Three-Dimensional Collagen I Promotes Gemcitabine Resistance in Pancreatic Cancer through MT1-MMP–Mediated Expression of HMGA2
Open Access
- 1 February 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 71 (3), 1019-1028
- https://doi.org/10.1158/0008-5472.can-10-1855
Abstract
One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagen-rich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)–dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP–dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP in the collagen microenvironment increases ERK1/2 phosphorylation and HMGA2 expression, and thereby further attenuates gemcitabine-induced checkpoint arrest. MT1-MMP also allows PDAC cells to continue to proliferate in the presence of gemcitabine in a xenograft mouse model. Clinically, human tumors with increased MT1-MMP show increased HMGA2 expression. Overall, our data show that collagen upregulation of MT1-MMP contributes to gemcitabine resistance in vitro and in a xenograft mouse model, and suggest that targeting MT1-MMP could be a novel approach to sensitize pancreatic tumors to gemcitabine. Cancer Res; 71(3); 1019–28. ©2010 AACR.Keywords
Other Versions
This publication has 51 references indexed in Scilit:
- Collagen regulation of let-7 in pancreatic cancer involves TGF-β1-mediated membrane type 1-matrix metalloproteinase expressionOncogene, 2010
- Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes*Published by Elsevier BV ,2010
- HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapyNucleic Acids Research, 2009
- Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7The EMBO Journal, 2009
- HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinomaLaboratory Investigation, 2008
- Molecular Dissection of the Structural Machinery Underlying the Tissue-invasive Activity of Membrane Type-1 Matrix MetalloproteinaseMolecular Biology of the Cell, 2008
- High mobility group AT‐hook 1 (HMGA1) is an independent prognostic factor and novel therapeutic target in pancreatic adenocarcinomaCancer, 2008
- MMPs as therapeutic targets—Still a viable option?Seminars in Cell & Developmental Biology, 2008
- The tumor suppressor microRNA let-7 represses the HMGA2 oncogeneGenes & Development, 2007
- Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapyNature Reviews Cancer, 2006