Abstract
SHH prevents progression to invasive bladder cancer by stimulating urothelial differentiation.
Major finding: SHH prevents progression to invasive bladder cancer by stimulating urothelial differentiation.
Mechanism: SHH signaling induces secretion of the differentiation factors BMP4 and BMP5 by stromal cells.
Impact: Pharmacologic activation of BMP signaling may be an effective therapy in bladder cancer.
Although invasive urothelial carcinoma is derived from Sonic hedgehog (SHH)–positive basal cells, the expression of SHH is lost in murine invasive bladder carcinomas, suggesting a protective role for this pathway and that SHH loss may promote tumor progression. Shin, Lim, and colleagues found that loss of SHH is indeed required for primary urothelial tumors to progress to invasive carcinomas and that expression of SHH in these tumors retains them in a differentiated state. Analysis of human bladder tissue samples confirmed that SHH expression is lost in muscle-invasive urothelial carcinomas compared with benign urothelium samples, consistent with previous experiments in mice. In addition, genetic ablation of the stromal response to Hedgehog signaling resulted in accelerated formation of invasive carcinomas and decreased survival in a mouse model of carcinogen-induced urothelial carcinoma. Disruption of Hedgehog signaling in preinvasive bladder tumors led to downregulation of cell differentiation genes, most notably bone morphogenic protein 4 (Bmp4) and Bmp5, which have been shown to promote terminal differentiation of bladder urothelium, supporting the hypothesis that Hedgehog signaling suppresses tumor progression by inducing a urothelial differentiation program. BMP4 and BMP5 were also expressed by human bladder stromal cells in response to activation of Hedgehog signaling. Furthermore, pharmacologic activation of the BMP pathway with low-dose FK506 treatment at concentrations below those required for immunosuppression stimulated urothelial differentiation and inhibited progression to invasive bladder carcinoma following carcinogen-induced tumorigenesis. These data identify a feedback loop in which SHH secreted from bladder epithelial cells activates the Hedgehog pathway in nearby stromal cells, which express differentiation factors such as BMPs that act on the epithelium to maintain its differentiated state. Moreover, these results suggest a therapeutic strategy to limit tumor progression in patients with noninvasive urothelial carcinoma.
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