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Unformatted text preview: et al.  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 ; and
C) exogenous stimulation by insulin-like growth factor-1
 and by adhesion receptor signaling (see below).
B-raf mutations have been detected in nonmalignant nevi
, 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 . 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 (Gleevec™,
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 . We
expect, in the next few years, a multitude of exciting new
therapeutic approaches in melanoma.
PROGRESSION: THE E-CADHERIN TO N-CADHERIN
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.
- Spring '14