Tumor expression of EGFR may enhance uveal melanoma metastasis by
different mechanisms. Binding of EGFR (e.g., by EGF or TGF-α, both
present in the eye) results in the activation of several pathways that
may lead to increased cell growth, DNA synthesis, motility, chemotaxis,
secretion of proteases, cell adhesion, and the expression of
oncogenes.
5 12 These effects all play an important role in
the metastatic cascade. An interesting question is whether EGFR is
involved in the preference of uveal melanoma cells to metastasize to
the liver. In human breast carcinoma, EGFR expression was correlated
with lymph node metastases,
13 whereas in studies with
human cutaneous melanoma cell lines, a positive correlation was found
between EGFR expression and the potential of lung metastases to develop
after subcutaneous inoculation of he tumor cells in nude
mice.
10 14 In colon carcinoma, EGFR expression was, as in
uveal melanoma, correlated with the development of liver
metastases.
15 In the liver, high levels of hepatocyte
growth factor and TGF-α which can bind to EGFR, are present. As also
has been suggested by Ma and Niederkorn,
4 the
presence of these EGFR ligands in the liver may be involved in the
preference of uveal melanoma cells to metastasize to this organ.
However, ligands for EGFR (e.g., TGF-α and EGF) have been found in
many other tissues and body fluids.
16 In the nude mice
studies of Ma and Niederkorn,
4 intravenously injected
human uveal melanoma cells were shown to accumulate predominantly
(70%) in the liver. Blocking EGFR with neutralizing antibodies reduced
liver metastasis and prolonged host survival. Of interest, anti-EGFR
antibody treatment reduced the number of EGFR-positive melanoma cells
in the liver, but did not affect the liver homing of EGFR-negative
tumor cells. Finally, EGFR has been shown to protect tumor cells
against the cytolytic effects of tumor necrosis
factor-α
4 and against killing by
interleukin-2–activated peripheral blood mononuclear
cells.
17 Prevention of tumor lysis may be an additional
mechanism by which EGFR contributes to tumor progression.