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Cancer Cell. 2014 Jun 16;25(6):735-47. doi: 10.1016/j.ccr.2014.04.021. Epub 2014 May 22.

Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.

Author information

1
Division of Gastroenterology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
3
Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
4
Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
6
Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
7
Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
8
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
9
Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: kenolive@columbia.edu.
10
Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bstanger@exchange.upenn.edu.

Abstract

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.

PMID:
24856585
PMCID:
PMC4096698
DOI:
10.1016/j.ccr.2014.04.021
[Indexed for MEDLINE]
Free PMC Article

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