Key Role for Hedgehog in Prostate Cancer

Abstract

Hedgehog proteins are ligands that activate a signaling pathway essential for pattern formation in development that is also required for the growth of certain cancers. Karhadkar et al. now report that prostate cancer, a common and deadly cancer in men, depends heavily on hedgehog signaling at multiple stages of cancer progression. In prostate cancer cell lines, expression of transcripts encoding components of the Hh pathway was increased, and treatment of cells with cyclopamine, an inhibitor of SMO (smoothened, the critical membrane signaling protein that initiates signaling), inhibited growth of the cell lines. Cyclopamine was very effective at preventing growth and causing regression of xenograft tumors generated in athymic mice from the cell lines. Tumors did not regrow after cyclopamine treatment was stopped, suggesting that maintenance of tumor stem cells that can renew the tumor was effectively inhibited. Such stem cells for prostate tumors appear to arise from epithelial progenitor cells. The authors found that such cells underwent unlimited growth and formed aggressive tumors when transfected with an activating component of the Hh pathway. In samples from human tumors, expression of Hh pathway components was increased in those tumors with metastatic properties. In particular, SMO mRNA was present in all metastatic cells but not present in normal prostate tissue. A similar correlation was seen between Hh signaling components and metastatic activity of several mouse tumor cell lines, and stable transfection of the Hh signaling component GLI caused a weakly metastatic cell line to become strongly lethal when inoculated into mice. Thus the authors conclude that Hh signaling has a key role in the generation of prostate cancer cells from the prostate epithelium, as well as the growth and metastasis of those cells. The findings could well be beneficial in improving diagnosis and treatment of prostate cancer. S. S. Karhadkar, G. S. Bova, N. Abdallah, S. Dhara, D. Gardner, A. Maitra, J. T. Isaacs, D. M. Berman, P. A. Beachy, Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431 , 707-712 (2004). [Online Journal]