Editors' ChoiceCancer

Hedgehog: From Foe to Friend in the Battle Against Bladder Cancer

Sci. Signal.  21 Oct 2014:
Vol. 7, Issue 348, pp. ec291
DOI: 10.1126/scisignal.aaa1020

Hedgehog (Hh) signaling regulates development in the embryo and stem cell maintenance and tissue regeneration in adults. Increased activation of the Hh pathway is implicated in various cancers; for example, sonic hedgehog (Shh) promotes basal epithelium stem cell proliferation in the development of bladder cancer in mice. Although Hh inhibitors are clinically effective in some cancers, they paradoxically accelerate the progression of others. Using a spectrum of human tumor tissue and a mouse model of chemical-induced bladder cancer, Shin et al. investigated the role of Hh in advanced bladder cancer. The expression of SHH and Hh pathway targets PTCH1 and GLI1 were decreased in invasive human bladder tumors compared with benign urothelial lesions. SHH expression was increased in cultured primary human bladder urothelial cells, but only primary bladder stromal cells showed induction of GLI1 in response to exogenous Shh or an Hh agonist, suggesting that stromal cells respond to secreted Shh. In mice with N-butyl-N-4-hydroxybutyl nitrosamine (BBN)–induced bladder cancer, the stromal-specific knockdown of Smo, encoding the Hh mediator smoothened, accelerated invasive carcinogenesis, decreased longevity, and decreased the expression of genes encoding secreted differentiation factors. Among the genes with decreased expression in response to Hh inhibition in the mouse, expression of the genes encoding bone morphogenetic protein 4 (BMP4) and BMP5 were increased in cultured bladder stromal cells stimulated with Shh. Pharmacological activation of BMP signaling using a low dose of FK506 induced the expression of differentiation genes in primary cultures of bladder urothelial or carcinoma cells. BMP4, BMP5, and BMP-target gene expression were reduced in invasive bladder carcinoma tissue compared with benign tissues, consistent with a loss of the Shh feed-forward signal in invasive tumors. Treating mice with BBN-induced bladder tumors with FK506 prevented progression to invasive disease. The findings suggest that stimulation of BMP signaling may be therapeutically beneficial in patients with advanced bladder cancer.

K. Shin, A. Lim, C. Zhao, D. Sahoo, Y. Pan, E. Spiekerkoetter, J. C. Liao, P. A. Beachy, Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26, 521–533 (2014). [PubMed]