Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis

Abstract

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 a1-null mice is reduced compared to that of wild type animals and that over-expression of matrix metalloproteinase 9 (MMP-9) in the a1-null and consequent generation of angiostatin (an inhibitor of endothelial cell growth) from circulating plasminogen was implicated in the mechanism of tumor inhibition. Our ®ndings 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 speci®cally 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 a1-null mice leads to decreased synthesis of angiostatin and consequent increased tumor growth and vascularization. In contrast, speci®cally enhancing MMP-9 expression in vivo caused a reduction in tumor vascularization. These ®ndings 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.

Gelatinase-mediated migration and invasion of cancer cells

“…Tumors grown in integrin α 1 knockout mice were significantly smaller than those grown in wild type mice, these tumors also showed remarkably reduced angiogenesis and increased plasma angiostatin. In further experiments elevated levels of MMP-7 and MMP-9 were found to be responsible for angiostatin generation (Pozzi et al, 2000) and low plasma levels of MMP-9 were associated with increased angiogenesis (Pozzi et al, 2002). A similar effect would propably be observed by MMP-9-generated endostatin (Ferreras et al, 2000).…”

Analysis of Host- and Tumor-Derived Proteinases Using a Custom Dual Species Microarray Reveals a Protective Role for Stromal Matrix Metalloproteinase-12 in Non–Small Cell Lung Cancer

“…We showed that the Hu/Mu ProtIn chip, which distinguishes human-and mouse-derived proteases and protease inhibitors, is a useful tool to identify tumor-and host-derived molecules important to tumor growth and progression. We have added stromal MMP-12 to the growing list of metalloproteinases that have now been shown to exert a protective role on tumor progression (27)(28)(29)(30). With the development of a variety of protease inhibitors to treat clinical diseases, studies, such as these, are necessary to narrow down the specificity required for inhibition of tumor progression.…”

Metalloproteinases and their inhibitors in tumor angiogenesis

“…Increased MMP-9 production resulted in an associated increase in angiostatin production and reduction in tumor-induced angiogenesis. 111 Overexpression of MMP-12 in a tumor-forming melanoma cell line suppressed the growth and vascularization of tumors formed by these cells when implanted subcutaneously into mice. Increased levels of angiostatin were present in both tumor tissue and serum of the mice carrying the MMP-12-transfected tumor cells versus the corresponding vector control-transfected tumor cells, suggesting that generation of angiostatin by MMP-12 was responsible for the decrease in tumor angiogenesis and growth.…”