MT1-MMP Cooperates with KrasG12D to Promote Pancreatic Fibrosis through Increased TGF-β Signaling
Open Access
- 1 October 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 9 (10), 1294-1304
- https://doi.org/10.1158/1541-7786.mcr-11-0023
Abstract
Pancreatic cancer is associated with a pronounced fibrotic reaction that was recently shown to limit delivery of chemotherapy. To identify potential therapeutic targets to overcome this fibrosis, we examined the interplay between fibrosis and the key proteinase membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14), which is required for growth and invasion in the collagen-rich microenvironment. In this article, we show that compared with control mice (Kras+/MT1-MMP−) that express an activating KrasG12D mutation necessary for pancreatic cancer development, littermate mice that express both MT1-MMP and KrasG12D (Kras+/MT1-MMP+) developed a greater number of large, dysplastic mucin-containing papillary lesions. These lesions were associated with a significant amount of surrounding fibrosis, increased α-smooth muscle actin (+) cells in the stroma, indicative of activated myofibroblasts, and increased Smad2 phosphorylation. To further understand how MT1-MMP promotes fibrosis, we established an in vitro model to examine the effect of expressing MT1-MMP in pancreatic ductal adenocarcinoma (PDAC) cells on stellate cell collagen deposition. Conditioned media from MT1-MMP–expressing PDAC cells grown in three-dimensional collagen enhanced Smad2 nuclear translocation, promoted Smad2 phosphorylation, and increased collagen production by stellate cells. Inhibiting the activity or expression of the TGF-β type I receptor in stellate cells attenuated MT1-MMP conditioned medium–induced collagen expression by stellate cells. In addition, a function-blocking anti–TGF-β antibody also inhibited MT1-MMP conditioned medium–induced collagen expression in stellate cells. Overall, we show that the bona fide collagenase MT1-MMP paradoxically contributes to fibrosis by increasing TGF-β signaling and that targeting MT1-MMP may thus help to mitigate fibrosis. Mol Cancer Res; 9(10); 1294–304. ©2011 AACR.Keywords
Other Versions
This publication has 52 references indexed in Scilit:
- Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes*Published by Elsevier BV ,2010
- Pancreatic CancerThe New England Journal of Medicine, 2010
- Matrix Metalloproteinases: Regulators of the Tumor MicroenvironmentCell, 2010
- Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-RasCancer Cell, 2009
- Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasiaProceedings of the National Academy of Sciences of the United States of America, 2008
- Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult miceProceedings of the National Academy of Sciences of the United States of America, 2008
- Induction of Smad1 by MT1-MMP contributes to tumor growthInternational Journal of Cancer, 2007
- Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult MiceCancer Cell, 2007
- Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT?Journal of Cellular Biochemistry, 2007
- Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expressionGenes & Development, 2006