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Cancers, Volume 7, Issue 3 (September 2015) – 43 articles

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Open AccessReview
Next-Generation Sequencing Approaches in Cancer: Where Have They Brought Us and Where Will They Take Us?
Cancers 2015, 7(3), 1925-1958; https://doi.org/10.3390/cancers7030869 - 23 Sep 2015
Cited by 29 | Viewed by 3232
Abstract
Next-generation sequencing (NGS) technologies and data have revolutionized cancer research and are increasingly being deployed to guide clinicians in treatment decision-making. NGS technologies have allowed us to take an “omics” approach to cancer in order to reveal genomic, transcriptomic, and epigenomic landscapes of [...] Read more.
Next-generation sequencing (NGS) technologies and data have revolutionized cancer research and are increasingly being deployed to guide clinicians in treatment decision-making. NGS technologies have allowed us to take an “omics” approach to cancer in order to reveal genomic, transcriptomic, and epigenomic landscapes of individual malignancies. Integrative multi-platform analyses are increasingly used in large-scale projects that aim to fully characterize individual tumours as well as general cancer types and subtypes. In this review, we examine how NGS technologies in particular have contributed to “omics” approaches in cancer research, allowing for large-scale integrative analyses that consider hundreds of tumour samples. These types of studies have provided us with an unprecedented wealth of information, providing the background knowledge needed to make small-scale (including “N of 1”) studies informative and relevant. We also take a look at emerging opportunities provided by NGS and state-of-the-art third-generation sequencing technologies, particularly in the context of translational research. Cancer research and care are currently poised to experience significant progress catalyzed by accessible sequencing technologies that will benefit both clinical- and research-based efforts. Full article
(This article belongs to the Special Issue Next Generation Sequencing Approaches in Cancer)
Open AccessReview
Therapy for BRAFi-Resistant Melanomas: Is WNT5A the Answer?
Cancers 2015, 7(3), 1900-1924; https://doi.org/10.3390/cancers7030868 - 17 Sep 2015
Cited by 12 | Viewed by 3167
Abstract
In recent years, scientists have advocated the use of targeted therapies in the form of drugs that modulate genes and proteins that are directly associated with cancer progression and metastasis. Malignant melanoma is a dreadful cancer type that has been associated with the [...] Read more.
In recent years, scientists have advocated the use of targeted therapies in the form of drugs that modulate genes and proteins that are directly associated with cancer progression and metastasis. Malignant melanoma is a dreadful cancer type that has been associated with the rapid dissemination of primary tumors to multiple sites, including bone, brain, liver and lungs. The discovery that approximately 40%–50% of malignant melanomas contain a mutation in BRAF at codon 600 gave scientists a new approach to tackle this disease. However, clinical studies on patients have shown that although BRAFi (BRAF inhibitors) trigger early anti-tumor responses, the majority of patients later develop resistance to the therapy. Recent studies have shown that WNT5A plays a key role in enhancing the resistance of melanoma cells to BRAFi. The focus of the current review will be on melanoma development, signaling pathways important to acquired resistance to BRAFi, and why WNT5A inhibitors are attractive candidates to be included in combinatorial therapies for melanoma. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
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Open AccessArticle
The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells
Cancers 2015, 7(3), 1885-1899; https://doi.org/10.3390/cancers7030867 - 17 Sep 2015
Cited by 15 | Viewed by 2774
Abstract
Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process [...] Read more.
Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, Cancers 2015, 7 1886 these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer. Full article
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Open AccessReview
The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis
Cancers 2015, 7(3), 1863-1884; https://doi.org/10.3390/cancers7030866 - 16 Sep 2015
Cited by 25 | Viewed by 4187
Abstract
The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance [...] Read more.
The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT. Full article
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Open AccessArticle
Exploration of Deregulated Long Non-Coding RNAs in Association with Hepatocarcinogenesis and Survival
Cancers 2015, 7(3), 1847-1862; https://doi.org/10.3390/cancers7030865 - 10 Sep 2015
Cited by 13 | Viewed by 2484
Abstract
Long non-coding RNAs (lncRNAs) are larger than 200 nucleotides in length and pervasively expressed across the genome. An increasing number of studies indicate that lncRNA transcripts play integral regulatory roles in cellular growth, division, differentiation and apoptosis. Deregulated lncRNAs have been observed in [...] Read more.
Long non-coding RNAs (lncRNAs) are larger than 200 nucleotides in length and pervasively expressed across the genome. An increasing number of studies indicate that lncRNA transcripts play integral regulatory roles in cellular growth, division, differentiation and apoptosis. Deregulated lncRNAs have been observed in a variety of human cancers, including hepatocellular carcinoma (HCC). We determined the expression profiles of 90 lncRNAs for 65 paired HCC tumor and adjacent non-tumor tissues, and 55 lncRNAs were expressed in over 90% of samples. Eight lncRNAs were significantly down-regulated in HCC tumor compared to non-tumor tissues (p < 0.05), but no lncRNA achieved statistical significance after Bonferroni correction for multiple comparisons. Within tumor tissues, carrying more aberrant lncRNAs (6–7) was associated with a borderline significant reduction Cancers 2015, 7 1848 in survival (HR = 8.5, 95% CI: 1.0–72.5). The predictive accuracy depicted by the AUC was 0.93 for HCC survival when using seven deregulated lncRNAs (likelihood ratio test p = 0.001), which was similar to that combining the seven lncRNAs with tumor size and treatment (AUC = 0.96, sensitivity = 87%, specificity = 87%). These data suggest the potential association of deregulated lncRNAs with hepatocarcinogenesis and HCC survival. Full article
(This article belongs to the Special Issue Non-Coding RNAs in Cancers)
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Open AccessReview
The Evolution of Therapies in Non-Small Cell Lung Cancer
Cancers 2015, 7(3), 1815-1846; https://doi.org/10.3390/cancers7030864 - 09 Sep 2015
Cited by 77 | Viewed by 6487
Abstract
The landscape of advanced non-small lung cancer (NSCLC) therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer [...] Read more.
The landscape of advanced non-small lung cancer (NSCLC) therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with appropriate tyrosine kinase inhibitors (TKIs). Other driver mutations such as ROS, MET, RET, BRAF have also been investigated with targeted agents with some success in the early phase clinical setting. Novel strategies in the field of immune-oncology have also led to the development of inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 receptor (PD-1), which are important pathways in allowing cancer cells to escape detection by the immune system. These inhibitors have been successfully tried in NSCLC and also now bring the exciting possibility of long term responses in advanced NSCLC. In this review recent data on novel targets and therapeutic strategies and their future prospects are discussed. Full article
(This article belongs to the Special Issue Non-Small Cell Lung Cancer Therapies)
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Open AccessArticle
MicroRNA Polymorphisms in Cancer: A Literature Analysis
Cancers 2015, 7(3), 1806-1814; https://doi.org/10.3390/cancers7030863 - 09 Sep 2015
Cited by 23 | Viewed by 2820
Abstract
Single nucleotide polymorphisms (SNPs) located in microRNA (miRNA) genes (miR-SNPs) have attracted increasing attention in recent years due to their involvement in the development of various types of cancer. Therefore, a systematic review on this topic was needed. From 55 scientific publications we [...] Read more.
Single nucleotide polymorphisms (SNPs) located in microRNA (miRNA) genes (miR-SNPs) have attracted increasing attention in recent years due to their involvement in the development of various types of cancer. Therefore, a systematic review on this topic was needed. From 55 scientific publications we collected 20 SNPs, which are located within 18 miRNA encoding genes and have been associated with 16 types of cancer. Among 20 miRNA gene polymorphisms 13 are located within the premature miRNA region, five within mature, and two within mature seed miRNA region. We graphically visualized a network of miRNA-cancer associations which revealed miRNA genes and cancer types with the highest number of connections. Our study showed that, despite a large number of variations currently known to be located within miRNA genes in humans, most of them have not yet been tested for association with cancer. MicroRNA SNPs collected in this study represent only 0.43% of known miRNA gene variations (20/4687). Results of the present study will be useful to researchers investigating the clinical use of miRNAs, such as the roles of miRNAs as diagnostic markers and therapeutic targets. Full article
(This article belongs to the Special Issue Non-Coding RNAs in Cancers)
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Open AccessReview
Hepatocyte Growth Factor from a Clinical Perspective: A Pancreatic Cancer Challenge
Cancers 2015, 7(3), 1785-1805; https://doi.org/10.3390/cancers7030861 - 03 Sep 2015
Cited by 11 | Viewed by 2734
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and incidence rates are rising. Both detection and treatment options for pancreatic cancer are limited, providing a less than 5% five-year survival advantage. The need for new biomarkers for [...] Read more.
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and incidence rates are rising. Both detection and treatment options for pancreatic cancer are limited, providing a less than 5% five-year survival advantage. The need for new biomarkers for early detection and treatment of pancreatic cancer demands the efficient translation of bench knowledge to provide clinical benefit. One source of therapeutic resistance is the pancreatic tumor microenvironment, which is characterized by desmoplasia and hypoxia making it less conducive to current therapies. A major factor regulating desmoplasia and subsequently promoting chemoresistance in pancreatic cancer is hepatocyte growth factor (HGF), the sole ligand for c-MET (mesenchymal-epithelial transition), an epithelial tyrosine kinase receptor. Binding of HGF to c-MET leads to receptor dimerization and autophosphorylation resulting in the activation of multiple cellular processes that support cancer progression. Inhibiting activation of c-MET in cancer cells, in combination with other approaches for reducing desmoplasia in the tumor microenvironment, might significantly improve the success of chemotherapy. Therefore, HGF makes a potent novel target for developing therapeutic strategies in combination with existing drugs for treating pancreatic adenocarcinoma. This review provides a comprehensive analysis of HGF and its promising potential as a chemotherapeutic target for pancreatic cancer. Full article
(This article belongs to the Special Issue Stress Responses in Tumors and The Tumor Microenvironment)
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Open AccessReview
Targeting RTK Signaling Pathways in Cancer
Cancers 2015, 7(3), 1758-1784; https://doi.org/10.3390/cancers7030860 - 03 Sep 2015
Cited by 146 | Viewed by 7700
Abstract
The RAS/MAP kinase and the RAS/PI3K/AKT pathways play a key role in the regulation of proliferation, differentiation and survival. The induction of these pathways depends on Receptor Tyrosine Kinases (RTKs) that are activated upon ligand binding. In cancer, constitutive and aberrant activations of [...] Read more.
The RAS/MAP kinase and the RAS/PI3K/AKT pathways play a key role in the regulation of proliferation, differentiation and survival. The induction of these pathways depends on Receptor Tyrosine Kinases (RTKs) that are activated upon ligand binding. In cancer, constitutive and aberrant activations of components of those pathways result in increased proliferation, survival and metastasis. For instance, mutations affecting RTKs, Ras, B-Raf, PI3K and AKT are common in perpetuating the malignancy of several types of cancers and from different tissue origins. Therefore, these signaling pathways became prime targets for cancer therapy. This review aims to provide an overview about the most frequently encountered mutations, the pathogenesis that results from such mutations and the known therapeutic strategies developed to counteract their aberrant functions. Full article
(This article belongs to the Special Issue Cancer Cell Proliferation)
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Open AccessArticle
Supportive Management of Mucositis and Metabolic Derangements in Head and Neck Cancer Patients
Cancers 2015, 7(3), 1743-1757; https://doi.org/10.3390/cancers7030862 - 03 Sep 2015
Cited by 13 | Viewed by 2765
Abstract
Oral mucositis (OM) is among the most undesirable, painful, and expensive toxicities of cytotoxic cancer therapy, and is disheartening for patients and frustrating for caregivers. Accurate assessment of the incidence of OM has been elusive, but accumulating data suggests that reported OM frequency [...] Read more.
Oral mucositis (OM) is among the most undesirable, painful, and expensive toxicities of cytotoxic cancer therapy, and is disheartening for patients and frustrating for caregivers. Accurate assessment of the incidence of OM has been elusive, but accumulating data suggests that reported OM frequency is significantly less than its actual occurrence. It has been suggested that over 90% of head and neck cancer (HNC) patients receiving radiotherapy (RT) with concurrent cisplatin experience severe OM with symptoms of extreme pain, mucosal ulceration and consequent limitations in swallowing and achieving adequate nutritional intake. This panoply of symptoms inevitably impacts a patients’ quality of life and their willingness to continue treatment. In spite of all the advances made in understanding the pathophysiology of OM, there is still no prophylactic therapy with proven efficacy. Strategies to limit the extent of OM and to manage its symptomatology include basic oral care, supportive medications, nutritional support and targeting aggressive treatments to high-risk patients. This review focuses on OM recognition, preventive measurements, and symptom-management strategies. Full article
Open AccessReview
Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review
Cancers 2015, 7(3), 1716-1742; https://doi.org/10.3390/cancers7030858 - 28 Aug 2015
Cited by 5 | Viewed by 3085
Abstract
Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated [...] Read more.
Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well. Full article
(This article belongs to the Special Issue Head and Neck Cancer)
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Open AccessReview
Analysis of Pre-Analytic Factors Affecting the Success of Clinical Next-Generation Sequencing of Solid Organ Malignancies
Cancers 2015, 7(3), 1699-1715; https://doi.org/10.3390/cancers7030859 - 28 Aug 2015
Cited by 47 | Viewed by 3172
Abstract
Application of next-generation sequencing (NGS) technology to routine clinical practice has enabled characterization of personalized cancer genomes to identify patients likely to have a response to targeted therapy. The proper selection of tumor sample for downstream NGS based mutational analysis is critical to [...] Read more.
Application of next-generation sequencing (NGS) technology to routine clinical practice has enabled characterization of personalized cancer genomes to identify patients likely to have a response to targeted therapy. The proper selection of tumor sample for downstream NGS based mutational analysis is critical to generate accurate results and to guide therapeutic intervention. However, multiple pre-analytic factors come into play in determining the success of NGS testing. In this review, we discuss pre-analytic requirements for AmpliSeq PCR-based sequencing using Ion Torrent Personal Genome Machine (PGM) (Life Technologies), a NGS sequencing platform that is often used by clinical laboratories for sequencing solid tumors because of its low input DNA requirement from formalin fixed and paraffin embedded tissue. The success of NGS mutational analysis is affected not only by the input DNA quantity but also by several other factors, including the specimen type, the DNA quality, and the tumor cellularity. Here, we review tissue requirements for solid tumor NGS based mutational analysis, including procedure types, tissue types, tumor volume and fraction, decalcification, and treatment effects. Full article
(This article belongs to the Special Issue Next Generation Sequencing Approaches in Cancer)
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Open AccessReview
Non-Canonical Hh Signaling in Cancer—Current Understanding and Future Directions
Cancers 2015, 7(3), 1684-1698; https://doi.org/10.3390/cancers7030857 - 27 Aug 2015
Cited by 32 | Viewed by 2974
Abstract
As a major regulatory pathway for embryonic development and tissue patterning, hedgehog signaling is not active in most adult tissues, but is reactivated in a number of human cancer types. A major milestone in hedgehog signaling in cancer is the Food and Drug [...] Read more.
As a major regulatory pathway for embryonic development and tissue patterning, hedgehog signaling is not active in most adult tissues, but is reactivated in a number of human cancer types. A major milestone in hedgehog signaling in cancer is the Food and Drug Administration (FDA) approval of a smoothened inhibitor Vismodegib for treatment of basal cell carcinomas. Vismodegib can block ligand-mediated hedgehog signaling, but numerous additional clinical trials have failed to show significant improvements in cancer patients. Amounting evidence indicate that ligand-independent hedgehog signaling plays an essential role in cancer. Ligand-independent hedgehog signaling, also named non-canonical hedgehog signaling, generally is not sensitive to smoothened inhibitors. What we know about non-canonical hedgehog signaling in cancer, and how should we prevent its activation? In this review, we will summarize recent development of non-canonical hedgehog signaling in cancer, and will discuss potential ways to prevent this type of hedgehog signaling. Full article
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Open AccessReview
The Role of Hedgehog Signaling in Tumor Induced Bone Disease
Cancers 2015, 7(3), 1658-1683; https://doi.org/10.3390/cancers7030856 - 26 Aug 2015
Cited by 12 | Viewed by 3517
Abstract
Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly [...] Read more.
Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors. Full article
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Open AccessReview
MicroRNAs and Chinese Medicinal Herbs: New Possibilities in Cancer Therapy
Cancers 2015, 7(3), 1643-1657; https://doi.org/10.3390/cancers7030855 - 24 Aug 2015
Cited by 42 | Viewed by 3168
Abstract
In recent decades Chinese medicine has been used worldwide as a complementary and alternative medicine to treat cancer. Plenty of studies have shown that microRNAs (miRNAs) play fundamental roles in many pathological processes, including cancer, while the anti-cancer mechanisms of Chinese medicinal herbs [...] Read more.
In recent decades Chinese medicine has been used worldwide as a complementary and alternative medicine to treat cancer. Plenty of studies have shown that microRNAs (miRNAs) play fundamental roles in many pathological processes, including cancer, while the anti-cancer mechanisms of Chinese medicinal herbs targeting miRNAs also have been extensively explored. Our previous studies and those of others on Chinese medicinal herbs and miRNAs in various cancer models have provided a possibility of new cancer therapies, for example, up-regulating the expression of miR-23a may activate the positive regulatory network of p53 and miR-23a involved in the mechanism underlying the anti-tumor effect of berberine in hepatocellular carcinoma (HCC). In this review, we survey the role of Chinese medicinal herbal products in regulating miRNAs in cancer and the use of mediating miRNAs for cancer treatment. In addition, the controversial roles of herb-derived exogenous miRNAs in cancer treatment are also discussed. It is expected that targeting miRNAs would provide a novel therapeutic approach in cancer therapy by improving overall response and survival outcomes in cancer treatment, especially when combined with conventional therapeutics and Chinese medicinal herbal products. Full article
(This article belongs to the Special Issue Non-Coding RNAs in Cancers)
Open AccessReview
Dichotomy in the Epigenetic Mark Lysine Acetylation is Critical for the Proliferation of Prostate Cancer Cells
Cancers 2015, 7(3), 1622-1642; https://doi.org/10.3390/cancers7030854 - 19 Aug 2015
Cited by 2 | Viewed by 2782
Abstract
The dynamics of lysine acetylation serve as a major epigenetic mark, which regulates cellular response to inflammation, DNA damage and hormonal changes. Microarray assays reveal changes in gene expression, but cannot predict regulation of a protein function by epigenetic modifications. The present study [...] Read more.
The dynamics of lysine acetylation serve as a major epigenetic mark, which regulates cellular response to inflammation, DNA damage and hormonal changes. Microarray assays reveal changes in gene expression, but cannot predict regulation of a protein function by epigenetic modifications. The present study employs computational tools to inclusively analyze microarray data to understand the potential role of acetylation during development of androgen-independent PCa. The data revealed that the androgen receptor interacts with 333 proteins, out of which at least 92 proteins were acetylated. Notably, the number of cellular proteins undergoing acetylation in the androgen-dependent PCa was more as compared to the androgen-independent PCa. Specifically, the 32 lysine-acetylated proteins in the cellular models of androgen-dependent PCa were mainly involved in regulating stability as well as pre- and post-processing of mRNA. Collectively, the data demonstrate that protein lysine acetylation plays a crucial role during the transition of androgen-dependent to -independent PCa, which importantly, could also serve as a functional axis to unravel new therapeutic targets. Full article
(This article belongs to the Special Issue Cancer Cell Proliferation)
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Open AccessArticle
Peri-Operative Management of Older Adults with Cancer—The Roles of the Surgeon and Geriatrician
Cancers 2015, 7(3), 1605-1621; https://doi.org/10.3390/cancers7030853 - 18 Aug 2015
Cited by 12 | Viewed by 2681
Abstract
Optimal surgical management of older adults with cancer starts pre-operatively. The surgeon plays a key role in the appropriate selection of patients and procedures, optimisation of their functional status prior to surgery, and provision of more intensive care for those who are at [...] Read more.
Optimal surgical management of older adults with cancer starts pre-operatively. The surgeon plays a key role in the appropriate selection of patients and procedures, optimisation of their functional status prior to surgery, and provision of more intensive care for those who are at high risk of post-operative complications. The literature, mainly based on retrospective, non-randomised studies, suggests that factors such as age, co-morbidities, pre-operative cognitive function and intensity of the surgical procedure all appear to contribute to the development of post-operative complications. Several studies have shown that a pre-operative geriatric assessment predicts post-operative mortality and morbidity as well as survival in older surgical cancer patients. Geriatricians are used to working in multidisciplinary teams that assess older patients and make individual treatment plans. However, the role of the geriatrician in the surgical oncology setting is not well established. A geriatrician could be a valuable contribution to the treatment team both in the pre-operative stage (patient assessment and pre-operative optimisation) and the post-operative stage (patient assessment and treatment of medical complications as well as discharge planning). Full article
(This article belongs to the Special Issue Cancers and Aging)
Open AccessArticle
Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma
Cancers 2015, 7(3), 1586-1604; https://doi.org/10.3390/cancers7030852 - 14 Aug 2015
Cited by 4 | Viewed by 3778
Abstract
Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the [...] Read more.
Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR). UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
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Open AccessReview
Hedgehog Signaling in the Maintenance of Cancer Stem Cells
Cancers 2015, 7(3), 1554-1585; https://doi.org/10.3390/cancers7030851 - 11 Aug 2015
Cited by 86 | Viewed by 3900
Abstract
Cancer stem cells (CSCs) represent a rare population of cells with the capacity to self-renew and give rise to heterogeneous cell lineages within a tumour. Whilst the mechanisms underlying the regulation of CSCs are poorly defined, key developmental signaling pathways required for normal [...] Read more.
Cancer stem cells (CSCs) represent a rare population of cells with the capacity to self-renew and give rise to heterogeneous cell lineages within a tumour. Whilst the mechanisms underlying the regulation of CSCs are poorly defined, key developmental signaling pathways required for normal stem and progenitor functions have been strongly implicated. Hedgehog (Hh) signaling is an evolutionarily-conserved pathway essential for self-renewal and cell fate determination. Aberrant Hh signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumourigenesis, including the maintenance of CSCs. Here, we discuss the mounting evidence suggestive of Hh-driven CSCs in the context of haematological malignancies and solid tumours and the novel strategies that hold the potential to block many aspects of the transformation attributed to the CSC phenotype, including chemotherapeutic resistance, relapse and metastasis. Full article
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Open AccessArticle
Treatment of Regional Metastatic Melanoma of Unknown Primary Origin
Cancers 2015, 7(3), 1543-1553; https://doi.org/10.3390/cancers7030849 - 10 Aug 2015
Cited by 5 | Viewed by 3049
Abstract
(1) Background: The purpose of this retrospective study was to evaluate the recurrence and survival rates of metastatic melanoma of unknown primary origin (MUP), in order to further refine current recommendations for the surgical treatment; (2) Methods: Medical data of all MUP patients [...] Read more.
(1) Background: The purpose of this retrospective study was to evaluate the recurrence and survival rates of metastatic melanoma of unknown primary origin (MUP), in order to further refine current recommendations for the surgical treatment; (2) Methods: Medical data of all MUP patients registered between 2000 and 2011, were analyzed. Seventy-eight patients were categorized in either lymph node (axilla, groin, head-and neck) or subcutaneous MUP. Axillary node MUPs were generally treated with dissections of levels I-III, inguinal node MUPs with combined superficial and deep groin dissections, and head-and-neck node MUPs with neck dissections to various extents, based on lymph drainage patterns. Subcutaneous lesions were excised with 1–2 cm margins. The primary outcome was treatment outcomes in terms of (loco)regional recurrence and survival rates; (3) Results: Lymph node MUP recurred regionally in 11% of patients, with an overall recurrence rate of 45%. In contrast, subcutaneous MUP recurred locally in 65% of patients with an overall recurrence rate of 78%. This latter group had a significantly shorter disease-free interval than patients with lymph node MUP (p = 0.000). In the entire study population, 5-year and 10-year overall survival rates were 56% and 47% respectively, with no differences observed between the various subgroups; (4) Conclusion: The relatively low regional recurrence rate after regional lymph node dissection (11%) supports its current status as standard surgical treatment for lymph node MUP. Subcutaneous MUP, on the contrary, appears to recur both locally (65%) and overall (78%) at a significantly higher rate, suggesting a different biological behavior. However, wide local excision remains the best available option for this specific group. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
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Open AccessReview
Molecular Targeted Intervention for Pancreatic Cancer
Cancers 2015, 7(3), 1499-1542; https://doi.org/10.3390/cancers7030850 - 10 Aug 2015
Cited by 19 | Viewed by 3405
Abstract
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet [...] Read more.
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. Full article
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Open AccessReview
Not so Fast: Co-Requirements for Sonic Hedgehog Induced Brain Tumorigenesis
Cancers 2015, 7(3), 1484-1498; https://doi.org/10.3390/cancers7030848 - 06 Aug 2015
Cited by 3 | Viewed by 2949
Abstract
The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a [...] Read more.
The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a more nuanced role for Shh signaling. We postulate that Shh signaling does not work alone but requires co-activation of other signaling pathways for tumorigenesis and stem cell maintenance. This review will focus on the interplay between the Shh pathway and these pathways to promote tumor growth in brain tumors, presenting opportunities for the study of combinatorial therapies. Full article
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Open AccessArticle
Breast Cancer in Elderly Caucasian Women—An Institution-Based Study of Correlation between Breast Cancer Prognostic Markers, TNM Stage, and Overall Survival
Cancers 2015, 7(3), 1472-1483; https://doi.org/10.3390/cancers7030846 - 31 Jul 2015
Cited by 6 | Viewed by 3462
Abstract
There is still a paucity of data on how breast cancer (BC) biology influences outcomes in elderly patients. We evaluated whether ER/PR/HER2 subtype and TNM stage of invasive BC had a significant impact on overall survival (OS) in a cohort of 232 elderly [...] Read more.
There is still a paucity of data on how breast cancer (BC) biology influences outcomes in elderly patients. We evaluated whether ER/PR/HER2 subtype and TNM stage of invasive BC had a significant impact on overall survival (OS) in a cohort of 232 elderly Caucasian female patients (≥70 year old (y/o)) from our institution over a ten-year interval (January 1998–July 2008). Five ER/PR/HER2 BC subtypes classified per 2011 St. Gallen International Expert Consensus recommendations were further subclassified into three subtypes (traditionally considered “favorable” subtype-ER+/PR+/HER2-, and traditionally considered “unfavorable” BC subtypes: HER2+ and triple negative). OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis, when controlled for TNM stage. The majority of our patients (178/232 = 76.8%) were of the “favorable” BC subtype; 23.2% patients were with “unfavorable” subtype (HER2+ = 12% (28/232) and triple negative = 11.2% (26/232)). Although a trend for better OS was noted in HER2+ patients (68%) vs. 56% in ER+/PR+ HER2- or 58% in triple negative patients, “favorable” BC subtype was not significantly predictive of better OS (p = 0.285). TNM stage was predictive of OS (p < 0.001). These results are similar to our published studies on Caucasian BC patients of all ages in which ER/PR/HER2 status was not predictive of OS, irrespective of classification system used. Full article
(This article belongs to the Special Issue Cancers and Aging)
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Open AccessReview
The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression
Cancers 2015, 7(3), 1447-1471; https://doi.org/10.3390/cancers7030845 - 31 Jul 2015
Cited by 21 | Viewed by 3797
Abstract
Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression [...] Read more.
Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer. Full article
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Open AccessArticle
Role of the Aryl Hydrocarbon Receptor in Colon Neoplasia
Cancers 2015, 7(3), 1436-1446; https://doi.org/10.3390/cancers7030847 - 31 Jul 2015
Cited by 16 | Viewed by 2975
Abstract
For both men and women, colorectal cancer (CRC) is the second leading cause of cancer death in the United States, primarily as a consequence of limited therapies for metastatic disease. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor with diverse functions [...] Read more.
For both men and women, colorectal cancer (CRC) is the second leading cause of cancer death in the United States, primarily as a consequence of limited therapies for metastatic disease. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor with diverse functions in detoxification of xenobiotics, inflammatory responses, and tissue homeostasis. Emerging evidence indicates that AhR also plays an important role in regulating intestinal cell proliferation and tumorigenesis. Here, we review both the pro- and anti-carcinogenic properties of AhR signaling and its potential role as a therapeutic target in CRC. Full article
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Open AccessArticle
Dosimetric Characteristics of a Two-Dimensional Diode Array Detector Irradiated with Passively Scattered Proton Beams
Cancers 2015, 7(3), 1425-1435; https://doi.org/10.3390/cancers7030844 - 30 Jul 2015
Cited by 1 | Viewed by 2663
Abstract
Purpose: To evaluate the dosimetric characteristics of a two-dimensional (2D) diode array detector irradiated with passively scattered proton beams. Materials and Methods: A diode array detector, MapCHECK (Model 1175, Sun Nuclear, Melbourne, FL, USA) was characterized in passive-scattered proton beams. The [...] Read more.
Purpose: To evaluate the dosimetric characteristics of a two-dimensional (2D) diode array detector irradiated with passively scattered proton beams. Materials and Methods: A diode array detector, MapCHECK (Model 1175, Sun Nuclear, Melbourne, FL, USA) was characterized in passive-scattered proton beams. The relative sensitivity of the diodes and absolute dose calibration were determined using a 250 MeV beam. The pristine Bragg curves (PBCs) measured by MapCHECK diodes were compared with those of an ion chamber using a range shift method. The water-equivalent thickness (WET) of the diode array detector’s intrinsic buildup also was determined. The inverse square dependence, linearity, and other proton dosimetric quantities measured by MapCHECK were also compared with those of the ion chambers. The change in the absolute dose response of the MapCHECK as a function of accumulated radiation dose was used as an indicator of radiation damage to the diodes. 2D dose distribution with and without the compensator were measured and compared with the treatment planning system (TPS) calculations. Results: The WET of the MapCHECK diode’s buildup was determined to be 1.7 cm. The MapCHECK-measured PBC were virtually identical to those measured by a parallel-plate ion chamber for 160, 180, and 250 MeV proton beams. The inverse square results of the MapCHECK were within ±0.4% of the ion chamber results. The linearity of MapCHECK results was within 1% of those from the ion chamber as measured in the range between 10 and 300 MU. All other dosimetric quantities were within 1.3% of the ion chamber results. The 2D dose distributions for non-clinical fields without compensator and the patient treatment fields with the compensator were consistent with the TPS results. The absolute dose response of the MapCHECK was changed by 7.4% after an accumulated dose increased by 170 Gy. Conclusions: The MapCHECK is a convenient and useful tool for 2D dose distribution measurements using passively scattered proton beams. Variations in MapCHECK’s dose response with increasing levels of total accumulated radiation dose should be carefully monitored. Full article
(This article belongs to the Special Issue Proton Therapy for Cancer)
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Open AccessReview
Long Non-Coding RNAs: The Key Players in Glioma Pathogenesis
Cancers 2015, 7(3), 1406-1424; https://doi.org/10.3390/cancers7030843 - 29 Jul 2015
Cited by 60 | Viewed by 3747
Abstract
Long non-coding RNAs (LncRNAs) represent a novel class of RNAs with no functional protein-coding ability, yet it has become increasingly clear that interactions between lncRNAs with other molecules are responsible for important gene regulatory functions in various contexts. Given their relatively high expressions [...] Read more.
Long non-coding RNAs (LncRNAs) represent a novel class of RNAs with no functional protein-coding ability, yet it has become increasingly clear that interactions between lncRNAs with other molecules are responsible for important gene regulatory functions in various contexts. Given their relatively high expressions in the brain, lncRNAs are now thought to play important roles in normal brain development as well as diverse disease processes including gliomagenesis. Intriguingly, certain lncRNAs are closely associated with the initiation, differentiation, progression, recurrence and stem-like characteristics in glioma, and may therefore be exploited for the purposes of sub-classification, diagnosis and prognosis. LncRNAs may also serve as potential therapeutic targets as well as a novel biomarkers in the treatment of glioma. In this article, the functional aspects of lncRNAs, particularly within the central nervous system (CNS), will be briefly discussed, followed by highlights of the important roles of lncRNAs in mediating critical steps during glioma development. In addition, the key lncRNA players and their possible mechanistic pathways associated with gliomagenesis will be addressed. Full article
(This article belongs to the Special Issue Non-Coding RNAs in Cancers)
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Open AccessReview
MicroRNAs in Cancer: A Historical Perspective on the Path from Discovery to Therapy
Cancers 2015, 7(3), 1388-1405; https://doi.org/10.3390/cancers7030842 - 27 Jul 2015
Cited by 72 | Viewed by 3968
Abstract
Recent progress in microRNA (miRNA) therapeutics has been strongly dependent on multiple seminal discoveries in the area of miRNA biology during the past two decades. In this review, we focus on the historical discoveries that collectively led to transitioning miRNAs into the clinic. [...] Read more.
Recent progress in microRNA (miRNA) therapeutics has been strongly dependent on multiple seminal discoveries in the area of miRNA biology during the past two decades. In this review, we focus on the historical discoveries that collectively led to transitioning miRNAs into the clinic. We highlight the pivotal studies that identified the first miRNAs in Caenorhabditis elegans to the more recent reports that have fueled the quest to understand the use of miRNAs as markers for cancer diagnosis and prognosis. In addition, we provide insights as to how unraveling basic miRNA biology has provided a solid foundation for advancing miRNAs, such as miR-34a, therapeutically. We conclude with a brief examination of the current challenges that still need to be addressed to accelerate the path of miRNAs to the clinic: including delivery vehicles, miRNA- and delivery-associated toxicity, dosage, and off target effects. Full article
(This article belongs to the Special Issue Non-Coding RNAs in Cancers)
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Open AccessReview
Vitamins and Melanoma
Cancers 2015, 7(3), 1371-1387; https://doi.org/10.3390/cancers7030841 - 24 Jul 2015
Cited by 12 | Viewed by 2830
Abstract
A tremendous amount of information was published over the past decades in relation to the role of vitamins in various neoplastic diseases. In particular, several studies showed an inverse relationship between selected vitamins intake and cancer risk. In this review we will focus [...] Read more.
A tremendous amount of information was published over the past decades in relation to the role of vitamins in various neoplastic diseases. In particular, several studies showed an inverse relationship between selected vitamins intake and cancer risk. In this review we will focus on the role played by vitamins in melanoma with particular regard to vitamin A, D, K, E and C. Given that vitamin supplementation is easy, convenient, and readily accepted by patients, in the future the use of vitamins in chemoprevention and therapy of melanoma could be encouraged if supported by pre-clinical and clinical evidence. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
Open AccessArticle
T-Cadherin Expression in Melanoma Cells Stimulates Stromal Cell Recruitment and Invasion by Regulating the Expression of Chemokines, Integrins and Adhesion Molecules
Cancers 2015, 7(3), 1349-1370; https://doi.org/10.3390/cancers7030840 - 21 Jul 2015
Cited by 9 | Viewed by 2790
Abstract
T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as [...] Read more.
T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as well as the enhanced metastasis. Since tumor progression is highly dependent upon cell migration and invasion, the aim of the present study was to elucidate the mechanisms of T-cadherin participation in these processes. Herein we show that T-cadherin expression results in the increased invasive potential due to the upregulated expression of pro-oncogenic integrins, chemokines, adhesion molecules and extracellular matrix components. The detected increase in chemokine expression could be responsible for the stromal cell recruitment. At the same time our previous data demonstrated that T-cadherin expression inhibited neoangiogenesis in the primary tumors. We demonstrate molecules and reduction in pro-angiogenic factors. Thus, T-cadherin plays a dual role in melanoma growth and progression: T-cadherin expression results in anti-angiogenic effects in melanoma, however, this also stimulates transcription of genes responsible for migration and invasion of melanoma cells. Full article
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