Unformatted text preview: te stem cells. A different mechanism to that of UV induced melanocyto‐genesis seems to be employed in wound healing and in epidermal repigmentation in the case of vitiligo, where newly formed melanocytes originate from the hair follicle [80,82,165‐167]. Those processes are clearly driven, in both of these situations, by the loss of local epidermal melanocytes, and only melanocytic bulge cells are available for repopulation of the epidermis. In summary, normal melanocytic cells have an in‐built capacity to proliferate and migrate when required. Since PAX3 is one of the key regulators of melanocyte proliferation and migration during embryonic development, it is likely that its role is maintained in melanocytes of the adult skin. Moreover, it is not known whether the same developmental processes are likely to be employed in melanoma development and progression. Initially malignant cells proliferate intensively, resulting in growth of the primary lesion. Some of these cells will be undifferentiated stem‐like cells, being able to self‐renew as well as produce progeny able to differentiate. Eventually, some of the melanoma cells will pass the basal membrane and invade the deeper layers of the dermis. This step requires cells to be able to actively migrate, modify their immediate surrounding, intercellular matrix, and survive independently of keratinocytes. Again, highly 25 Chapter I – Thesis Overview motile melanoma cells will migrate into the circulation and spread to distal locations where they can generate metastases. Given that PAX3 is a key regulator of these crucial cellular processes of differentiation, proliferation, survival and migration during melanocyte development, it may regulate similar processes in normal melanocytes, predisposing them to malignant transformation. Similarly, it might regulate these same processes in melanoma, given its high expression here, driving its progression. 26 Chapter I – Thesis Overview
iv. RESEARCH DESIGN, HYPOTHESIS AND AIMS Evidence supports a key role for PAX3 in melanocyte development during embryogenesis, regulating cellular processes such as differentiation, survival, proliferation and migration [10‐12,14,15...
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- pH, ........., Melanocyte