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New Perspectives on Melanoma_ The Role of PAX3

The likelihood of melanomas arising from

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Unformatted text preview: owth inhibition by melanoma cells is strongly linked to metastatic melanoma progression [119,124,125]. It is interesting that TGFβ1 treatment in growth inhibition‐resistant melanoma cells does not downregulate PAX3 expression, and overexpression of PAX3 in TGFβ‐sensitive melanoma cells results in their desensitisation [20], suggesting that resistance to TGFβ observed in some melanoma cells might be PAX3‐mediated. 17 Chapter I – Thesis Overview 2. Melanoma Melanoma is a highly metastatic tumour arising from cutaneous melanocytic cells. Some melanomas retain the physical characteristics of melanocytes, namely pigmentation, giving melanomas a highly pigmented phenotype; on the other hand some melanomas lose this ability and are amelanotic. Melanomas are, in general, significantly heterogeneous, in terms of cell morphology, level of pigmentation and marker expression [29,126]. Melanoma cells are also highly resistant to drug treatment by employing various mechanisms that confer multidrug resistance, including controlled drug uptake and export via membrane transporter systems, as well as drug trapping and export via melanosomes (Figure 1.2.1.) [127,128]. In addition, melanomas show a higher propensity to metastasise, relative to other skin cancers [129]. Figure 1.2.1. Drug resistance mechanisms in melanomas. Melanoma cells become resistant to anticancer drugs by several sequentially occurring mechanisms. Initially drug resistance occurs as a result of reduced drug influx (e.g., reduced endocytosis, reduced activity of an importer, or increased energy‐dependent efflux). Once drugs enter cells, they can be trapped in subcellular organelles, such as melanosomes or other vesicles, and exported from cells by enhanced melanosome transfer mechanisms. I–IV refers to stage I– IV melanosomes (adapted from [127]). Morphologically, melanomas consist of atypical, rounded (epithelioid) or spindle (lentiginous) shaped cells, which initially aggregate in the epidermis and form ‘nests’ or ‘branches’ above the basal membrane. Histologically, several stages of melanoma development are evident, associated with worsening prognosis and 18 Chapter I – Thesis O...
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