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Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3091-100. doi: 10.1073/pnas.1411679111. Epub 2014 Jul 14.

Stromal response to Hedgehog signaling restrains pancreatic cancer progression.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine,Division of Oncology, Department of Medicine.
2
Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
3
Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305;
4
Institute for Stem Cell Biology and Regenerative Medicine.
5
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and.
6
Department of Chemical and Systems Biology, and.
7
Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; pbeachy@stanford.edu Bardeesy.Nabeel@mgh.harvard.edu.
8
Institute for Stem Cell Biology and Regenerative Medicine,Department of Biochemistry,Howard Hughes Medical Institute, Stanford, CA 94305 pbeachy@stanford.edu Bardeesy.Nabeel@mgh.harvard.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.

KEYWORDS:

Sonic hedgehog; cancer therapy; cerulein; hedgehog agonist; tumor stroma

PMID:
25024225
PMCID:
PMC4121834
DOI:
10.1073/pnas.1411679111
[Indexed for MEDLINE]
Free PMC Article

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