Hedgehog Signaling Restrains Bladder Cancer Progression by Eliciting Stromal Production of Urothelial Differentiation Factors

Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer. [Display omitted] •SHH expression is absent in human invasive urothelial carcinoma•Genetic ablation of stromal Hh response accelerates bladder cancer progression•Epithelial Hh elicits stromal expression of differentiation factors BMP4 and BMP5•Pharmacological activation of the BMP pathway impedes tumor progression Shin et al. find that ablation of stromal Hedgehog response leads to loss of BMP4 and BMP5 differentiation factors and accelerated bladder cancer progression, providing a possible explanation for the absence of SHH expression in human invasive urothelial carcinoma.