatment. Targeted stem cell specific treatment of cancers may not result in “complete” or “partial” responses radiologically, as stem cell targeting may not reduce the tumor bulk, but eliminate further tumorigenic potential. These changes are discussed using breast, pancreatic, and lung cancer as examples. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessArticle
Metastasizing, Luciferase Transduced MAT‑Lu Rat Prostate Cancer Models: Follow up of Bolus and Metronomic Therapy with Doxorubicin as Model Drug
Cancers 2011, 3(2), 2679-2695; https://doi.org/10.3390/cancers3022679
Received: 4 May 2011 / Revised: 16 May 2011 / Accepted: 16 June 2011 / Published: 17 June 2011
Cited by 1 | Viewed by 4881 | PDF Full-text (707 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The most fatal outcomes of prostate carcinoma (PCa) result from hormone-refractory variants of the tumor, especially from metastatic spread rather than from primary tumor burden. The goal of the study was to establish and apply rat MAT-Lu prostate cancer tumor models for improved [...] Read more.
The most fatal outcomes of prostate carcinoma (PCa) result from hormone-refractory variants of the tumor, especially from metastatic spread rather than from primary tumor burden. The goal of the study was to establish and apply rat MAT-Lu prostate cancer tumor models for improved non-invasive live follow up of tumor growth and metastasis by in vivo bioluminescence. We established luciferase transduced MAT-Lu rat PCa cells and studied tumor growth and metastatic processes in an ectopic as well as orthotopic setting. An intravenous bolus treatment with doxorubicin was used to demonstrate the basic applicability of in vivo imaging to follow up therapeutic intervention in these models. In vitro analysis of tissue homogenates confirmed major metastatic spread of subcutaneous tumors into the lung. Our sensitive method, however, for the first time detects metastasis also in lymph node (11/24), spleen (3/24), kidney (4/24), liver (5/24), and bone tissue (femur or spinal cord - 5/20 and 12/20, respectively). Preliminary data of orthotopic implantation (three animals) showed metastatic invasion to investigated organs in all animals but with varying preference (e.g., to lymph nodes). Intravenous bolus treatment of MAT-Lu PCa with doxorubicin reduced subcutaneous tumor growth by about 50% and the number of animals affected by metastatic lesions in lymph nodes (0/4), lung (3/6) or lumbar spine (0/2), as determined by in vivo imaging and in vitro analysis. Additionally, the possible applicability of the luciferase transduced MAT-Lu model(s) to study basic principles of metronomic therapies via jugular vein catheter, using newly established active microport pumping systems, is presented. Full article
(This article belongs to the Special Issue Prostate Cancer)
Open AccessReview
The Role of Epidermal Growth Factor Receptor Mutations and Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer
Cancers 2011, 3(2), 2667-2678; https://doi.org/10.3390/cancers3022667
Received: 28 April 2011 / Revised: 1 June 2011 / Accepted: 7 June 2011 / Published: 10 June 2011
Cited by 3 | Viewed by 4379 | PDF Full-text (198 KB) | HTML Full-text | XML Full-text
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) cases comprise approximately 85% of the lung cancer cases. Before the era of target therapy, platinum-based doublet chemotherapy only led to a median survival of 8–9 months and a [...] Read more.
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) cases comprise approximately 85% of the lung cancer cases. Before the era of target therapy, platinum-based doublet chemotherapy only led to a median survival of 8–9 months and a one-year survival of 30%–40% in patients with advanced NSCLC. In July 2002, gefitinib, a small-molecule epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), was approved for the treatment of patients with advanced NSCLC in Japan. After the widespread use of gefitinib in the treatment of NSCLC, there have been many new studies regarding the association between the clinical anticancer efficacy of gefitinib and the somatic EGFR mutation status in patients with NSCLC. This article summarizes the role of EGFR mutations in lung cancer and the use of EGFR antagonists in the treatment of lung cancer and its associated adverse effects. Full article
(This article belongs to the Special Issue Lung Cancer)
Open AccessReview
Glioblastoma Stem-Like Cells—Biology and Therapeutic Implications
Cancers 2011, 3(2), 2655-2666; https://doi.org/10.3390/cancers3022655
Received: 4 March 2011 / Revised: 4 May 2011 / Accepted: 31 May 2011 / Published: 10 June 2011
Cited by 21 | Viewed by 4680 | PDF Full-text (357 KB) | HTML Full-text | XML Full-text
Abstract
The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods [...] Read more.
The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods for optimizing the derivation and culturing of stem-like cells also known as tumor stem cells (TSCs) from patient-derived GBM tissue samples. The hallmarks of TSCs are that they must be able to self-renew and retain tumorigenicity. The isolation, optimization and derivation of TSCs as outlined in this review, will be important in understanding biology and therapeutic applications related to these cells. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview
Regulation of Autophagy by Kinases
Cancers 2011, 3(2), 2630-2654; https://doi.org/10.3390/cancers3022630
Received: 16 March 2011 / Revised: 15 May 2011 / Accepted: 27 May 2011 / Published: 9 June 2011
Cited by 86 | Viewed by 4829 | PDF Full-text (403 KB) | HTML Full-text | XML Full-text
Abstract
Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, [...] Read more.
Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets. Full article
Open AccessReview
Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies
Cancers 2011, 3(2), 2597-2629; https://doi.org/10.3390/cancers3022597
Received: 11 March 2011 / Revised: 2 May 2011 / Accepted: 31 May 2011 / Published: 9 June 2011
Cited by 53 | Viewed by 4147 | PDF Full-text (488 KB) | HTML Full-text | XML Full-text
Abstract
Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the [...] Read more.
Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview
State of the Art in Tumor Antigen and Biomarker Discovery
Cancers 2011, 3(2), 2554-2596; https://doi.org/10.3390/cancers3022554
Received: 6 April 2011 / Revised: 24 May 2011 / Accepted: 27 May 2011 / Published: 9 June 2011
Cited by 13 | Viewed by 4534 | PDF Full-text (417 KB) | HTML Full-text | XML Full-text
Abstract
Our knowledge of tumor immunology has resulted in multiple approaches for the treatment of cancer. However, a gap between research of new tumors markers and development of immunotherapy has been established and very few markers exist that can be used for treatment. The [...] Read more.
Our knowledge of tumor immunology has resulted in multiple approaches for the treatment of cancer. However, a gap between research of new tumors markers and development of immunotherapy has been established and very few markers exist that can be used for treatment. The challenge is now to discover new targets for active and passive immunotherapy. This review aims at describing recent advances in biomarkers and tumor antigen discovery in terms of antigen nature and localization, and is highlighting the most recent approaches used for their discovery including “omics” technology. Full article
(This article belongs to the Special Issue Cancer Vaccines and Immunotherapy)
Open AccessArticle
Tumor Cell Seeding During Surgery—Possible Contribution to Metastasis Formations
Cancers 2011, 3(2), 2540-2553; https://doi.org/10.3390/cancers3022540
Received: 1 April 2011 / Revised: 23 May 2011 / Accepted: 26 May 2011 / Published: 8 June 2011
Cited by 7 | Viewed by 4102 | PDF Full-text (317 KB) | HTML Full-text | XML Full-text
Abstract
In spite of optimal local control in breast cancer, distant metastases can develop as a systemic part of this disease. Surgery is suspected to contribute to metastasis formation activating dormant tumor cells. Here we add data that seeding of cells during surgery may [...] Read more.
In spite of optimal local control in breast cancer, distant metastases can develop as a systemic part of this disease. Surgery is suspected to contribute to metastasis formation activating dormant tumor cells. Here we add data that seeding of cells during surgery may add to the risk of metastasis formation. The change in circulating epithelial tumor cells (CETC) was monitored in 66 breast cancer patients operated on with breast conserving surgery or mastectomy and during the further course of the disease, analyzing CETC from unseparated white blood cells stained with FITC-anti-EpCAM. An increase in cell numbers lasting until the start of chemotherapy was observed in about one third of patients. It was more preeminent in patients with low numbers of CETC before surgery and, surprisingly, in patients without involved lymph nodes. Patients with the previously reported behavior—Reincrease in cell numbers during adjuvant chemotherapy and subsequent further increase during maintenance therapy—were at increased risk of relapse. In addition to tumor cells already released during growth of the tumor, cell seeding during surgery may contribute to the early peak of relapses observed after removal of the primary tumor and chemotherapy may only marginally postpone relapse in patients with aggressively growing tumors. Full article
Open AccessReview
Cell Death Pathways in Photodynamic Therapy of Cancer
Cancers 2011, 3(2), 2516-2539; https://doi.org/10.3390/cancers3022516
Received: 24 March 2011 / Revised: 26 April 2011 / Accepted: 3 May 2011 / Published: 3 June 2011
Cited by 213 | Viewed by 8666 | PDF Full-text (655 KB) | HTML Full-text | XML Full-text
Abstract
Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic [...] Read more.
Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessArticle
Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer
Cancers 2011, 3(2), 2501-2515; https://doi.org/10.3390/cancers3022501
Received: 4 February 2011 / Revised: 25 April 2011 / Accepted: 17 May 2011 / Published: 25 May 2011
Cited by 2 | Viewed by 4709 | PDF Full-text (539 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited [...] Read more.
Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment- and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Graphical abstract

Open AccessReview
Targeting the Mammalian Target of Rapamycin (mTOR) in Cancer Therapy: Lessons from Past and Future Perspectives
Cancers 2011, 3(2), 2478-2500; https://doi.org/10.3390/cancers3022478
Received: 6 April 2011 / Revised: 13 May 2011 / Accepted: 16 May 2011 / Published: 24 May 2011
Cited by 22 | Viewed by 4909 | PDF Full-text (544 KB) | HTML Full-text | XML Full-text
Abstract
Over the last decade, extensive studies have been made to understand the role played by the mammalian target of rapamycin (mTOR) in cancer. Knowledge in this field has been gained from discoveries in basic research as well as from observations made in patients [...] Read more.
Over the last decade, extensive studies have been made to understand the role played by the mammalian target of rapamycin (mTOR) in cancer. Knowledge in this field has been gained from discoveries in basic research as well as from observations made in patients treated with allosteric mTOR inhibitors such as rapamycin. Despite promising preclinical studies, targeting mTOR in cancer therapy has shown limited clinical benefits so far. However, recent findings have revealed the complexity of the functions of mTOR in cancer and have helped develop new strategies to improve the anticancer efficacy of mTOR inhibitors. In particular, a complex network between mTOR and other signaling pathways has been identified that influences the anticancer efficacy of mTOR inhibitors. In addition, an emerging role of mTOR in the tumor microenvironment has been suggested. In this review, we confront the major findings that have been made in the past, both in experimental settings as well as in clinical trials. We further review the strategies that have been designed to further improve the efficacy of therapies targeting mTOR. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
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Graphical abstract

Open AccessReview
Roles of StearoylCoA Desaturase-1 in the Regulation of Cancer Cell Growth, Survival and Tumorigenesis
Cancers 2011, 3(2), 2462-2477; https://doi.org/10.3390/cancers3022462
Received: 21 March 2011 / Revised: 27 April 2011 / Accepted: 11 May 2011 / Published: 20 May 2011
Cited by 31 | Viewed by 5541 | PDF Full-text (299 KB) | HTML Full-text | XML Full-text
Abstract
The development and maintenance of defining features of cancer, such as unremitting cell proliferation, evasion of programmed cell death, and the capacity for colonizing local tissues and distant organs, demand a massive production of structural, signaling and energy-storing lipid biomolecules of appropriate fatty [...] Read more.
The development and maintenance of defining features of cancer, such as unremitting cell proliferation, evasion of programmed cell death, and the capacity for colonizing local tissues and distant organs, demand a massive production of structural, signaling and energy-storing lipid biomolecules of appropriate fatty acid composition. Due to constitutive activation of fatty acid biosynthesis, cancer cell lipids are enriched with saturated (SFA) and, in particular, monounsaturated fatty acids (MUFA), which are generated by StearoylCoA desaturase-1, the main enzyme that transforms SFA into MUFA. An increasing number of experimental and epidemiological studies suggest that high levels of SCD1 activity is a major factor in establishing the biochemical and metabolic perturbations that favors the oncogenic process. This review examines evidence that suggests the critical implication of SCD1 in the modulation of multiple biological mechanisms, specifically lipid biosynthesis and proliferation and survival signaling pathways that contribute to the development and progression of cancer. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Graphical abstract

Open AccessReview
Epidermal Growth Factor Receptor (EGFR) Crosstalks in Liver Cancer
Cancers 2011, 3(2), 2444-2461; https://doi.org/10.3390/cancers3022444
Received: 20 April 2011 / Revised: 6 May 2011 / Accepted: 12 May 2011 / Published: 18 May 2011
Cited by 29 | Viewed by 5956 | PDF Full-text (360 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocarcinogenesis is a complex multistep process in which many different molecular pathways have been implicated. Hepatocellular carcinoma (HCC) is refractory to conventional chemotherapeutic agents, and the new targeted therapies are meeting with limited success. Interreceptor crosstalk and the positive feedback between different signaling [...] Read more.
Hepatocarcinogenesis is a complex multistep process in which many different molecular pathways have been implicated. Hepatocellular carcinoma (HCC) is refractory to conventional chemotherapeutic agents, and the new targeted therapies are meeting with limited success. Interreceptor crosstalk and the positive feedback between different signaling systems are emerging as mechanisms of targeted therapy resistance. The identification of such interactions is therefore of particular relevance to improve therapeutic efficacy. Among the different signaling pathways activated in hepatocarcinogenesis the epidermal growth factor receptor (EGFR) system plays a prominent role, being recognized as a “signaling hub” where different extracellular growth and survival signals converge. EGFR can be transactivated in response to multiple heterologous ligands through the physical interaction with multiple receptors, the activity of intracellular kinases or the shedding of EGFR-ligands. In this article we review the crosstalk between the EGFR and other signaling pathways that could be relevant to liver cancer development and treatment. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
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Graphical abstract

Open AccessArticle
Comparison of Dose Response Models for Predicting Normal Tissue Complications from Cancer Radiotherapy: Application in Rat Spinal Cord
Cancers 2011, 3(2), 2421-2443; https://doi.org/10.3390/cancers3022421
Received: 14 March 2011 / Revised: 20 April 2011 / Accepted: 10 May 2011 / Published: 18 May 2011
Cited by 10 | Viewed by 4378 | PDF Full-text (910 KB) | HTML Full-text | XML Full-text
Abstract
Seven different radiobiological dose-response models have been compared with regard to their ability to describe experimental data. The first four models, namely the critical volume, the relative seriality, the inverse tumor and the critical element models are mainly based on cell survival biology. [...] Read more.
Seven different radiobiological dose-response models have been compared with regard to their ability to describe experimental data. The first four models, namely the critical volume, the relative seriality, the inverse tumor and the critical element models are mainly based on cell survival biology. The other three models: the Lyman (Gaussian distribution), the parallel architecture and the Weibull distribution models are semi-empirical and rather based on statistical distributions. The maximum likelihood estimation was used to fit the models to experimental data and the χ2-distribution, AIC criterion and F-test were applied to compare the goodness-of-fit of the models. The comparison was performed using experimental data for rat spinal cord injury. Both the shape of the dose-response curve and the ability of handling the volume dependence were separately compared for each model. All the models were found to be acceptable in describing the present experimental dataset (p > 0.05). For the white matter necrosis dataset, the Weibull and Lyman models were clearly superior to the other models, whereas for the vascular damage case, the Relative Seriality model seems to have the best performance although the Critical volume, Inverse tumor, Critical element and Parallel architecture models gave similar results. Although the differences between many of the investigated models are rather small, they still may be of importance in indicating the advantages and limitations of each particular model. It appears that most of the models have favorable properties for describing dose-response data, which indicates that they may be suitable to be used in biologically optimized intensity modulated radiation therapy planning, provided a proper estimation of their radiobiological parameters had been performed for every tissue and clinical endpoint. Full article
(This article belongs to the Special Issue Radiation and Cancers)
Open AccessReview
Differentiation Therapy of Acute Myeloid Leukemia
Cancers 2011, 3(2), 2402-2420; https://doi.org/10.3390/cancers3022402
Received: 30 January 2011 / Revised: 29 April 2011 / Accepted: 5 May 2011 / Published: 16 May 2011
Cited by 11 | Viewed by 4801 | PDF Full-text (340 KB) | HTML Full-text | XML Full-text
Abstract
Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that [...] Read more.
Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that a variety of agents stimulate differentiation of the cell lines isolated from leukemic patients. One of the differentiation-inducing agents, all-trans retinoic acid (ATRA), which can induce granulocytic differentiation in myeloid leukemic cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a t(15;17)(q22;q12) chromosomal translocation. Because differentiation therapy using ATRA has significantly improved prognosis for patients with APL, many efforts have been made to find alternative differentiating agents. Since 1,25-dihydroxyvitamin D3 (1,25D) is capable of inducing in vitro monocyte/macrophage differentiation of myeloid leukemic cells, clinical trials have been performed to estimate its potential to treat patients with AML or myelodysplastic syndrome (MDS). Unfortunately therapeutic concentrations of 1,25D can induce potentially fatal systemic hypercalcemia, thus limiting clinical utility of that compound. Attempts to overcome this problem have focused on the synthesis of 1,25D analogs (VDAs) which retain differentiation inducing potential, but lack its hypercalcemic effects. This review aims to discuss current problems and potential solutions in differentiation therapy of AML. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview
Systematic Review of Breast Cancer Biology in Developing Countries (Part 2): Asian Subcontinent and South East Asia
Cancers 2011, 3(2), 2382-2401; https://doi.org/10.3390/cancers3022382
Received: 19 January 2011 / Revised: 21 March 2011 / Accepted: 14 April 2011 / Published: 13 May 2011
Cited by 15 | Viewed by 4015 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
There has been no systematic appraisal of ethnicity-based variations in breast cancer (BC) biology amongst women from developing countries. A qualitative systematic review was conducted of breast cancer size, stage, grade, histological type, extra-mammary involvement, hormone receptor status as well as patient demographics. [...] Read more.
There has been no systematic appraisal of ethnicity-based variations in breast cancer (BC) biology amongst women from developing countries. A qualitative systematic review was conducted of breast cancer size, stage, grade, histological type, extra-mammary involvement, hormone receptor status as well as patient demographics. This review includes patients from Africa, the Middle East, Eastern Europe, Mexico, the Caribbean and South America. BC in these regions present at an earlier age with large aggressive tumours. Distant metastases are frequently present at the time of diagnosis. African women have a higher frequency of triple negative tumours. Over half of Middle Eastern women have lymph node involvement at the time of diagnosis. Despite experiencing a lower incidence compared to the Ashkenazi Jewish population, Palestinian women have poorer five-year survival outcomes. The majority of women from Mexico and South America have stage two or three disease whilst over sixty percent of women from Eastern Europe have either stage one or stage two disease. The biological characteristics of BC in the Caribbean cannot be fully assessed due to a paucity of data from the region. BC amongst the developing world is characterised by an early peak age of onset with aggressive biological characteristics. Strategies that improve breast cancer awareness, address amenable risk factors and improve early detection are essential. Full article
Open AccessReview
Systematic Review of Breast Cancer Biology in Developing Countries (Part 1): Africa, the Middle East, Eastern Europe, Mexico, the Caribbean and South America
Cancers 2011, 3(2), 2358-2381; https://doi.org/10.3390/cancers3022358
Received: 19 January 2011 / Revised: 21 March 2011 / Accepted: 14 April 2011 / Published: 13 May 2011
Cited by 17 | Viewed by 4868 | PDF Full-text (285 KB) | HTML Full-text | XML Full-text
Abstract
There has been no systematic appraisal of ethnicity-based variations in breast cancer (BC) biology amongst women from developing countries. A qualitative systematic review was conducted of breast cancer size, stage, grade, histological type, extra-mammary involvement, hormone receptor status as well as patient demographics. [...] Read more.
There has been no systematic appraisal of ethnicity-based variations in breast cancer (BC) biology amongst women from developing countries. A qualitative systematic review was conducted of breast cancer size, stage, grade, histological type, extra-mammary involvement, hormone receptor status as well as patient demographics. This review includes patients from Africa, the Middle East, Eastern Europe, Mexico, the Caribbean and South America. BC in these regions present at an earlier age with large aggressive tumours. Distant metastases are frequently present at the time of diagnosis. African women have a higher frequency of triple negative tumours. Over half of Middle Eastern women have lymph node involvement at the time of diagnosis. Despite experiencing a lower incidence compared to the Ashkenazi Jewish population, Palestinian women have poorer five-year survival outcomes. The majority of women from Mexico and South America have stage two or three disease whilst over sixty percent of women from Eastern Europe have either stage one or stage two disease. The biological characteristics of BC in the Caribbean cannot be fully assessed due to a paucity of data from the region. BC amongst the developing world is characterised by an early peak age of onset with aggressive biological characteristics. Strategies that improve breast cancer awareness, address amenable risk factors and improve early detection are essential. Full article
Open AccessReview
Tomato Lycopene and Lung Cancer Prevention: From Experimental to Human Studies
Cancers 2011, 3(2), 2333-2357; https://doi.org/10.3390/cancers3022333
Received: 7 March 2011 / Revised: 28 April 2011 / Accepted: 3 May 2011 / Published: 11 May 2011
Cited by 37 | Viewed by 5623 | PDF Full-text (286 KB) | HTML Full-text | XML Full-text
Abstract
Increasing evidence suggests that tomato lycopene may be preventive against the formation and the development of lung cancer. Experimental studies demonstrated that lycopene may inhibit the growth of several cultured lung cancer cells and prevent lung tumorigenesis in animal models through various mechanisms, [...] Read more.
Increasing evidence suggests that tomato lycopene may be preventive against the formation and the development of lung cancer. Experimental studies demonstrated that lycopene may inhibit the growth of several cultured lung cancer cells and prevent lung tumorigenesis in animal models through various mechanisms, including a modulation of redox status, cell cycle arrest and/or apoptosis induction, a regulation of growth factor signaling, changes in cell growth-related enzymes, an enhancement of gap junction communication and a prevention of smoke-induced inflammation. In addition, lycopene also inhibited cell invasion, angiogenesis, and metastasis. Several lycopene metabolites have been identified, raising the question as to whether the preventive effects of lycopene on cancer risk is, at least in part, due to its metabolites. Despite these promising reports, it is difficult at the moment to directly relate available experimental data to human pathophysiology. More well controlled clinical intervention trials are needed to further clarify the exact role of lycopene in the prevention of lung cancer cell growth. Such studies should take into consideration subject selection, specific markers of analysis, the levels of carotenoids being tested, metabolism and isomerization of lycopene, interaction with other bioactive food components. This article reviews data on the cancer preventive activities of lycopene, possible mechanisms involved, and the relationship between lycopene consumption and human cancer risk. Full article
(This article belongs to the Special Issue Lung Cancer)
Open AccessArticle
Different Aspects of Self-Reported Quality of Life in 450 German Melanoma Survivors
Cancers 2011, 3(2), 2316-2332; https://doi.org/10.3390/cancers3022316
Received: 30 January 2011 / Revised: 15 April 2011 / Accepted: 28 April 2011 / Published: 11 May 2011
Cited by 8 | Viewed by 4228 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
The present study was aimed at assessing quality of life (QoL) in a total of 450 melanoma patients who filled out the EORTC QLQ-C30 (Q1; 15 months post diagnosis) as part of the OVIS Study. Follow-up questionnaires (Q2) were administered two years after [...] Read more.
The present study was aimed at assessing quality of life (QoL) in a total of 450 melanoma patients who filled out the EORTC QLQ-C30 (Q1; 15 months post diagnosis) as part of the OVIS Study. Follow-up questionnaires (Q2) were administered two years after Q1. The analyses presented herein were based on the following assumptions: QoL of melanoma patients is worse than that of a German reference population. Further, both tumor location and tumor stage have an influence on self-reported QoL, with patients with tumors located on face, head, neck, and advanced tumor stage (T3/T4) reporting the worst QoL levels. Finally, patients’ QoL improves over time based on the theory of disease adaptation. In contrast to the above assumptions, with the exception of global health/QoL scores, differences between OVIS and the reference population were below the minimal clinical important difference of ten points. Furthermore, no clinically meaningful differences were found between patients after stratifying our data by tumor location and tumor stage. Finally, no clinically relevant changes were seen between Q1 and Q2 across all scales of the EORTC QLQ-C30. However, when data were stratified by patients with stable disease versus those with progression, clinically relevant differences were found between Q1 and Q2 predominantly in women in the latter group regarding emotional function, insomnia, dyspnoea, and fatigue. The lack of clinically meaningful differences across strata (tumor location; tumor stage), time, and patients compared to a reference population is surprising. However, it is possible that the instrument used, a generic QoL instrument, is generally not sensitive enough to detect differences in melanoma patients. Our findings may further be explained by the fact that all patients included in our sample had been diagnosed well before Q1, i.e., main illness adaptation processes may have occurred before study entry. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview
The Role of High Frequency Dynamic Threshold (HiDT) Serum Carcinoembryonic Antigen (CEA) Measurements in Colorectal Cancer Surveillance: A (Revisited) Hypothesis Paper
Cancers 2011, 3(2), 2302-2315; https://doi.org/10.3390/cancers3022302
Received: 25 January 2011 / Revised: 22 April 2011 / Accepted: 4 May 2011 / Published: 11 May 2011
Cited by 8 | Viewed by 4213 | PDF Full-text (194 KB) | HTML Full-text | XML Full-text
Abstract
Following curative treatment for colorectal cancer (CRC), 30% to 50% of patients will develop recurrent disease. For CRC there are several lines of evidence supporting the hypothesis that early detection of metachronous disease offers a second opportunity for cure. This paper revisits the [...] Read more.
Following curative treatment for colorectal cancer (CRC), 30% to 50% of patients will develop recurrent disease. For CRC there are several lines of evidence supporting the hypothesis that early detection of metachronous disease offers a second opportunity for cure. This paper revisits the potential role of serum carcinoembryonic antigen (CEA) in follow-up. A comprehensive review of the literature (1978–2008) demonstrates that the initial promise of serum CEA as an effective surveillance tool has been tarnished through perpetuation of poorly designed studies. Specific limitations included: testing CEA as only an ‘add-on’ diagnostic tool; lack of standardization of threshold values; use of static thresholds; too low measurement frequency. Major changes in localizing imaging techniques and treatment of metastatic CRC further cause a decrease of clinical applicability of past trial outcomes. In 1982, Staab hypothesized that the optimal benefit of serum CEA as a surveillance tool is through high-frequency triage using a dynamic threshold (HiDT). Evidence supporting this hypothesis was found in the biochemical characteristics of serum CEA and retrospective studies showing the superior predictive value of a dynamic threshold. A multi-centred randomized phase III study optimizing the usage of HiDT against resectability of recurrent disease is commencing recruitment in the Netherlands. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessArticle
Neoadjuvant Therapy in Patients with Pancreatic Cancer: A Disappointing Therapeutic Approach?
Cancers 2011, 3(2), 2286-2301; https://doi.org/10.3390/cancers3022286
Received: 17 March 2011 / Revised: 9 April 2011 / Accepted: 26 April 2011 / Published: 9 May 2011
Cited by 1 | Viewed by 4948 | PDF Full-text (199 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates [...] Read more.
Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessArticle
Tetrandrine, a Compound Common in Chinese Traditional Medicine, Preferentially Kills Breast Cancer Tumor Initiating Cells (TICs) In Vitro
Cancers 2011, 3(2), 2274-2285; https://doi.org/10.3390/cancers3022274
Received: 12 January 2011 / Revised: 12 April 2011 / Accepted: 15 April 2011 / Published: 4 May 2011
Cited by 13 | Viewed by 5675 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
Tetrandrine is a bisbenzylisoquinoline alkaloid found in Stephania tetrandra, a Chinese medicine commonly used as an anti-inflammatory. It has extensive pharmacological activity, including positive ion channel blockade and inhibition of multiple drug resistance proteins. These activities are very similar to that of [...] Read more.
Tetrandrine is a bisbenzylisoquinoline alkaloid found in Stephania tetrandra, a Chinese medicine commonly used as an anti-inflammatory. It has extensive pharmacological activity, including positive ion channel blockade and inhibition of multiple drug resistance proteins. These activities are very similar to that of salinomycin, a known drug targeting breast cancer initiation cells (TICs). Herein, we tested tetrandrine targeting of breast cancer TICs. SUM-149, an inflammatory breast cancer cell line and SUM-159, a non-inflammatory metaplastic breast cancer cell line were used in these studies. In proliferation assays using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), we found that the IC50 for inhibition of proliferation is 15.3 ± 4.1 µM for SUM-149 and 24.3 ± 2.1 µM for SUM-159 cells. Tetrandrine also inhibited mammosphere formation, a surrogate for breast cancer TICs growth in vitro with IC50 around 1 µM for SUM-149 and around 2 µM for SUM-159 cells. Tetrandrine has similar effects on the mammosphere formation from cells isolated from fresh patient sample. Moreover, tetrandrine decreases the aldehyde dehydrogenase (ALDH) positive population in SUM-159 by 45% ± 5.45% P = 0.005. In summary, tetrandrine demonstrates significant efficacy against in vitro surrogates for inflammatory and aggressive breast cancer TICs. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview
Targeted Therapy in Nonmelanoma Skin Cancers
Cancers 2011, 3(2), 2255-2273; https://doi.org/10.3390/cancers3022255
Received: 11 March 2011 / Revised: 11 April 2011 / Accepted: 26 April 2011 / Published: 3 May 2011
Cited by 7 | Viewed by 4298 | PDF Full-text (260 KB) | HTML Full-text | XML Full-text
Abstract
Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall [...] Read more.
Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview
Targeted Therapy for Biliary Tract Cancer
Cancers 2011, 3(2), 2243-2254; https://doi.org/10.3390/cancers3022243
Received: 4 March 2011 / Revised: 10 April 2011 / Accepted: 13 April 2011 / Published: 3 May 2011
Cited by 7 | Viewed by 4373 | PDF Full-text (229 KB) | HTML Full-text | XML Full-text
Abstract
It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine [...] Read more.
It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine was reported to show survival benefits over gemcitabine alone in randomized clinical trials conducted in the United Kingdom and Japan. Thus, the combination of cisplatin plus gemcitabine is now recognized as the standard therapy for unresectable biliary tract cancer. One of the next issues that need to be addressed is whether molecular targeted agents might also be effective against biliary tract cancer. Although some targeted agents have been investigated as monotherapy for first-line chemotherapy, none were found to exert satisfactory efficacy. On the other hand, monoclonal antibodies such as bevacizumab and cetuximab have also been investigated in combination with a gemcitabine-based regimen and have been demonstrated to show promising activity. Furthermore, clinical trials using new targeted agents for biliary tract cancer are also proposed. This cancer is a relatively rare and heterogeneous tumor consisting of cholangiocarcinoma and gallbladder carcinoma. Therefore, a large randomized clinical trial is necessary to confirm the efficacy of chemotherapy, and international collaboration is important. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessArticle
Therapeutic Response in Patients with Advanced Malignancies Treated with Combined Dendritic Cell–Activated T Cell Based Immunotherapy and Intensity–Modulated Radiotherapy
Cancers 2011, 3(2), 2223-2242; https://doi.org/10.3390/cancers3022223
Received: 7 March 2011 / Revised: 14 April 2011 / Accepted: 19 April 2011 / Published: 28 April 2011
Cited by 6 | Viewed by 5348 | PDF Full-text (576 KB) | HTML Full-text | XML Full-text
Abstract
Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional [...] Read more.
Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies. Full article
(This article belongs to the Special Issue Cancer Vaccines and Immunotherapy)
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Open AccessReview
Cell Autonomous and Non-Autonomous Functions of IKKβ and NF-κB during the Pathogenesis of Gastrointestinal Tumors
Cancers 2011, 3(2), 2214-2222; https://doi.org/10.3390/cancers3022214
Received: 6 February 2011 / Revised: 4 April 2011 / Accepted: 14 April 2011 / Published: 28 April 2011
Cited by 1 | Viewed by 6210 | PDF Full-text (633 KB) | HTML Full-text | XML Full-text
Abstract
Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types [...] Read more.
Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types of tumors. However, NF-κB has a distinct role in cancer cells and in inflammatory cells. While in tumor cells NF-κB controls cell survival, in inflammatory cells NF-κB activates genes that encode pro-inflammatory cytokines which further act in a paracrine manner within the tumor microenvironment to contribute to tumorigenesis. Inactivation of NF-κB can also reduce chemoresistance and radioresistance of cancer cells. Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Graphical abstract

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