Overexpression of Smoothened Activates the Sonic Hedgehog Signaling Pathway in Pancreatic Cancer–Associated Fibroblasts
- 14 March 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 16 (6), 1781-1789
- https://doi.org/10.1158/1078-0432.ccr-09-1913
Abstract
Purpose: Accumulating evidence suggests that cancer-associated stromal fibroblasts (CAF) contribute to tumor growth by actively communicating with cancer cells. Our aim is to identify signaling pathways involved in tumor-stromal cell interactions in human pancreatic cancer. Experimental Design: We established primary fibroblast cultures from human pancreatic adenocarcinomas and nonneoplastic pancreas tissues. To identify differentially expressed genes in CAFs, we did gene expression profiling of human pancreatic CAFs and nonneoplastic pancreatic fibroblasts. Results: The Hedgehog receptor Smoothened (SMO) was upregulated in CAFs relative to control fibroblasts. CAFs expressing SMO could transduce the Sonic hedgehog signal to activate Gli1 expression, and small interfering RNA knockdown of SMO blocked the induction of Gli1 in these cells. Stromal fibroblasts of human primary pancreatic adenocarcinomas overexpressed Smo compared with normal pancreatic fibroblasts. Conclusions: These findings implicate overexpression of Smo as a mechanism for the activation of Hedgehog signaling in human pancreatic CAFs and suggest that stromal cells may be a therapeutic target for Smo antagonists in pancreatic cancer. Clin Cancer Res; 16(6); 1781–9Keywords
Other Versions
This publication has 37 references indexed in Scilit:
- Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic CancerScience, 2009
- Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesisProceedings of the National Academy of Sciences of the United States of America, 2009
- GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformationGenes & Development, 2009
- Sonic Hedgehog Promotes Desmoplasia in Pancreatic CancerClinical Cancer Research, 2008
- Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic AnalysesScience, 2008
- An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancerMolecular Cancer Therapeutics, 2008
- Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancerGut, 2008
- Sonic hedgehog acts at multiple stages during pancreatic tumorigenesisProceedings of the National Academy of Sciences of the United States of America, 2007
- Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid CancersCancer Research, 2007
- ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progressionOncogene, 2006