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Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells.

Abstract：

: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 alpha1-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 alpha1-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.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Chen X,Su Y,Fingleton B,Acuff H,Matrisian LM,Zent R,Pozzi A

doi

10.1002/ijc.20997

keywords:

subject

Has Abstract

pub_date

2005-08-10 00:00:00

pages

52-61

issue

eissn

0020-7136

issn

1097-0215

journal_volume

116

pub_type

杂志文章

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Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells.