Endothelins and their receptors have been implicated in the development and progression of prostatic, ovarian, and cervical cancers and melanomas45 through autocrine and paracrine signaling pathways. The three isopeptides that constitute the endothelin family serve as potent mitogens of these tumors. In ovarian carcinoma xenographs, in which the endothelin A receptor (EtAR) is highly expressed, the selective bioavailable antagonist ABT-627 (atrasentan) was shown to significantly inhibit tumor growth associated with a reduction in microvessel density and expression of VEGF and matrix metalloproteinase-2.46 Combined treatment with paclitaxel led to an additive antitumor effect, suggesting that inhibition of the EtAR signaling is a promising therapeutic strategy for ovarian carcinoma.
Endothelin receptors are required for the proliferation of normal melanocytes and for the proliferation, adhesion, migration, and invasion of melanoma cells.47 Endothelin acting on the ETAR,48 a predominantly expressed receptor on tumor cells, induces vascular endothelial growth factor (VEGF) production by increasing levels of hypoxia-inducible factor 1a.45 Specific endothelin receptor antagonists affect melanoma tumor growth in vitro and in vivo.49-50
The ETbR has been associated with cutaneous melanoma and serves as a tumor progression marker. Its activation leads to loss of cell-cell adhesion through decreased expression of cell adhesion molecule E-cadherin and associated cadherin proteins, inhibition of intercellular communication by phosphorylation of gap junc-tional protein connexin 43, and increased expression of integrins and metallopro-teinases.50 Downstream activation of focal adhesion kinase and p44/p42 MAPK signaling pathways by this receptor is responsible for enhanced cell proliferation, adhesion, migration, and metalloproteinase-dependent invasion. Interestingly, the small molecule A-192621, an orally available nonpeptide ETBR antagonist, inhibits melanoma growth in nude mice, indicating that interruption of the ETBR signaling pathway may represent a novel therapeutic approach to target melanoma.
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Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.