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Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma

2014; Cell Press; Volume: 25; Issue: 6 Linguagem: Inglês

10.1016/j.ccr.2014.04.021

1878-3686

Andrew D. Rhim, Paul E. Oberstein, Dafydd Thomas, Emily T. Mirek, Carmine F. Palermo, Stephen A. Sastra, Erin N. Dekleva, Tyler Saunders, Claudia P. Becerra, Ian Tattersall, C. Benedikt Westphalen, Jan Kitajewski, Maite G. Fernández‐Barrena, Martín E. Fernández-Zapico, Christine A. Iacobuzio‐Donahue, Kenneth P. Olive, Ben Z. Stanger,

Tumors and Oncological Cases

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.