New Perspectives on Melanoma_ The Role of PAX3

Similarly ectopic expression of pax3 promotes growth

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Unformatted text preview: esis Overview Interestingly, microarray analysis has identified two clearly distinguishable gene‐ expression profiles corresponding to the phenotype of two melanoma cell subpopulations: one population of proliferative, more differentiated, weakly metastatic cells which show a Wnt‐signalling gene expression signature, reflected through upregulation of MITF and its downstream melanogenic targets; and a less differentiated/stem‐like, highly motile aggressive population of cells, which show upregulation of TGFβ‐signalling genes, involved in modifying the extracellular environment [124,125]. Induction of TGFβ‐like signalling in melanoma, inhibits Wnt signalling by driving the expression of Wnt‐inhibitor factors, thus leading to less proliferative but more metastatic melanoma cells. This scenario is reminiscent of normal melanocyte stem cells, residing in the bulge that is a Wnt–protected area, lacking MITF and other melanogenic markers, in contrast to their differentiating progeny in the Wnt‐responsive hair follicle [118,149,150]. 22 Chapter I – Thesis Overview 3. PAX3 expression in melanoma and other neural crest derived malignancies The involvement of PAX proteins in cancer is well known [14,15,53]. A multitude of studies consistently show PAX3 expression in melanoma [21‐26,73,151]. Research from our own lab, shows PAX3 in peripheral blood of melanoma patients at various stages of melanoma, including many years after removal of the primary lesion [152]. Inaddition to melanoma, PAX3 has also been found in tumours arising from other neural crest‐derived tissues, such as classic medulloblastoma, benign peripheral glial tumour neurofibroma (precursor of malignant nerve sheath tumour), Erwin’s sarcoma, and supratentorial primitive neuroectodermal tumour [17]. PAX3 is also know to be associated with paediatric alveolar rhabdomyosarcoma (ARMS), which is caused by the gene fusion resulting from the t(2;13)(q35;q14) translocation which juxtaposed the PAX3 (or its analogous...
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