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Cancer Cell Biology
Increased plasma MMP9 in integrin α1-null mice enhances lung metastasis of colon carcinoma cells
Article first published online: 8 MAR 2005
Copyright © 2005 Wiley-Liss, Inc.
International Journal of Cancer
Volume 116, Issue 1, pages 52–61, 10 August 2005
How to Cite
Chen, X., Su, Y., Fingleton, B., Acuff, H., Matrisian, L. M., Zent, R. and Pozzi, A. (2005), Increased plasma MMP9 in integrin α1-null mice enhances lung metastasis of colon carcinoma cells. Int. J. Cancer, 116: 52–61. doi: 10.1002/ijc.20997
- Issue published online: 12 MAY 2005
- Article first published online: 8 MAR 2005
- Manuscript Accepted: 27 DEC 2004
- Manuscript Received: 16 OCT 2004
- National Cancer Institute/National Institutes of Health. Grant Numbers: R01 CA94849-01, P50 CA90949
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. Grant Number: P50-DK39261-16
- Department of Veterans Affairs
- American Heart Association
- matrix metalloproteinase inhibitor;
Inhibitors of matrix metalloproteinases (MMPs) were developed as anticancer agents based on the observation that MMPs facilitate local tumor spread and metastasis by promoting matrix degradation and cell migration. Unfortunately, these inhibitors were unsuccessful in the clinical treatment of several cancers, including lung cancer. A possible reason contributing to their failure is that MMP activity is critical for the generation of inhibitors of tumor angiogenesis, including angiostatin. Thus, MMPs might play opposing roles in tumor vascularization and invasion. To determine which effect of elevated MMP levels dominates in the progression of metastatic cancer, experimental lung metastasis assays were performed in integrin α1-null mice, a genetic model for increased plasma levels of MMP9 and MMP9-generated angiostatin (Pozzi et al., Proc. Natl. Acad. Sci. USA 2000;97:2202–7). We show that while the number of lung colonies in integrin α1-null mice was significantly increased compared to their wild-type counterparts, tumor volume was markedly reduced. In vivo treatment with the MMP inhibitor doxycycline resulted in a significant decrease in the number of lung colonies in both genotypes, but the tumors that formed were bigger and more vascularized. Increased tumor vascularization paralleled decreased plasma levels of MMP9 and consequent decreased angiostatin synthesis. These results demonstrate that while inhibition of MMPs prevents and/or reduces tumor invasion and lung metastasis, it has the paradoxical effect of increasing the size and vascularization of metastatic tumors due to decreased generation of inhibitors of endothelial cell proliferation. The continued growth of these large well-vascularized tumors may explain the poor efficacy of MMP inhibitors in lung cancer clinical trials. © 2005 Wiley-Liss, Inc.