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PMID: 24856585 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 25 ·No. 6 ·2014-06-16 ·Pages 735-47

Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, Fernandez-Zapico ME, Iacobuzio-Donahue C, Olive KP, Stanger BZ

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.

MeSH Terms
Animals Antibodies, Monoclonal/pharmacology Carcinoma, Pancreatic Ductal/drug therapy,genetics,metabolism,pathology Cell Line, Tumor Disease Models, Animal Disease Progression Gene Knockdown Techniques Hedgehog Proteins/deficiency,genetics,metabolism Humans Immunoglobulin G/pharmacology Mice Mice, Transgenic Pancreatic Neoplasms/drug therapy,genetics,metabolism,pathology Random Allocation Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors Signal Transduction Stromal Cells/metabolism,pathology
Chemicals
Antibodies, Monoclonal DC101 monoclonal antibody Hedgehog Proteins Immunoglobulin G Receptors, Vascular Endothelial Growth Factor
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Rhim Andrew D
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.
Oberstein Paul E
Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
Thomas Dafydd H
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.
Mirek Emily T
Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Palermo Carmine F
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.
Sastra Stephen A
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.
Dekleva Erin N
Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Saunders Tyler
Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
Becerra Claudia P
Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
Tattersall Ian W
Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
Westphalen C Benedikt
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.
Kitajewski Jan
Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
Fernandez-Barrena Maite G
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Fernandez-Zapico Martin E
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Iacobuzio-Donahue Christine
Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
Olive Kenneth P
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.
Stanger Ben Z
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.
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2014.04.021
Email
kenolive@columbia.edu
bstanger@exchange.upenn.edu
Published
2014-06-16
Epub
2014-00-22
Pages
735-47
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC4096698
Subset
IM
Grants
NCI NIH HHS · R01 CA136526 · United States
NCI NIH HHS · CA046952 · United States
NIDDK NIH HHS · K08 DK088945 · United States
NIDDK NIH HHS · P30 DK050306 · United States
NCI NIH HHS · T32CA009503 · United States
NCRR NIH HHS · S10 RR025482 · United States
NIDDK NIH HHS · DK034933 · United States
NIDDK NIH HHS · P30 DK034933 · United States
NCI NIH HHS · CA169123 · United States
NCI NIH HHS · P30 CA015083 · United States
NIDDK NIH HHS · P30 DK084567 · United States
NIDDK NIH HHS · P30DK050306 · United States
NCI NIH HHS · R01 CA177857 · United States
NCRR NIH HHS · S10 RR025686 · United States
NIDDK NIH HHS · DK083111 · United States
NCI NIH HHS · P30CA013696 · United States
NCI NIH HHS · T32 CA009503 · United States
NCI NIH HHS · CA177857 · United States
NCI NIH HHS · R01 CA157980 · United States
NCI NIH HHS · R01 CA169123 · United States
NCI NIH HHS · P30 CA013696 · United States
NCI NIH HHS · P30 CA016520 · United States
NCI NIH HHS · CA136526 · United States
NIDDK NIH HHS · DP2 DK083111 · United States
NCRR NIH HHS · S10RR025686 · United States
NIDDK NIH HHS · DK083355 · United States
NHLBI NIH HHS · R01 HL112626 · United States
NIDDK NIH HHS · R01 DK083355 · United States
NIDDK NIH HHS · DK088945 · United States
NCI NIH HHS · CA157980 · United States
Corrections
CommentIn
PMID: 24898060
CommentIn
PMID: 24912392
CommentIn
PMID: 24937454
CommentIn
PMID: 25860583
External Links
PubMed source DOI: 10.1016/j.ccr.2014.04.021 PMC Full Text View journal details
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