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Unformatted text preview: velopment of melanoma is
associated with the loss of E-cadherin and the appearance of
N-cadherin (Fig. 2).
Cadherins are cell-surface glycoproteins that promote
calcium-dependent cell-cell adhesion, and they are expressed
in developmental-, cell-, and tissue-specific manners. The
major adhesion mediator between keratinocytes and normal
melanocytes is E-cadherin, which disappears during
melanoma progression . While normal melanocytes
express E-cadherin, this molecule is not found on nevus or
melanoma cells [33, 35]. The loss of E-cadherin likely plays
a crucial role in tumor progression. Cells that have lost
epithelial differentiation, as manifested by the loss of functional E-cadherin, show increased mobility and invasiveness. Keratinocytes can no longer control melanoma cells
that have lost E-cadherin. When melanoma cells are forced
to express E-cadherin and are cocultured with keratinocytes,
they dramatically change: melanomas adhere to keratinocytes, no longer express invasion-related molecules, and lose
their invasive capacities .
Instead of E-cadherin, melanoma cells express N-cadherin, which allows them to change cellular partners.
Melanoma cells adhere through N-cadherin to fibroblasts
and endothelial cells. N-cadherin is a survival factor for
melanoma cells as they migrate through the dermis .
Melanoma cells establish gap junctions with fibroblasts;
gap junctions are small channels for electrolyte transport.
N-cadherin is also a major adhesion receptor when
melanoma cells adhere to each other; coreceptors such as
MCAM facilitate cluster formation.
Along with the upregulation of N-cadherin and the
increased association of melanoma cells with stromal fibroblasts and endothelial cells, occurs a major shift in expression
of cell surface receptors on malignant cells. Major changes in
expression levels occur for cell-cell and cell-matrix adhesion
receptors. One of the most important molecules is the vitronectin receptor αvβ3. It is a multifunctional receptor binding not only vitronectin but over ten other matrix proteins, and 185 it is also involved in cell-cell adhesion . Overexpression
of β3 integrin in melanoma cells leads to highly increased
invasiveness and tumorigenicity . Signaling through the
αvβ3 receptor in melanoma cells occurs through the MAPK
proliferation pathway, whereas signaling for the other major Recent Advances in Melanoma Biology
adhesion receptor, MCAM or CD146, occurs through the survival AKT pathway . Thus, adhesion receptors cooperate
with receptor tyrosine kinases for activation of the major
proliferation and survival pathways . Antagonists for
the αvβ3 receptor are currently in clinical trials . They Figure 1. Photograph (A) and histologic section (B) depicting UV-light-induced melanocytic lesions in human skin. A) An abdominal human
skin graft on a severe combined immunodeficient (SCID) mouse developed this melanocytic lesion following 4 weeks of injections of bFGF/Ad5
(once weekly) and UV-B irradiation (30-50 mJ/cm2, three times each wee...
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- Spring '14