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Cancers, Volume 6, Issue 3 (September 2014) – 30 articles , Pages 1220-1820

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707 KiB  
Review
Human Papillomavirus Induced Transformation in Cervical and Head and Neck Cancers
by Allie K. Adams, Trisha M. Wise-Draper and Susanne I. Wells
Cancers 2014, 6(3), 1793-1820; https://doi.org/10.3390/cancers6031793 - 15 Sep 2014
Cited by 43 | Viewed by 8188
Abstract
Human papillomavirus (HPV) is one of the most widely publicized and researched pathogenic DNA viruses. For decades, HPV research has focused on transforming viral activities in cervical cancer. During the past 15 years, however, HPV has also emerged as a major etiological agent [...] Read more.
Human papillomavirus (HPV) is one of the most widely publicized and researched pathogenic DNA viruses. For decades, HPV research has focused on transforming viral activities in cervical cancer. During the past 15 years, however, HPV has also emerged as a major etiological agent in cancers of the head and neck, in particular squamous cell carcinoma. Even with significant strides achieved towards the screening and treatment of cervical cancer, and preventive vaccines, cervical cancer remains the leading cause of cancer-associated deaths for women in developing countries. Furthermore, routine screens are not available for those at risk of head and neck cancer. The current expectation is that HPV vaccination will prevent not only cervical, but also head and neck cancers. In order to determine if previous cervical cancer models for HPV infection and transformation are directly applicable to head and neck cancer, clinical and molecular disease aspects must be carefully compared. In this review, we briefly discuss the cervical and head and neck cancer literature to highlight clinical and genomic commonalities. Differences in prognosis, staging and treatment, as well as comparisons of mutational profiles, viral integration patterns, and alterations in gene expression will be addressed. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
427 KiB  
Review
Drug Resistance in Cancer: An Overview
by Genevieve Housman, Shannon Byler, Sarah Heerboth, Karolina Lapinska, Mckenna Longacre, Nicole Snyder and Sibaji Sarkar
Cancers 2014, 6(3), 1769-1792; https://doi.org/10.3390/cancers6031769 - 05 Sep 2014
Cited by 1686 | Viewed by 49386
Abstract
Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, [...] Read more.
Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study. Full article
(This article belongs to the Special Issue Cancer Drug Resistance)
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1169 KiB  
Article
Circulating Biomarkers in Advanced Colorectal Cancer Patients Randomly Assigned to Three Bevacizumab-Based Regimens
by Antonia Martinetti, Rosalba Miceli, Elisa Sottotetti, Maria Di Bartolomeo, Filippo De Braud, Arpine Gevorgyan, Katia Fiorella Dotti, Emilio Bajetta, Manuela Campiglio, Francesca Bianchi, Giacomo Bregni and Filippo Pietrantonio
Cancers 2014, 6(3), 1753-1768; https://doi.org/10.3390/cancers6031753 - 29 Aug 2014
Cited by 16 | Viewed by 5818
Abstract
The need to identify biomarkers for bevacizumab-based treatment in advanced colorectal cancer is imperative. The aim of this study was to investigate the prognostic role of circulating VEGF, PDGF, SDF-1, osteopontin and CEA in patients randomly assigned to three bevacizumab-based regimens. Plasma samples [...] Read more.
The need to identify biomarkers for bevacizumab-based treatment in advanced colorectal cancer is imperative. The aim of this study was to investigate the prognostic role of circulating VEGF, PDGF, SDF-1, osteopontin and CEA in patients randomly assigned to three bevacizumab-based regimens. Plasma samples from 50 patients treated at a single Institution were analysed using the multiplex assay BioPlex™ 2200 (Bio-Rad Laboratories, Inc, Berkeley, CA, USA) at baseline, before first three cycles and subsequently every three cycles until disease progression. Prognostic analyses of baseline values were performed using multivariable Cox models, including disease extension >10 cm or ≤10 cm (measured as the sum of the diameters for all target lesions) as adjustment factor. The association between progression-free and overall survival and biomarkers modulation during treatment was studied using multivariable Cox models, which included summary statistics synthesizing during-treatment modulation together with disease extension. The biomarkers significantly associated with disease extension were baseline CEA (p = 0.012) and SDF-1 (p = 0.030). High values of VEGF and SDF-1 tended to be associated with worse prognosis, especially in terms of overall survival. The negative prognostic trend was more marked for baseline CEA as compared to other biomarkers; increasing values during treatment was significantly related to worse prognosis independently of disease extension (p = 0.007 and 0.016 for progression-free and overall survival, respectively). VEGF is related to bevacizumab pharmacodynamics and is associated to other angiogenic cytokines; some of the proposed biomarkers such as SDF-1 and CEA should be further validated for prognosis assessment and monitoring of bevacizumab-based treatment of advanced colorectal cancer. Full article
(This article belongs to the Special Issue Cancer Drug Resistance)
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1294 KiB  
Article
The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models
by Friedhelm Bladt, Manja Friese-Hamim, Christian Ihling, Claudia Wilm and Andree Blaukat
Cancers 2014, 6(3), 1736-1752; https://doi.org/10.3390/cancers6031736 - 19 Aug 2014
Cited by 56 | Viewed by 10366
Abstract
The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy [...] Read more.
The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling. Full article
(This article belongs to the Special Issue MET in Cancer)
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527 KiB  
Article
Tobacco Exposure and Complications in Conservative Laryngeal Surgery
by Francesca Romana Fiorini, Alberto Deganello, Guglielmo Larotonda, Giuditta Mannelli and Oreste Gallo
Cancers 2014, 6(3), 1727-1735; https://doi.org/10.3390/cancers6031727 - 19 Aug 2014
Cited by 9 | Viewed by 5569
Abstract
Smoking is an important risk factor in the development of head and neck cancer. However, little is known about its effects on postoperative complications in head and neck cancer surgery. We performed a retrospective analysis on 535 consecutive laryngeal cancer patients submitted to [...] Read more.
Smoking is an important risk factor in the development of head and neck cancer. However, little is known about its effects on postoperative complications in head and neck cancer surgery. We performed a retrospective analysis on 535 consecutive laryngeal cancer patients submitted to open partial laryngectomy at the Otolaryngology-Head and Neck Surgery Department of Florence University to evaluate a possible correlation between smoking and surgical complications. Patients were grouped in non smokers and smokers and evaluated for airway, swallowing, local and fistula complications by multivariate analysis: 507 (95%) patients were smokers, 69% presented supraglottic, 30% glottic and 1% transglottic cancer. The most common operation was supraglottic horizontal laryngectomy in 58%, followed by supracricoid partial laryngectomy in 27% and frontolateral hemilaryngectomy in 15% of cases. The incidence of overall complications was 30%, airway complications representing the most frequent (14%), followed by swallowing (7%), local (6%) and fistula complications (3%). Smokers developed more local complications (p = 0.05, univariate, p = 0.04, multivariate analysis) and pharyngocutaneous fistula (p = 0.01, univariate, p = 0.03, multivariate analysis). Full article
(This article belongs to the Special Issue Tobacco-related Cancers)
723 KiB  
Review
Human Papillomavirus in Head and Neck Cancer
by Anna Rosa Garbuglia
Cancers 2014, 6(3), 1705-1726; https://doi.org/10.3390/cancers6031705 - 18 Aug 2014
Cited by 31 | Viewed by 9344
Abstract
Human papillomavirus (HPV) is currently considered to be a major etiologic factor, in addition to tobacco and alcohol, for oropharyngeal cancer (OPC) development. HPV positive OPCs are epidemiologically distinct from HPV negative ones, and are characterized by younger age at onset, male predominance, [...] Read more.
Human papillomavirus (HPV) is currently considered to be a major etiologic factor, in addition to tobacco and alcohol, for oropharyngeal cancer (OPC) development. HPV positive OPCs are epidemiologically distinct from HPV negative ones, and are characterized by younger age at onset, male predominance, and strong association with sexual behaviors. HPV16 is the most prevalent types in oral cavity cancer (OCC), moreover the prevalence of beta, and gamma HPV types is higher than that of alpha HPV in oral cavity. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
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Article
Oral Human Papillomavirus (HPV) Infection among Unvaccinated High-Risk Young Adults
by Gypsyamber D'Souza, Nicole Kluz, Alicia Wentz, Renee M. Youngfellow, Anne Griffioen, Emily Stammer, Yingshi Guo, Weihong Xiao and Maura L. Gillison
Cancers 2014, 6(3), 1691-1704; https://doi.org/10.3390/cancers6031691 - 14 Aug 2014
Cited by 27 | Viewed by 6937
Abstract
Oral HPV infection, the cause of most oropharyngeal cancer in the U.S., is not well studied among high-risk young adults. Men (n = 340) and women (n = 270) aged 18–25 years attending Baltimore County STD clinics were recruited if they [...] Read more.
Oral HPV infection, the cause of most oropharyngeal cancer in the U.S., is not well studied among high-risk young adults. Men (n = 340) and women (n = 270) aged 18–25 years attending Baltimore County STD clinics were recruited if they declined HPV vaccination. Each participant had a 30-second oral rinse and gargle sample tested for 37 types of HPV DNA, and a risk-factor survey. Factors associated with prevalent infection were explored using log binomial regression. Men had higher prevalence of any oral HPV (15.3% vs. 7.8%, p = 0.004) and vaccine-type oral HPV (i.e., HPV16/18/6/11: 5.0% vs. 1.1%, p = 0.007) infection than women. In multivariate analysis, male gender (aPR = 1.93, 95% CI = 1.10–3.39), number of recent oral sex partners (p-trend = 0.013) and having ever performed oral sex on a woman (aPR = 1.73, 95% CI = 1.06–2.82) were associated with increased oral HPV prevalence. Performing oral sex on a woman may confer higher risk of oral HPV acquisition than performing oral sex on a man. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
2746 KiB  
Review
Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment
by Theerawut Chanmee, Pawared Ontong, Kenjiro Konno and Naoki Itano
Cancers 2014, 6(3), 1670-1690; https://doi.org/10.3390/cancers6031670 - 13 Aug 2014
Cited by 1152 | Viewed by 42218
Abstract
During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, [...] Read more.
During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy. Full article
(This article belongs to the Special Issue Tumor Associated Macrophages)
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2256 KiB  
Review
The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?
by Marjorie Boissinot, Mathias Vilaine and Sylvie Hermouet
Cancers 2014, 6(3), 1631-1669; https://doi.org/10.3390/cancers6031631 - 12 Aug 2014
Cited by 26 | Viewed by 12076
Abstract
Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid [...] Read more.
Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs). Full article
(This article belongs to the Special Issue MET in Cancer)
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470 KiB  
Review
Epstein-Barr Virus-Encoded RNAs: Key Molecules in Viral Pathogenesis
by Dai Iwakiri
Cancers 2014, 6(3), 1615-1630; https://doi.org/10.3390/cancers6031615 - 06 Aug 2014
Cited by 50 | Viewed by 10499
Abstract
The Epstein-Barr virus (EBV) is known as an oncogenic herpesvirus that has been implicated in the pathogenesis of various malignancies. EBV-encoded RNAs (EBERs) are non-coding RNAs expressed abundantly in latently EBV-infected cells. Herein, I summarize the current understanding of the functions of EBERs, [...] Read more.
The Epstein-Barr virus (EBV) is known as an oncogenic herpesvirus that has been implicated in the pathogenesis of various malignancies. EBV-encoded RNAs (EBERs) are non-coding RNAs expressed abundantly in latently EBV-infected cells. Herein, I summarize the current understanding of the functions of EBERs, including the interactions with cellular factors through which EBERs contribute to EBV-mediated pathogenesis. Previous studies have demonstrated that EBERs are responsible for malignant phenotypes in lymphoid cells, and can induce several cytokines that can promote the growth of various EBV-infected cancer cells. EBERs were also found to bind retinoic acid-inducible gene I (RIG-I) and thus activate its downstream signaling. Furthermore, EBERs induce interleukin-10, an autocrine growth factor for Burkitt’s lymphoma cells, by activating RIG-I/interferon regulatory factor 3 pathway, suggesting that EBER-mediated innate immune signaling modulation contributes to EBV-mediated oncogenesis. Recently, EBV-infected cells were reported to secret EBERs, which were then recognized by toll-like receptor 3 (TLR3), leading to the induction of type I interferon and inflammatory cytokines, and subsequent immune activation. Furthermore, EBER1 was detected in the sera of patients with active EBV-infectious diseases, suggesting that EBER1-meidated TLR3 signaling activation could account for the pathogenesis of active EBV-infectious diseases. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
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851 KiB  
Review
DNA Mismatch Repair and Oxidative DNA Damage: Implications for Cancer Biology and Treatment
by Gemma Bridge, Sukaina Rashid and Sarah A. Martin
Cancers 2014, 6(3), 1597-1614; https://doi.org/10.3390/cancers6031597 - 05 Aug 2014
Cited by 91 | Viewed by 12167
Abstract
Many components of the cell, including lipids, proteins and both nuclear and mitochondrial DNA, are vulnerable to deleterious modifications caused by reactive oxygen species. If not repaired, oxidative DNA damage can lead to disease-causing mutations, such as in cancer. Base excision repair and [...] Read more.
Many components of the cell, including lipids, proteins and both nuclear and mitochondrial DNA, are vulnerable to deleterious modifications caused by reactive oxygen species. If not repaired, oxidative DNA damage can lead to disease-causing mutations, such as in cancer. Base excision repair and nucleotide excision repair are the two DNA repair pathways believed to orchestrate the removal of oxidative lesions. However, recent findings suggest that the mismatch repair pathway may also be important for the response to oxidative DNA damage. This is particularly relevant in cancer where mismatch repair genes are frequently mutated or epigenetically silenced. In this review we explore how the regulation of oxidative DNA damage by mismatch repair proteins may impact on carcinogenesis. We discuss recent studies that identify potential new treatments for mismatch repair deficient tumours, which exploit this non-canonical role of mismatch repair using synthetic lethal targeting. Full article
(This article belongs to the Special Issue Role of Oxidatively-Induced DNA Damage in Carcinogenesis)
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Article
STAT3 Activities and Energy Metabolism: Dangerous Liaisons
by Annalisa Camporeale, Marco Demaria, Emanuele Monteleone, Carlotta Giorgi, Mariusz R. Wieckowski, Paolo Pinton and Valeria Poli
Cancers 2014, 6(3), 1579-1596; https://doi.org/10.3390/cancers6031579 - 31 Jul 2014
Cited by 32 | Viewed by 8982
Abstract
STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. [...] Read more.
STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. We have recently demonstrated that constitutively active STAT3 drives a metabolic switch towards aerobic glycolysis through the transcriptional induction of Hif-1α and the down-regulation of mitochondrial activity, in both MEF cells expressing constitutively active STAT3 (Stat3C/C) and STAT3-addicted tumor cells. This novel metabolic function is likely involved in mediating pre-oncogenic features in the primary Stat3C/C MEFs such as resistance to apoptosis and senescence and rapid proliferation. Moreover, it strongly contributes to the ability of primary Stat3C/C MEFs to undergo malignant transformation upon spontaneous immortalization, a feature that may explain the well known causative link between STAT3 constitutive activity and tumor transformation under chronic inflammatory conditions. Taken together with the recently uncovered role of STAT3 in regulating energy metabolism from within the mitochondrion when phosphorylated on Ser 727, these data place STAT3 at the center of a hub regulating energy metabolism under different conditions, in most cases promoting cell survival, proliferation and malignant transformation even though with distinct mechanisms. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
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363 KiB  
Article
Simultaneous Expression of Cancer Stem Cell-Like Properties and Cancer-Associated Fibroblast-Like Properties in a Primary Culture of Breast Cancer Cells
by Mami Ishikawa, Takahiro Inoue, Takuma Shirai, Kazuhiko Takamatsu, Shiori Kunihiro, Hirokazu Ishii and Takahito Nishikata
Cancers 2014, 6(3), 1570-1578; https://doi.org/10.3390/cancers6031570 - 31 Jul 2014
Cited by 22 | Viewed by 7056
Abstract
The importance of cancer-associated fibroblasts (CAFs) in cancer biology has been recently highlighted owing to their critical roles in cancer growth, progression, metastasis, and therapeutic resistance. We have previously established a primary culture of breast cancer cells, which showed epithelial-mesenchymal transition and cancer [...] Read more.
The importance of cancer-associated fibroblasts (CAFs) in cancer biology has been recently highlighted owing to their critical roles in cancer growth, progression, metastasis, and therapeutic resistance. We have previously established a primary culture of breast cancer cells, which showed epithelial-mesenchymal transition and cancer stem cell-like properties. In this study, we found that the primary culture also showed CAF-like properties. For example, hypoxia inducible factor 1α (HIF1A) and its downstream genes, nuclear factor-kappa B2 (NF-κB2) and BCL2/adenovirus E1B 19 kd-interacting protein 3 (BNIP3), and many enzymes involved in glycolysis, such as GAPDH, LDH, PGAM1, and PKM2, were highly overexpressed in the primary culture. Moreover, media conditioned with the primary culture cells enhanced the growth of breast cancer cells. Similar to previous CAF studies, this enhancement suggested to be occurred through fibroblast growth factor signaling. This MCKH primary culture cell, which showed simultaneous expression of tumorigenic and CAF properties, offers a unique experimental system for studying the biology of CAFs. Full article
(This article belongs to the Special Issue Breast Cancer Biology and Treatment)
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Article
An RNA Aptamer Targets the PDZ-Binding Motif of the HPV16 E6 Oncoprotein
by Tamara A. Belyaeva, Clare Nicol, Özlem Cesur, Gilles Travé, George Eric Blair and Nicola J. Stonehouse
Cancers 2014, 6(3), 1553-1569; https://doi.org/10.3390/cancers6031553 - 24 Jul 2014
Cited by 15 | Viewed by 7775
Abstract
Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus which is the primary causative agent of cervical cancer. Cell transformation arises from deregulated expression of the E6 and E7 oncogenes. E6 has been shown to bind a number of cellular proteins, including [...] Read more.
Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus which is the primary causative agent of cervical cancer. Cell transformation arises from deregulated expression of the E6 and E7 oncogenes. E6 has been shown to bind a number of cellular proteins, including p53 and proteins containing a PDZ domain. This study reports the first RNA aptamers to E6. These have been employed as molecular tools to further investigate E6-p53 and E6-PDZ interactions. This study is focussed on two aptamers (termed F2 and F4) which induced apoptosis in cells derived from an HPV16-transformed cervical carcinoma. The molecules were able to inhibit the interaction between E6 and PDZ1 from Magi1, with F2 being the most effective inhibitor. Neither of the aptamers inhibited E6-p53 interaction or p53 degradation. This study shows the specificity of this approach and highlights the potential benefits of the E6 aptamers as potential therapeutic or diagnostic agents in the future. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
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580 KiB  
Review
Targeting MET Amplification as a New Oncogenic Driver
by Hisato Kawakami, Isamu Okamoto, Wataru Okamoto, Junko Tanizaki, Kazuhiko Nakagawa and Kazuto Nishio
Cancers 2014, 6(3), 1540-1552; https://doi.org/10.3390/cancers6031540 - 22 Jul 2014
Cited by 85 | Viewed by 11090
Abstract
Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy [...] Read more.
Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy. Full article
(This article belongs to the Special Issue MET in Cancer)
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Article
Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis
by Takuji Tanaka, Masahito Shimizu, Takahiro Kochi, Yohei Shirakami, Takayuki Mori, Naoki Watanabe, Takafumi Naiki, Hisataka Moriwaki, Kazuto Yoshimi, Tadao Serikawa and Takashi Kuramoto
Cancers 2014, 6(3), 1522-1539; https://doi.org/10.3390/cancers6031522 - 21 Jul 2014
Cited by 5 | Viewed by 6386
Abstract
Despite widening interest in the possible association between infection/ inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to [...] Read more.
Despite widening interest in the possible association between infection/ inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation. Full article
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733 KiB  
Review
Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked
by Rosalina Wisastra and Frank J. Dekker
Cancers 2014, 6(3), 1500-1521; https://doi.org/10.3390/cancers6031500 - 17 Jul 2014
Cited by 130 | Viewed by 11905
Abstract
Cancer and inflammation are intimately linked due to specific oxidative processes in the tumor microenvironment. Lipoxygenases are a versatile class of oxidative enzymes involved in arachidonic acid metabolism. An increasing number of arachidonic acid metabolites is being discovered and apart from their classically [...] Read more.
Cancer and inflammation are intimately linked due to specific oxidative processes in the tumor microenvironment. Lipoxygenases are a versatile class of oxidative enzymes involved in arachidonic acid metabolism. An increasing number of arachidonic acid metabolites is being discovered and apart from their classically recognized pro-inflammatory effects, anti-inflammatory effects are also being described in recent years. Interestingly, these lipid mediators are involved in activation of pro-inflammatory signal transduction pathways such as the nuclear factor κB (NF-κB) pathway, which illustrates the intimate link between lipid signaling and transcription factor activation. The identification of the role of arachidonic acid metabolites in several inflammatory diseases led to a significant drug discovery effort around arachidonic acid metabolizing enzymes. However, to date success in this area has been limited. This might be attributed to the lack of selectivity of the developed inhibitors and to a lack of detailed understanding of the functional roles of arachidonic acid metabolites in inflammatory responses and cancer. This calls for a more detailed investigation of the activity of arachidonic acid metabolizing enzymes and development of more selective inhibitors. Full article
(This article belongs to the Special Issue Role of Oxidatively-Induced DNA Damage in Carcinogenesis)
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624 KiB  
Article
Comparison of Intracellular Stress Response of NCI-H526 Small Cell Lung Cancer (SCLC) Cells to Platinum(II) Cisplatin and Platinum(IV) Oxoplatin
by Gerhard Hamilton
Cancers 2014, 6(3), 1487-1499; https://doi.org/10.3390/cancers6031487 - 08 Jul 2014
Cited by 4 | Viewed by 7326
Abstract
In attempts to develop an orally applicable platinum-based drug, platinum(IV) drugs which exhibit higher in vivo stability compared to the platinum(II) drug cisplatin were formulated. The first such chemotherapeutic agent, namely satraplatin, failed to receive approval. In the present work, we checked the [...] Read more.
In attempts to develop an orally applicable platinum-based drug, platinum(IV) drugs which exhibit higher in vivo stability compared to the platinum(II) drug cisplatin were formulated. The first such chemotherapeutic agent, namely satraplatin, failed to receive approval. In the present work, we checked the initial cellular stress response of the chemosensitive NCI-H526 small cell lung cancer (SCLC) cells by determination of the relative phosphorylation of 46 specific phosphorylation sites of 38 selected proteins in a six hours response to cisplatin (platinum(II)) or oxoplatin (platinum(IV)), respectively. Oxoplatin is considered as prodrug of cisplatin, although several findings point to differences in intracellular effects. Cisplatin induced hyperphosphorylation of p38α MAPK and AMPKα1, whereas oxoplatin treatment resulted in increased phosphorylation of a large number of signaling proteins involved in stress response/drug resistance, including JNK, GSK-3α, AMPKα1, src kinases, STATs, CHK-2 and especially focal adhesion kinase (FAK). Cisplatin exerts markedly higher cytotoxicity upon four hours short-term exposure in comparison to oxoplatin and, correspondingly, the extended initial stress response to the platinum(IV) drug oxoplatin thus is expected to increase clinical drug resistance. Induction of a substantial stress response to any prodrug of a platinum-based compound may likewise limit the effectivity of its active metabolite(s), such contributing to the failure of selected derivatized platinum complexes. Full article
(This article belongs to the Special Issue Kinases and Cancer)
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Article
Phosphorylation of Large T Antigen Regulates Merkel Cell Polyomavirus Replication
by Jason Diaz, Xin Wang, Sabrina H. Tsang, Jing Jiao and Jianxin You
Cancers 2014, 6(3), 1464-1486; https://doi.org/10.3390/cancers6031464 - 08 Jul 2014
Cited by 18 | Viewed by 7822
Abstract
Merkel Cell Polyomavirus (MCPyV) was recently discovered as a novel human polyomavirus that is associated with ~80% of Merkel Cell Carcinomas. The Large Tumor antigen (LT) is an early viral protein which has a variety of functions, including manipulation of the cell cycle [...] Read more.
Merkel Cell Polyomavirus (MCPyV) was recently discovered as a novel human polyomavirus that is associated with ~80% of Merkel Cell Carcinomas. The Large Tumor antigen (LT) is an early viral protein which has a variety of functions, including manipulation of the cell cycle and initiating viral DNA replication. Phosphorylation plays a critical regulatory role for polyomavirus LT proteins, but no investigation of MCPyV LT phosphorylation has been performed to date. In this report mass spectrometry analysis reveals three unique phosphorylation sites: T271, T297 and T299. In vivo replication assays confirm that phosphorylation of T271 does not play a role in viral replication, while modification at T297 and T299 have dramatic and opposing effects on LT’s ability to initiate replication from the viral origin. We test these mutants for their ability to bind, unwind, and act as a functional helicase at the viral origin. These studies provide a framework for understanding how phosphorylation of LT may dynamically regulate viral replication. Although the natural host cell of MCPyV has not yet been established, this work provides a foundation for understanding how LT activity is regulated and provides tools for better exploring this regulation in both natural host cells and Merkel cells. Full article
(This article belongs to the Special Issue Merkel Cell Carcinoma)
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Review
The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma
by Tasuku Matsuoka and Masakazu Yashiro
Cancers 2014, 6(3), 1441-1463; https://doi.org/10.3390/cancers6031441 - 07 Jul 2014
Cited by 151 | Viewed by 21149
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key signaling pathways induced by various receptor-tyrosine kinases. Accumulating evidence shows that this pathway is an important promoter of cell growth, metabolism, survival, metastasis, and resistance to chemotherapy. Genetic alterations [...] Read more.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key signaling pathways induced by various receptor-tyrosine kinases. Accumulating evidence shows that this pathway is an important promoter of cell growth, metabolism, survival, metastasis, and resistance to chemotherapy. Genetic alterations in the PI3K/Akt/mTOR pathway in gastric carcinoma have often been demonstrated. Many kinds of molecular targeting therapies are currently undergoing clinical testing in patients with solid tumors. However, with the exception of the ErbB2-targeting antibody, targeting agents, including PI3K/Akt/mTOR inhibitors, have not been approved for treatment of patients with gastric carcinoma. This review summarizes the current knowledge on PI3K/Akt/mTOR signaling in the pathogenesis of gastric carcinoma and the possible therapeutic targets for gastric carcinoma. Improved knowledge of the PI3K/Akt/mTOR pathway in gastric carcinoma will be useful in understanding the mechanisms of tumor development and for identifying ideal targets of anticancer therapy for gastric carcinoma. Full article
(This article belongs to the Special Issue Kinases and Cancer)
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Review
STAT3 in Cancer—Friend or Foe?
by Hai-Feng Zhang and Raymond Lai
Cancers 2014, 6(3), 1408-1440; https://doi.org/10.3390/cancers6031408 - 03 Jul 2014
Cited by 101 | Viewed by 10061
Abstract
The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade. Mounting evidence has shown that constitutive activation of STAT3 is a frequent biochemical aberrancy in cancer cells, and this abnormality directly contributes to tumorigenesis and [...] Read more.
The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade. Mounting evidence has shown that constitutive activation of STAT3 is a frequent biochemical aberrancy in cancer cells, and this abnormality directly contributes to tumorigenesis and shapes many malignant phenotypes in cancer cells. Nevertheless, results from more recent experimental and clinicopathologic studies have suggested that STAT3 also can exert tumor suppressor effects under specific conditions. Importantly, some of these studies have demonstrated that STAT3 can function either as an oncoprotein or a tumor suppressor in the same cell type, depending on the specific genetic background or presence/absence of specific coexisting biochemical defects. Thus, in the context of cancer biology, STAT3 can be a friend or foe. In the first half of this review, we will highlight the “evil” features of STAT3 by summarizing its oncogenic functions and mechanisms. The differences between the canonical and non-canonical pathway will be highlighted. In the second half, we will summarize the evidence supporting that STAT3 can function as a tumor suppressor. To explain how STAT3 may mediate its tumor suppressor effects, we will discuss several possible mechanisms, one of which is linked to the role of STAT3β, one of the two STAT3 splicing isoforms. Taken together, it is clear that the roles of STAT3 in cancer are multi-faceted and far more complicated than one appreciated previously. The new knowledge has provided us with new approaches and strategies when we evaluate STAT3 as a prognostic biomarker or therapeutic target. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
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Review
STAT3: An Anti-Invasive Factor in Colorectal Cancer?
by Petrus Rudolf De Jong, Ji-Hun Mo, Alexandra R. Harris, Jongdae Lee and Eyal Raz
Cancers 2014, 6(3), 1394-1407; https://doi.org/10.3390/cancers6031394 - 03 Jul 2014
Cited by 14 | Viewed by 11247
Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) is activated in a majority of cancers, and promotes tumorigenesis and even metastasis through transcriptional activation of its target genes. Recently, we discovered that STAT3 suppresses epithelial-to-mesenchymal transition (EMT) and thus metastasis in a mouse [...] Read more.
Signal Transducer and Activator of Transcription 3 (STAT3) is activated in a majority of cancers, and promotes tumorigenesis and even metastasis through transcriptional activation of its target genes. Recently, we discovered that STAT3 suppresses epithelial-to-mesenchymal transition (EMT) and thus metastasis in a mouse model of colorectal cancer (CRC), while it did not affect the overall tumor burden. Furthermore, we found that STAT3 in intestinal epithelial cells (IEC) suppresses EMT by regulating stability of an EMT inducer, SNAI-1 (Snail-1). Here, STAT3 functions as an adaptor rather than a transcription factor in the post-translational modification of SNAI-1. In this review, we discuss the unexpected and contradictory role of STAT3 in metastasis of CRC and its clinical implications. Full article
(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)
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Article
Heat Shock Protein 90 (HSP90) and Her2 in Adenocarcinomas of the Esophagus
by Julia Slotta-Huspenina, Karl-Friedrich Becker, Marcus Feith, Axel Walch and Rupert Langer
Cancers 2014, 6(3), 1382-1393; https://doi.org/10.3390/cancers6031382 - 27 Jun 2014
Cited by 13 | Viewed by 6927
Abstract
Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas. The activity of Her2 has been shown to be modulated by molecular chaperones such as HSP90. We analyzed expression/amplification data for HSP90 and Her2 on 127 primary resected esophageal [...] Read more.
Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas. The activity of Her2 has been shown to be modulated by molecular chaperones such as HSP90. We analyzed expression/amplification data for HSP90 and Her2 on 127 primary resected esophageal adenocarcinomas in order to evaluate a possible relationship between these two molecules. HSP90 expression determined by immunohistochemistry was observed in various levels. Thirty nine (39) tumors (30.7%) were classified as Her2-positive according to their immunoreactivity and amplification status. There was a significant correlation between HSP90 expression and Her2-status (p = 0.008). This could also be demonstrated by quantitative protein expression analysis with reverse phase protein arrays (r = 0.9; p < 0.001). Her2-status was associated withpT-category (p = 0.041), lymph node metastases (p = 0.049) and tumor differentiation (p = 0.036) with a higher percentage of cases with negative Her2 status in lower tumor stagesA negative Her2-status was also associated with better survival in univariate and multivariate analysis (p = 0.001 and p = 0.014). For HSP90, no associations between clinical and pathological parameters were found. The observed association between HSP90 expression and Her2 suggests a co-regulation of these molecules in at least a subset of esophageal adenocarcinomas. Anti-HSP90 drugs, which recently have been introduced in cancer treatment, may also be an option for these tumors by targeting HSP90 alone or in combination with Her2. Full article
(This article belongs to the Special Issue Heat Shock Proteins in Cancer: Chaperones of Tumorigenesis)
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Review
Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma
by Kim De Veirman, Luigia Rao, Elke De Bruyne, Eline Menu, Els Van Valckenborgh, Ivan Van Riet, Maria Antonia Frassanito, Lucia Di Marzo, Angelo Vacca and Karin Vanderkerken
Cancers 2014, 6(3), 1363-1381; https://doi.org/10.3390/cancers6031363 - 27 Jun 2014
Cited by 72 | Viewed by 14096
Abstract
Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim [...] Read more.
Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease. Full article
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Article
Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations
by Mirco Pistelli, Miriam Caramanti, Tommasina Biscotti, Alfredo Santinelli, Alessandra Pagliacci, Mariagrazia De Lisa, Zelmira Ballatore, Francesca Ridolfi, Elena Maccaroni, Raffaella Bracci, Rossana Berardi, Nicola Battelli and Stefano Cascinu
Cancers 2014, 6(3), 1351-1362; https://doi.org/10.3390/cancers6031351 - 27 Jun 2014
Cited by 60 | Viewed by 8162
Abstract
Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis [...] Read more.
Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target. Full article
(This article belongs to the Special Issue Breast Cancer Biology and Treatment)
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Review
Merkel Cell Carcinoma in Immunosuppressed Patients
by Janice E. Ma and Jerry D. Brewer
Cancers 2014, 6(3), 1328-1350; https://doi.org/10.3390/cancers6031328 - 27 Jun 2014
Cited by 71 | Viewed by 7033
Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the [...] Read more.
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients. Full article
(This article belongs to the Special Issue Merkel Cell Carcinoma)
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Review
Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Prostate Cancer Progression
by Yixuan Gong, Uma D. Chippada-Venkata and William K. Oh
Cancers 2014, 6(3), 1298-1327; https://doi.org/10.3390/cancers6031298 - 27 Jun 2014
Cited by 132 | Viewed by 15471
Abstract
Matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases involved in the degradation of the extracellular matrix, play an important role in tissue remodeling associated with various physiological processes such as morphogenesis, angiogenesis, and tissue repair, as well as pathological processes including cirrhosis, arthritis [...] Read more.
Matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases involved in the degradation of the extracellular matrix, play an important role in tissue remodeling associated with various physiological processes such as morphogenesis, angiogenesis, and tissue repair, as well as pathological processes including cirrhosis, arthritis and cancer. The MMPs are well established as mediators of tumor invasion and metastasis by breaking down connective tissue barriers. Although there has been a vast amount of literature on the role of MMPs in invasion, metastasis and angiogenesis of various cancers, the role of these endopeptidases in prostate cancer progression has not been systematically reviewed. This overview summarizes findings on the tissue and blood expression of MMPs, their function, regulation and prognostic implication in human prostate cancer, with a focus on MMP-2, -7, -9, MT1-MMP and tissue inhibitor of metalloproteinase 1 (TIMP-1). This review also summarizes the efficacy and failure of early-generation matrix metalloproteinase inhibitors (MMPIs) in the treatment of metastatic prostate cancer and highlights the lessons and challenges for next generation MMPIs. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Cancer Progress)
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Review
Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus
by Gabrielė Stakaitytė, Jennifer J. Wood, Laura M. Knight, Hussein Abdul-Sada, Noor Suhana Adzahar, Nnenna Nwogu, Andrew Macdonald and Adrian Whitehouse
Cancers 2014, 6(3), 1267-1297; https://doi.org/10.3390/cancers6031267 - 27 Jun 2014
Cited by 38 | Viewed by 15061
Abstract
A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of [...] Read more.
A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of MCC. It is found clonally integrated into the majority of MCC tumours, which require MCPyV oncoproteins to survive. Since its discovery, research has begun to reveal the molecular virology of MCPyV, as well as how it induces tumourigenesis. It is thought to be a common skin commensal, found at low levels in healthy individuals. Upon loss of immunosurveillance, MCPyV reactivates, and a heavy viral load is associated with MCC pathogenesis. Although MCPyV is in many ways similar to classical oncogenic polyomaviruses, such as SV40, subtle differences are beginning to emerge. These unique features highlight the singular position MCPyV has as the only human oncogenic polyomavirus, and open up new avenues for therapies against MCC. Full article
(This article belongs to the Special Issue Merkel Cell Carcinoma)
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Review
Diagnosis and Management of Merkel Cell Carcinoma of the Head and Neck: Current Trends and Controversies
by Mark S. Swanson and Uttam K. Sinha
Cancers 2014, 6(3), 1256-1266; https://doi.org/10.3390/cancers6031256 - 27 Jun 2014
Cited by 8 | Viewed by 5330
Abstract
Merkel cell carcinoma is an aggressive neuroendocrine cutaneous malignancy with a predilection for regional and distant metastasis. This malignancy presents most commonly on the head and neck of elderly Caucasian males, with a higher prevalence in the immunosuppressed. A high index of suspicion [...] Read more.
Merkel cell carcinoma is an aggressive neuroendocrine cutaneous malignancy with a predilection for regional and distant metastasis. This malignancy presents most commonly on the head and neck of elderly Caucasian males, with a higher prevalence in the immunosuppressed. A high index of suspicion must be maintained due to the often asymptomatic presentation. Lip tumors, scalp tumors, local invasion, nodal metastasis, distant metastasis, and lymphovascular invasion are poor prognostic factors. Up to 8.7% of patients present with distant metastasis, and PET-CT is an accurate staging tool with a 90% sensitivity. Combined aggressive surgical resection with adjuvant radiotherapy affords the best regional control rates. The regional lymphatics must be addressed with either sentinel lymph node biopsy, surgery, or elective radiation due to the risk of occult metastasis. Addition of chemotherapy has no proven benefit in locoregional control. Full article
(This article belongs to the Special Issue Merkel Cell Carcinoma)
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Review
Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs)
by Isao Okazaki, Takuji Noro, Nobuhiro Tsutsui, Eigoro Yamanouchi, Hajime Kuroda, Masayuki Nakano, Hiroaki Yokomori and Yutaka Inagaki
Cancers 2014, 6(3), 1220-1255; https://doi.org/10.3390/cancers6031220 - 27 Jun 2014
Cited by 41 | Viewed by 9707
Abstract
Nonalcoholic steatohepatitis (NASH) is emerging worldwide because life-styles have changed to include much over-eating and less physical activity. The clinical and pathophysiological features of NASH are very different from those of HBV- and HCV-chronic liver diseases. The prognosis of NASH is worse among [...] Read more.
Nonalcoholic steatohepatitis (NASH) is emerging worldwide because life-styles have changed to include much over-eating and less physical activity. The clinical and pathophysiological features of NASH are very different from those of HBV- and HCV-chronic liver diseases. The prognosis of NASH is worse among those with nonalcoholic fatty liver diseases (NAFLD), and some NASH patients show HCC with or without cirrhosis. In the present review we discuss fibrogenesis and the relationship between fibrosis and HCC occurrence in NASH to clarify the role of MMPs and TIMPs in both mechanisms. Previously we proposed MMP and TIMP expression in the multi-step occurrence of HCC from the literature based on viral-derived HCC. We introduce again these expressions during hepatocarcinogenesis and compare them to those in NASH-derived HCC, although the relationship with hepatic stem/progenitor cells (HPCs) invasion remains unknown. Signal transduction of MMPs and TIMPs is also discussed because it is valuable for the prevention and treatment of NASH and NASH-derived HCC. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Cancer Progress)
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