Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis.

Pozzi A, LeVine WF, Gardner HA
Oncogene. 2002 21 (2): 272-81

PMID: 11803470 · DOI:10.1038/sj.onc.1205045

Angiogenesis is essential for tumor growth and blocking this process might be a valid tool for the control of cancer growth. We showed previously that tumor angiogenesis in integrin alpha1-null mice is reduced compared to that of wild type animals and that over-expression of matrix metalloproteinase 9 (MMP-9) in the alpha1-null and consequent generation of angiostatin (an inhibitor of endothelial cell growth) from circulating plasminogen was implicated in the mechanism of tumor inhibition. Our findings suggested that secretion of excess MMPs generates inhibitors of endothelial cell proliferation, including but not necessarily limited to angiostatin, resulting ultimately in auto-inhibition of angiogenesis. Thus MMP inhibitors used as anti-tumor drugs might in fact cause a paradoxical increase in tumor angiogenesis and tumor growth. In order to determine whether MMP-9 expression was directly involved in the regulation of tumor growth, we specifically inhibited or enhanced MMP-9 synthesis in vitro and in vivo, and subsequently analysed primary endothelial cell proliferation and angiostatin synthesis, as well as tumor vascularization and development. We provide evidence that reduction of plasma levels of MMP-9 in either normal or integrin alpha1-null mice leads to decreased synthesis of angiostatin and consequent increased tumor growth and vascularization. In contrast, specifically enhancing MMP-9 expression in vivo caused a reduction in tumor vascularization. These findings are the opposite to other studies suggesting a pro-tumorigenic role for MMP-9, and may account for some of the recently observed failures of anti MMP therapy in tumor treatment.

MeSH Terms (21)

Angiostatins Animals Antigens, CD Antineoplastic Agents Carcinoma, Renal Cell Cell Division Colonic Neoplasms Doxycycline Endothelium, Vascular Growth Substances Integrin alpha1 Kidney Neoplasms Matrix Metalloproteinase 9 Mice Mice, Inbred BALB C Mice, Inbred Strains Mice, Knockout Neovascularization, Pathologic Peptide Fragments Plasminogen Tumor Cells, Cultured

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