Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cutaneous malignant melanoma is an aggressive form of skin cancer, characterized by strong chemoresistance and poor patient prognosis. The molecular mechanisms underlying its resistance to chemotherapy remain unclear but are speculated to involve the dysregulation of apoptotic pathways. In this study, we sought to determine whether PUMA (p53 upregulated modulator of apoptosis) contributes to human melanoma formation, tumor progression, and survival. We used tissue microarray and immunohistochemistry to examine PUMA expression in 107 primary melanomas, 51 metastatic melanomas, and 64 dysplastic nevi. Here we report that PUMA expression is significantly weaker in primary melanomas compared to dysplastic nevi (P<0.0001), and is further reduced in metastatic melanomas compared to primary tumors (P=0.001). We show that weak PUMA expression in melanoma correlates with poorer overall and disease-specific 5-year survival (P<0.005 and P<0.001, respectively) of melanoma patients and that PUMA expression in tumor tissue is an independent predictor of both overall and disease-specific 5-year survival (P=0.05). Additionally, we show that exogenous PUMA expression in human melanoma cell lines (both wild type and mutant p53) results in significant apoptotic cell death. Our results suggest that PUMA expression may be an important prognostic marker for human melanoma and that adenoviral delivery of PUMA sensitizes melanoma cells to apoptosis.
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PMID:PUMA expression is significantly reduced in human cutaneous melanomas. 1569 57

Carcinogenesis is a multi-step series of somatic genetic events. The complexity of this multi-hit process makes it difficult to determine each single event and the definitive outcome of such events. To investigate the genetic alterations in cancer-related genes, sensitive and reliable detection methods are of major importance for generating relevant results. Another critical issue is the quality of starting material which largely affects the outcome of the analysis. Microdissection of cells defined under the microscope ensures a selection of representative material for subsequent genetic analysis. Skin cancer provides an advantageous model for studying the development of cancer. Detectable lesions occur early during tumor progression, facilitating molecular analysis of the cell populations from both preneoplastic and neoplastic lesions. Alterations of the p53 tumor suppressor gene are very common in non-melanoma skin cancer, and dysregulation of p53 pathways appear to be an early event in the tumor development. A high frequency of epidermal p53 clones has been detected in chronically sun-exposed skin. The abundance of clones containing p53 mutated keratinocytes adjacent to basal cell (BCC) and squamous cell carcinoma (SCC) suggests a role in human skin carcinogenesis. Studies using p53 mutations as a clonality marker have suggested a direct link between actinic keratosis, SCC in situ and invasive SCC. Microdissection-based studies have also shown that different parts of individual BCC tumors can share a common p53 mutation yet differ with respect to additional alterations within the p53 gene, consistent with subclonal development within tumors. Here, we present examples of using well-defined cell populations, including single cells, from complex tissue in combination with molecular tools to reveal features involved in skin carcinogenesis.
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PMID:Genetic tumor archeology: microdissection and genetic heterogeneity in squamous and basal cell carcinoma. 1574 39

Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.
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PMID:Photochemoprevention of ultraviolet B signaling and photocarcinogenesis. 1574 45

Malignant melanoma is still the most frequent cause of death due to skin cancer with a rising incidence and mortality. Despite continued progress in understanding the pathophysiology of tumor progression and metastasis, curative therapeutic options are still missing for metastatic melanoma. The ability of a malignant melanoma to metastasize is partially derived from the capacity to avoid destruction by an intact immune system. Thus, a better understanding of the immunological processes that lead to the escape of melanoma cells from immune recognition could help to develop preventive strategies or effective new therapies. Therefore, an analysis of the MHC class I pathway and molecules involved in peptide loading of the MHC class I molecules could provide an important clue to future immune-based melanoma therapies, and might also help to select patients who could be expected to profit from T-cell-based immunotherapy. In this review article, we report on current data and concepts about the generation of MHC class I peptide complexes in human malignant melanoma.
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PMID:[Role of MHC class I molecules in anti-tumoral mechanisms in human malignant melanoma]. 1616 61

Large-scale genomic and proteomic analysis has provided a wealth of information on biologically relevant systems, and the ability to analyze this information is crucial to uncovering important biological relationships. However, it has proven difficult to compare large datasets from different sources due to different gene and protein identifiers assigned by individual laboratories and database systems. Here, we describe the design of a fully automated blast program (BlastPro) that facilitates rapid comparison of large protein-protein, nucleotide--nucleotide, or nucleotide--protein datasets from numerous, independent studies. Using this system, we compared several published genomic and proteomic databases for proteins that are upregulated in highly motile, metastatic tumor cells. Analysis of five independent studies comprised of greater than 1 x 10(6) genomic sequences and greater than 1,000 proteins revealed that the cytoskeletal-associated protein alpha-actinin is increased at both the mRNA and protein level in metastatic breast, prostate, and skin cancer cells. Interestingly, spatial analysis of alpha-actinin expression revealed that it is amplified 8-fold in the leading pseudopodium compared to the cell body compartment of migrating cells. These findings indicate that amplification of alpha-actinin and its localization to the leading pseudopodium are potential biomarkers of cancer progression to a more metastatic phenotype. Together, our results demonstrate that the BlastPro system can be used to compare large genomic and proteomic datasets to reveal important biological relationships including those associated with cancer progression.
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PMID:Computational methods for comparison of large genomic and proteomic datasets reveal protein markers of metastatic cancer. 1660 98

IKK (I kappaB kinase) alpha is essential for embryonic skin development in mice. Mice deficient in IKKalpha display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKKalpha in human skin diseases remains largely unknown. To shed light on the role of IKKalpha in human skin diseases, we examined IKKalpha expression and Ikkalpha mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKKalpha expression in poorly differentiated human SCCs and identified Ikkalpha mutations in exon 15 of Ikkalpha in eight of nine human SCCs, implying that IKKalpha is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKKalpha in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKKalpha transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKKalpha in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases.
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PMID:A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas. 1707 94

Inorganic arsenic (arsenite and arsenate) in drinking water has been associated with skin cancers and increased incidence of cardiovascular diseases. Additionally, studies have demonstrated the pro-angiogenic effect of arsenite and its potential promotion of tumor angiogenesis and tumor progression. Furthermore, recent reports demonstrated reversal of skin co-carcinogenesis by an organoselenium compound. The present study was undertaken to determine the effect and mechanism on angiogenesis of arsenite at low level and its potential reversal by various selenium-derived compounds. The pro-angiogenesis effects and mechanisms of sodium arsenite were determined using the chick chorioallantoic membrane (CAM) model over 3 days and compared with standard pro-angiogenesis factors, such as basic fibroblast growth factor (b-FGF). Additionally, the potential effect of various selenium-derived compounds--such as dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine--in reversing the pro-angiogenesis effect of arsenite or b-FGF was also determined in the CAM model. The pro-angiogenesis effect of arsenite or b-FGF was significantly (P < 0.01) blocked by dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine. The pro-angiogenesis effect of either sodium arsenite at 33 nM or b-FGF was blocked (P < 0.01) by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation inhibitor, PD 98059. Additionally, the pro-angiogenic effect of arsenic or b-FGF was blocked as well (P < 0.01) by the alphavbeta3 antagonist, XT199. These data suggest that the pro-angiogenesis effect of arsenic is initiated at the plasma membrane integrin alphavbeta3, involves activation of the ERK1/2 pathway and is effectively reversed by various selenium-derived compounds.
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PMID:Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds. 1715 27

Melanoma is the most aggressive form of skin cancer and advantages stages are inevitably resistant to conventional therapeutic agents. In particular, the inability of undergo apoptosis in response to chemotherapy and other external stimuli poses a selective advantage for tumor progression, metastasis formation as well as resistance to therapy in melanoma. Herein, we will review the discovery of MDR transporters and the apoptotic mechanisms used by melanoma cells. Furthermore, the novel strategies to overcome tumor chemoresistance will also discuss. In particular, we will review the cancer stem cell hypothesis and how the failure of MDR reversal agents might increase the therapeutic index of substrate antineoplastic agents.
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PMID:Drug resistance in melanoma: new perspectives. 1730 41

Malignant melanoma is the most invasive and deadly form of skin cancer with no effective therapy to treat advanced disease, leading to poor survival rates. Akt3 signaling plays an important role in deregulating apoptosis in approximately 70% of melanomas. Thus, targeting Akt3 signaling in melanoma patients has significant therapeutic potential for inhibiting melanomas, but no Akt3-specific chemotherapeutic agent exists. Unfortunately, nonspecific Akt inhibitors can cause systemic toxicity or increase metastasis. Identifying and targeting the Akt3 substrate that deregulates apoptosis might circumvent these complications but would require demonstration of its functional importance in disrupting normal apoptosis. In this study, PRAS40 was identified as an Akt3 substrate that deregulated apoptosis to promote melanoma tumorigenesis. Levels of phosphorylated PRAS40 (pPRAS40) increased during melanoma tumor progression paralleling increasing Akt3 activity. Majority of melanomas from patients with elevated Akt activity also had correspondingly higher levels of pPRAS40. Targeting PRAS40 or upstream Akt3 similarly reduced anchorage-independent growth in culture and inhibited tumor development in mice. Mechanistically, decreased pPRAS40 increased tumor cell apoptosis as well as sensitivity of melanoma cells to apoptosis-inducing agents, thereby decreasing chemoresistance. Collectively, these studies provide a solid mechanistic basis for targeting PRAS40 to inhibit the Akt3 signaling cascade and thereby retard melanoma development.
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PMID:PRAS40 deregulates apoptosis in malignant melanoma. 1744 74

Non-melanoma skin cancers (NMSC) are the most common malignant tumors in white population and their incidence has been increasing worldwide. Molecular events regulating cell survival, apoptosis, growth arrest as well as cell differentiation, are important contributors to the overall kinetics of benign and malignant cell growth and play a role in their development, progression and regression. Failure of these pathways can result in the loss of control over proliferation and lead to tumor development through the inactivation of tumor suppressor genes or the activation of oncogenes. Also, immunological mechanisms have been implicated in a phenomenon of tumor progression as well as spontaneous tumor regression. We have tried to summarize the main events in etiopatogenesis, development, progression and in some cases skin cancer regression. Further studies are needed to elucidate completely the details of apoptotic control in normal skin and determine factors resulting in apoptotic disbalance and disease.
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PMID:Apoptosis in skin cancer development and regression. 1746 44


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