TY - JOUR
T1 - Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma
AU - Rhim, Andrew D.
AU - Oberstein, Paul E.
AU - Thomas, Dafydd H.
AU - Mirek, Emily T.
AU - Palermo, Carmine F.
AU - Sastra, Stephen A.
AU - Dekleva, Erin N.
AU - Saunders, Tyler
AU - Becerra, Claudia P.
AU - Tattersall, Ian W.
AU - Westphalen, C. Benedikt
AU - Kitajewski, Jan
AU - Fernandez-Barrena, Maite G.
AU - Fernandez-Zapico, Martin E.
AU - Iacobuzio-Donahue, Christine
AU - Olive, Kenneth P.
AU - Stanger, Ben Z.
N1 - Funding Information:
We thank E. Collisson, R. Hruban, A. Rustgi, R. Vonderheide, and T. Wang for helpful discussions, as well as B. Orelli, M. Badgley, and J. Eberle for assistance in preparing the manuscript. We also thank Infinity Pharmaceuticals for providing IPI-926 and A. Joyner for providing Gli1-GFP mice. This study was funded by the NIH (DK088945, CA177857, DK034933, and CA046952 [to A.D.R.]; T32CA009503 [to D.H.T.]; CA136526 [to M.E.F.Z.]; CA157980 [to K.P.O.]; and CA169123, DK083355, and DK083111 [to B.Z.S.]) and AGA/FDHN (Fellow to Faculty Transition Award [to A.D.R.] and Bernard L. Schwartz Designated Research Award in Pancreatic Cancer [to K.P.O.]). This work was supported in part by the NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases (P30DK050306) and its core facilities (Molecular Pathology and Imaging Core, Molecular Biology/Gene Expression Core, Transgenic and Chimeric Mouse Core, and Cell Culture Core) at the University of Pennsylvania and by the Molecular Pathology Shared Resource, the Confocal and Specialized Imaging Shared Resource, and the Small Animal Imaging Shared Resource within the Columbia University Herbert Irving Comprehensive Cancer Center (P30CA013696). The confocal microscope was purchased with grant S10RR025686.
PY - 2014/6/16
Y1 - 2014/6/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2014.04.021
DO - 10.1016/j.ccr.2014.04.021
M3 - Article
C2 - 24856585
AN - SCOPUS:84902435628
VL - 25
SP - 735
EP - 747
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -