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Autocrine inhibitory influences of alpha-melanocyte-stimulating
hormone in malignant pleural mesothelioma.
Catania A, Colombo G, Carlin A, Garofalo L,
Gatti S, Buffa R, Carboni N, Rosso L, Santambrogio L, Cantalamessa L, Lipton JM.
ABSTRACT
Malignant pleural mesothelioma is a highly aggressive tumor arising from the
mesothelial cells that line the pleural cavities. This tumor is resistant to
most conventional anticancer treatments and appears to be very sensitive to
growth-promoting influences of cytokines and growth factors. Identification of
natural inhibitory pathways that control growth should aid discovery of novel
therapeutic approaches. We hypothesized that alpha-melanocyte-stimulating
hormone (alpha-MSH), which is produced by many cell types and antagonizes
cytokines and growth factors, could be an endogenous inhibitory molecule in
mesothelioma. Twelve mesothelioma cell lines were established from pleural
effusions of patients with malignant mesothelioma. Mesothelioma cells were found
to express mRNA for proopiomelanocortin and its processing enzymes; release
alpha-MSH peptide into supernatants; and express melanocortin 1 receptor (MC1R),
the high-affinity receptor for alpha-MSH. Immunoneutralization of MC1R in the
cell lines enhanced expression of interleukin-8 (IL-8), IL-6, and transforming
growth factor-beta. These molecules promote mesothelioma proliferation and are
considered therapeutic targets in this tumor. Coincubation of mesothelioma cells
with synthetic alpha-MSH significantly reduced cell proliferation. The present
research shows an autocrine-inhibitory circuit based on alpha-MSH and its
receptor MC1R. Activation of MC1R by selective peptides or peptidomimetics might
provide a novel strategy to reduce mesothelioma cell proliferation by taking
advantage of this endogenous inhibitory circuit.
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