Hedgehog Signaling and Urological Cancers

Hedgehog (Hh) signaling is aberrantly activated in several hematological and solid cancers. Therapeutic options are sometimes lacking for urological cancers because their mechanisms of progression are imperfectly understood. Studies establishing the anti-tumor effects and safety of inhibitors of Hh pathways are needed for tumors in which the Hh pathways are activated. At present vismodegib is clinically available for basal cell carcinoma, and is expected to be extended to treat other cancers. Cholecalciferol, the precursor of active vitamin D3, is a strong inhibitor of Shh-Gli signaling and may have growth inhibitory effects in renal cancer. As a supplementary therapy it may promote tumor regression. Preclinical data in prostate cancer suggest that while suppressing Hh signaling could reduce invasion and metastasis, it may also result in acquired drug resistance after long-term use. Combining Hh inhibitors with ionizing radiation and/ or chemotherapy could improve treatment while lessening the risk of acquired drug resistance. Expression of Shhrelated ligand gene and Shh-Gli-inducible target genes like FOXM1 or IGF2 is characteristic of urothelial tumor samples. Overexpression of Shh is observed in 96% of non-muscle invasive bladder cancer and 52% of muscle invasive bladder cancer samples. This review summarizes recently reported trends in Hh signaling activation studies in urological cancer, especially focusing on possible clinical applications.