Unformatted text preview: actively suppress apoptosis. Genetic alterations consistent with advanced melanomas include loss of phosphatase and tensin homolog (PTEN) (which inhibits apoptosis by serine/threoninprotein kinase AKT activation), RAS and RAF activating mutations and β‐catenin activation [106,138]. Changes also occur in a network of cell adhesion molecules that enable melanoma cell detachment. These include loss of E‐Cadherin, essential for melanocyte homeostasis , and upregulation of N‐Cadherin which mediates gap junctions with N‐cadherin‐expressing dermal fibroblasts . Further changes that affect basal membrane integrity include upregulation of matrix metalloproteinase‐2 that enables invasion of the deeper layers . Additionally, dermal invasion correlates with the production of immune modifying factors such as interleukins, chemokines and TGFβ . Finally, vascularisation and melanoma growth, seen at later metastatic stages, are regulated by several factors including connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet‐derived growth factor (PDGF) . An alternative to the linear progression model, is the melanoma ‘stem cell’ model, in which progression towards a metastatic fate is driven by melanoma stem‐like cells, as observed in other cancers [143‐147]. According to this model tumours contain two distinctive cell subpopulations: one slow cycling population, that resembles normal stem cells in terms of ability to self‐renew and give rise to a differentiating progeny, carry tumourigenic potential; and another that derives from these tumourigenic cells, has higher proliferative potential (maybe limited), but will not seed new tumours. Further research suggests that the two subpopulations of melanoma cells, with stem‐like and more differentiated proliferative phenotype, are only temporarily distinct and that these phenotypes are actually interchangeable [124,148]. 21 Chapter I – Th...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.
- Spring '14