New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: with these results, we have observed PAX3 and MCAM co‐expressing melanocytes in the growing hair follicle, but not in epidermal melanocytes [2]. MCAM upregulation in melanoma is associated with metastatic progression [229], and PAX3‐transfection into melanocytes or medulloblastoma cells has been previously shown to result in MCAM upregulation [121,204]. CSPG4 is a chondroitin sulphate proteoglycan that promotes cell motility and invasion by recruiting specific MT‐MMPs (membrane type matrix metalloproteinases) and MMPs to the cell membrane [290,291]. Interestingly, CSPG4 was found expressed in many cancers including melanoma [292]. Treatments targeting CSPG4 specifically inhibit melanoma growth in vivo and in vitro [293,294]. CSPG4 has also been associated with epidermal and follicular stem cells, where it is believed to contribute to their patterning and distribution [295,296]. CXCR4 is a chemokine receptor associated with the metastatic spread and progression of many tumours, including melanoma [276,297‐300]. CXCR4, and its ligand CXCL12, regulate chemotactic migration and “homing” of tumour cells to a secondary organ/site, and facilitate tumour cell extravasation [278,297,301]. CXCL12 and CXCR4 are shown to similarly regulate melanocyte stem cell migration and their proper positioning during hair cycle [302]. It was shown that CXCR4 is upregulated by PAX3‐FKHR in rhabdomyosarcomas [206,280,281,303]. 102 Chapter V – General Discussion From these results it is clear that melanocytic cells possess the potential and in fact the need to migrate. This intrinsic ability of melanocytes to migrate could possibly contribute to the aggressive and motile phenotype of transformed melanoma cells. The fact that all of the genes associated with metastatic progression of melanoma tested here, such as MCAM, CSPG4 and CXCR4, are shown here to be direct targets of PAX3 in both melanocytes and melanoma cells, strongly supports the role of PAX3 in regulating cell motility, possibly contributing to melanoma dissemination. Dif...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.

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