Rhim, Andrew?D., Oberstein, Paul?E., Thomas, Dafydd?H., Mirek, Emily?T., Palermo, Carmine?F., Sastra, Stephen?A., Dekleva, Erin?N., Saunders, Tyler, Becerra, Claudia?P., Tattersall, Ian?W., Westphalen, C.?Benedikt, Kitajewski, Jan, Fernandez-Barrena, Maite?G., Fernandez-Zapico, Martin?E., Iacobuzio-Donahue, Christine, Olive, Kenneth?P., and Stanger, Ben?Z.
Summary: Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation—features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth. [ABSTRACT FROM AUTHOR]