Autocrine inhibitory influences of α-melanocyte-stimulating hormone in malignant pleural mesothelioma

Malignant pleural mesothelioma is a highly aggressive tumor arising from the mesothe- lial cells that line the pleural cavities. This tumor is resistant to most conventional anticancer treat- ments and appears to be very sensitive to growth- promoting influences of cytokines and growth fac- tors. Identification of natural inhibitory pathways that control growth should aid discovery of novel therapeutic approaches. We hypothesized that -melanocyte-stimulating hormone (-MSH), which is produced by many cell types and antagonizes cytokines and growth factors, could be an endoge- nous, inhibitory molecule in mesothelioma. Twelve mesothelioma cell lines were established from pleu- ral effusions of patients with malignant mesotheli- oma. Mesothelioma cells were found to express mRNA for proopiomelanocortin and its processing enzymes; release -MSH peptide into supernatants; and express melanocortin 1 receptor (MC1R), the high-affinity receptor for -MSH. Immunoneutral- ization of MC1R in the cell lines enhanced expres- sion of interleukin-8 (IL-8), IL-6, and transforming growth factor-. These molecules promote me- sothelioma proliferation and are considered ther- apeutic targets in this tumor. Coincubation of me- sothelioma cells with synthetic -MSH significantly reduced cell proliferation. The present research shows an autocrine-inhibitory circuit based on -MSH and its receptor MC1R. Activation of MC1R by selective peptides or peptidomimetics might provide a novel strategy to reduce mesothe- lioma cell proliferation by taking advantage of this endogenous, inhibitory circuit. J. Leukoc. Biol. 75: 000-000; 2004.