Melanoma genetics and the development of rational therapeutics.

Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 05/2005; 115(4):813-24. DOI: 10.1172/JCI24808
Source: PubMed

ABSTRACT Melanoma is a cancer of the neural crest-derived cells that provide pigmentation to skin and other tissues. Over the past 4 decades, the incidence of melanoma has increased more rapidly than that of any other malignancy in the United States. No current treatments substantially enhance patient survival once metastasis has occurred. This review focuses on recent insights into melanoma genetics and new therapeutic approaches being developed based on these advances.

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    ABSTRACT: Fish melanoma models are increasingly used in studies of both spontaneous and induced melanoma formation. The melanoma Xiphophorus model was the first genetic model of melanoma available to researchers since the 1920s (Klin Wochenschrift 7:1561–1562, 1928; Z Indukt Abstammungs 44:253–257, 1927). Recently, transgenesis has been used to develop zebrafish and medaka models for melanoma research (Methods Mol Biol 461:521–539, 2008). These models are now starting to produce a wealth of novel information on the genetics of melanoma (including somatic mutations), signaling pathways and molecular mechanisms, immune responses, and determinants of metastasis. Moreover, the models are extremely well suited for drug/small-molecule screens aimed at discovering new therapeutic strategies in general treatment and personalized medicine and for the study of cancer-immune cell interactions. This review provides a summary of current and prospective studies in fish models of melanoma and pinpoints the translational potentials of melanoma models in fish.
    Current Pathobiology Reports. 06/2014; 2(2).
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    ABSTRACT: Microphthalmia-associated transcription factor (MITF) acts via pigment epithelium-derived factor (PEDF), an antiangiogenic protein, to regulate retinal pigment epithelium migration. PEDF expression and/or regulation during melanoma development have not been investigated previously. Using immunohistochemistry, we determined expression of PEDF in common and dysplastic melanocytic nevi, melanoma in situ, invasive melanoma, and metastatic melanoma (n = 102). PEDF expression was consistently decreased in invasive and metastatic melanoma, compared with nevi and melanoma in situ (P < 0.0001). PEDF was lost in thicker melanomas (P = 0.003), and correlated with depth of invasion (P = 0.003) and distant metastasis (P = 0.0331), but only marginally with mitotic index, AJCC stage, nodal metastasis, or blood vascular density (0.05 < P < 0.10). Quantitative real-time PCR and microarray analyses confirmed PEDF down-regulation at the mRNA level in several melanoma lines, compared with melanocytes. MITF positively correlated with PEDF expression in invasive melanomas (P = 0.0003). Searching for PEDF regulatory mechanisms revealed two occupied conserved E-boxes (DNA recognition elements) in the first intron of the human and mouse PEDF promoter regions, confirmed by binding assays. Dominant-negative and siRNA approaches in vivo demonstrated direct transcriptional influence of MITF on PEDF, establishing the PEDF gene (SERPINF1) as a MITF target in melanocytes and melanoma cells. These findings suggest that loss of PEDF expression promotes early invasive melanoma growth. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 11/2014; · 4.60 Impact Factor
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