Carcinomas Contain a Matrix Metalloproteinase–Resistant Isoform of Type I Collagen Exerting Selective Support to Invasion
- 1 June 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (11), 4366-4374
- https://doi.org/10.1158/0008-5472.can-09-4057
Abstract
Collagen fibers affect metastasis in two opposing ways, by supporting invasive cells but also by generating a barrier to invasion. We hypothesized that these functions might be performed by different isoforms of type I collagen. Carcinomas are reported to contain α1(I)3 homotrimers, a type I collagen isoform normally not present in healthy tissues, but the role of the homotrimers in cancer pathophysiology is unclear. In this study, we found that these homotrimers were resistant to all collagenolytic matrix metalloproteinases (MMP). MMPs are massively produced and used by cancer cells and cancer-associated fibroblasts for degrading stromal collagen at the leading edge of tumor invasion. The MMP-resistant homotrimers were produced by all invasive cancer cell lines tested, both in culture and in tumor xenografts, but they were not produced by cancer-associated fibroblasts, thereby comprising a specialized fraction of tumor collagen. We observed the homotrimer fibers to be resistant to pericellular degradation, even upon stimulation of the cells with proinflammatory cytokines. Furthermore, we confirmed an enhanced proliferation and migration of invasive cancer cells on the surface of homotrimeric versus normal (heterotrimeric) type I collagen fibers. In summary, our findings suggest that invasive cancer cells may use homotrimers for building MMP-resistant invasion paths, supporting local proliferation and directed migration of the cells whereas surrounding normal stromal collagens are cleaved. Because the homotrimers are universally secreted by cancer cells and deposited as insoluble, MMP-resistant fibers, they offer an appealing target for cancer diagnostics and therapy. Cancer Res; 70(11); 4366–74. ©2010 AACR.Keywords
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This publication has 51 references indexed in Scilit:
- Differential Matrix Rigidity Response in Breast Cancer Cell Lines Correlates with the Tissue TropismPLOS ONE, 2009
- The Mechanical Rigidity of the Extracellular Matrix Regulates the Structure, Motility, and Proliferation of Glioma CellsCancer Research, 2009
- Extracellular Matrix Rigidity Promotes Invadopodia ActivityCurrent Biology, 2008
- Segregation of Type I Collagen Homo- and Heterotrimers in FibrilsJournal of Molecular Biology, 2008
- Membrane type 1-matrix metalloproteinase: Substrate diversity in pericellular proteolysis☆Seminars in Cell & Developmental Biology, 2007
- Ectopic Expression of Vascular Cell Adhesion Molecule-1 as a New Mechanism for Tumor Immune EvasionCancer Research, 2007
- Fibroblasts in cancerNature Reviews Cancer, 2006
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002
- Characterization of collagen synthesized by normal and chemically transformed rat liver epithelial cell linesBiochemistry, 1980
- Procollagen and collagen produced by a teratocarcinoma-derived cell line, TSD4: Evidence for a new molecular form of collagenCell, 1977