Complex Roles for Hedgehog Signaling in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is associated with desmoplasia (fibrosis and stromal cell infiltration). The secreted growth factor Shh (Sonic hedgehog) is increased in invasive tumors and metastases of patients with PDAC and in samples from all stages of cancer progression in genetic mouse models of PDAC. The expression of Shh is restricted to the tumor epithelium in PDAC, and knockout of the gene encoding the Shh receptor Smoothened (Smo) in stromal cells or pharmacological inhibition of Shh signaling reduces the growth of human PDAC xenografts in mice, suggesting that Shh signals in a paracrine manner to support tumor growth. However, clinical trials using Smo inhibitors in PDAC patients have shown little to no efficacy when combined with traditional chemotherapeutics. Lee et al . found that inhibition of Shh signaling in genetic mouse models of PDAC accelerated cancer progression. In three different genetic mouse models of PDAC, inhibition of Shh signaling by pancreas-specific knockout of Shh or by pharmacological inhibition with the clinically approved Smo inhibitor vismodegib resulted in enhanced progression and lethality of the disease. Induction of acute pancreatitis in mice by injection of the peptide ceruletide leads to pancreatic cell death and subsequent regeneration, but in mice overexpressing the oncogenic form of KRAS in the pancreas, regeneration is inhibited because of neoplastic transformation of dedifferentiated cells. Pharmacological activation of Shh signaling with SAG21k in ceruletide-injected mice from one of the genetic models of PDAC increased the number of stromal cells and the percentage of stromal cells expressing a marker of activated Shh signaling and decreased tumor epithelial cell proliferation and the neoplastic area of the pancreas, whereas treating these mice with vismodegib had the opposite effect. Thus, these results suggest that Shh signaling may be required to support stromal fibroblasts that limit tumor epithelial cell proliferation. Furthermore, this study highlights that xenograft models may not recapitulate all aspects of human disease and that the tumor microenvironment plays important roles in disease progression and prevention. J. J. Lee, R. M. Perera, H. Wang, D. -C. Wu, X. S. Liu, S. Han, J. Fitamant, P. D. Jones, K. S. Ghanta, S. Kawano, J. M. Nagle, V. Deshpande, Y. Boucher, T. Kato, J. K. Chen, J. K. Willmann, N. Bardeesy, P. A. Beachy, Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl. Acad. Sci. U.S.A. 111 , E3091–E3100 (2014). [Abstract][Full Text]