The Oncologist-2004-Perlis-182-7

Davies et al 26 detected an activating mutation in

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Unformatted text preview: et al. [26] detected an activating mutation in the B-raf protooncogene in 60%-70% of melanoma cell lines and tissues. The B-rafV599E missense mutation represents over 80% of the B-raf alleles described to date [27, 28], resulting in constitutive and maximal activation of B-Raf kinase activity. Thus, activation of the mitogen-activated protein kinase (MAPK) pathway in melanoma occurs through multiple mechanisms: A) mutation in the B-raf gene; B) stimulation by the endogenous growth factors, bFGF and hepatocyte growth factor [28]; and C) exogenous stimulation by insulin-like growth factor-1 [29] and by adhesion receptor signaling (see below). B-raf mutations have been detected in nonmalignant nevi [30], suggesting that B-Raf is insufficient for transformation. The results also indicate that nevi already have some characteristics of malignant cells, even if only 1 in 10,000 actually progresses to melanoma. B-raf mutations occur rarely in nonsun-exposed melanomas such as acral lentiginous melanoma, vulvar melanoma, and ocular melanoma [25]. However, there are no classical UV-radiation-induced signature mutations in the gene, suggesting that other mechanisms are important for the etiology of these genetic aberrations. The enzymatic nature of the B-Raf kinase has now spurred an intense effort of investigation, because a small molecule inhibitor of the Abl and Kit tyrosine kinases, imatinib mesylate (Gleevecâ„¢, STI-571) induced dramatic responses in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) cases. The results in CML and GIST are highly encouraging, and there is much hope that related inhibitors of B-Raf will be effective in melanoma therapy. Several major drug companies have initiated drug screening and preclinical studies. One B-Raf inhibitor, BAY 43-9006, is already in clinical trials of melanoma patients [25]. We expect, in the next few years, a multitude of exciting new therapeutic approaches in melanoma. PROGRESSION: THE E-CADHERIN TO N-CADHERIN SWITCH Clinical and pathological features of melanoma suggest that it often progresses along five distinct steps [31, 32]. The first step consists of structurally normal melanocytes forming common acquired and congenital nevi. Dysplastic nevi (moles) with structural and architectural atypia define the second step. The third step is called the radial growth 184 phase (RGP) primary melanoma. Cells from RGP lesions can individually invade the dermis but have no capacity to metastasize. The vertical growth phase (VGP), the fourth step in progression, involves primary melanoma cells that have invaded the dermis as a large cluster of cells and have metastatic potential. The final step is metastatic melanoma to distant organ sites. The development of melanoma may be seen as a disruption of normal homeostatic mechanisms in the skin. Such mechanisms control when and how cells proliferate, differentiate, and undergo apoptosis. Disruption of these homeostatic controls can lead to progression of melanoma in which adhesion molecules, such as E-cadherin and N-cadherin, play key roles [33-35]. The de...
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This document was uploaded on 03/06/2014.

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