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A phenotype switching model for melanoma progression implication for therapy

Dummer, R.; Eichhoff, O.; Widmer, D.; Hoek, K.

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doi: 10.1097/01.cmr.0000382759.93495.9f
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Detailed genetic investigations in melanoma cell cultures derived from various patients have contributed to the identification of subgroups of melanomas who share deletions amplifications and mutations and has resulted in a genetic classification of melanomas. However these genetic changes do not translate into corresponding transcriptional profiles. In contrast, ongoing investigations on the transcriptome of melanoma cell cultures have identified two dominant transcriptional profiles that are associated with specific features in vitro. One transcriptional profile is characterized by a strong melanocytic signature with many pigmentation genes and the master regulators MITF and Sox-10. The other profile has a TGF-beta like signature and has weak signals for melanocytic genes. The melanocytic profile is associated with a high proliferation rate and therefore is called proliferative whereas the TGF-beta signal dominated one is associated with low proliferation but high invasiveness in vitro and therefore is called invasive. There is evidence that these phenotypes may switch in response to microenvironmental changes in vivo in animal models as well in human biopsies.

The simultaneous presence of invasive and proliferative cells in melanoma lesions can explain the incredible resistance of melanoma metastases to many therapeutic strategies. Most current treatment options such as chemotherapy and specific immunotherapy will target proliferative and well-differentiated cells and fail to hit invasive cells that can switch back to proliferative phenotype whenever the therapeutic pressure is released. Future successful therapeutic approaches will have to target both proliferative and invasive cells or freeze the tumor cell population in one phenotype.

© 2010 Lippincott Williams & Wilkins, Inc.