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Unformatted text preview: acquisition of additional mutations (Figure 1.2.2) [104,106,135]. The majority of 19 Chapter I – Thesis Overview melanomas however arise de novo, and do not necessarily follow this model of progression. Figure 1.2.2. Schematic representation of the linear model of melanoma progression. This
diagram shows consecutive steps in melanoma progression, from (a) normal epidermal
melanocytes, (b) through the formation of naevi, (c) pagetoid spread of atypical cells in radial
growth phase, (d) to the vertical growth of the lesion and dermal invasion (Adapted from ). According to the linear model, three major steps/events are required for melanoma progression, including clonal expansion of cells harbouring initial mutation/s, acquisition of additional mutations allowing cells to overcome senescence, and finally acquisition of mutations which result in suppression of apoptosis [104,106,137]. Initial mutations in melanocytes, such as activating mutations in BRAF, NRAS, or KIT, or amplification of cyclin D1 (CCND1) or cyclindependant kinase 4 (CDK4), result in their increased proliferation. Over‐activation of proliferative signals (oncogenic stress) is known to trigger cellular senescence, and benign pigmented moles/naevi can be described as a senescent, clonal proliferation of melanocytes [104,106,137]. Additional mutations, such as inactivation of cyclin‐dependant kinase inhibitor p16/ retinoblastoma protein (RB) pathways or activation of telomerase, are required to enable cells to overcome senescence and to become proliferative and immortalised [104,106]. Lesions with changes described above, are early malignant melanocytic lesions, known as superficial spreading melanomas. Melanoma cells at this stage are still dependant on keratinocytes and their signalling network for maintaining survival and can only proliferate close to the epidermis. This is described as the radial growth phase (RGP) of melanoma. Additional changes are required to allow 20 Chapter I – Thesis Overview melanoma cells to escape keratinocyte dependence and invade deeper layers of the skin, a stage that characterises the vertical growth phase (VGP) of melanoma progression. This stage requires mutations that...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.
- Spring '14