Paracrine Sonic Hedgehog Signaling Derived from Tumor Epithelial Cells: A Key Regulator in the Pancreatic Tumor Microenvironment

Activation of the hedgehog (Hh) signaling pathway is involved in embryo development and tumorigenesis. While normal pancreatic tissue exhibits little Hh pathway activity, patients with pancreatic adenocarcinoma have high levels of Hh pathway signaling in both the tumor epithelia and the surrounding stromal tissue. Hh ligands expressed by pancreatic cancers promote tumor growth indirectly by activating Hh signaling in the surrounding stroma. This paracrine activation of Hh signaling in the tumor microenvironment provides a more favorable environment for tumor cellular proliferation, metastasis, and resistance to therapy. Taken together, these findings are of valuable implications for the use of Hh pathway inhibitors currently in development and inhibition of the Hh pathway paracrine loop in pancreatic cancer.