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 a1null 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.

Forced Expression of MMP9 Rescues the Loss of Angiogenesis and Abrogates Metastasis of Pancreatic Tumors Triggered by the Absence of Host SPARC

“…However, results from this study supported by previous compelling reports suggest that the underlying mechanisms and the function of MMP9 in metastasis are more complex (31,46,47). Our study demonstrates that orthotopic implantation of tumor cells forced to express MMP9 results in a decrease in metastatic burden compared to parental PAN02 tumor cells.…”

“…These findings highlight the complex nature of MMP9 activity in the tumor microenvironment and might be partly explained by the paradigm that excess MMP9 expression inhibits tumor progression by generating endothelial cell inhibitors from both ECM and non-ECM sources, such as angiostatin and tumstatin (46,48). Thus, the outcome of MMP activity in the tumor microenvironment may be dependent on a variety of factors including ECM deposition, the presence of other proteases and cytokines, the time, level, and site of MMP production, and the level and activity of adaptor proteins such as SPARC.…”

Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease

“…MMP-9 knockout mice exhibit significantly reduced carotid artery intimal hyperplasia,13 and thus, upregulation of MMP-9 may contribute to the exaggerated intimal hyperplasia observed in MMD pathology. MMP-9 also hydrolyses plasminogen to form angiostatin, which is a strong inhibitor of angiogenesis,14 and stable overexpression of MMP-9 results in increased angiostatin levels and decreased angiogenesis in a mouse model of colon cancer 15. Other angiogenesis inhibitors such as endostatin and tumstatin can be generated from the C-terminal domain of collagen chains via the action of MMP-9 16 17.…”

Loss of Integrin α1β1 Ameliorates Kras-Induced Lung Cancer

“…Of the 24 heterodimers identified thus far, the integrin family contains four major collagen receptors, namely integrins α1β1, α2β1, α10β1, and α11β1 (3-6). Integrin α1β1 is the principal collagen IV receptor and upon engagement by this ligand it regulates many cell functions, such as support of cell proliferation and survival (7) as well as synthesis of collagen (8), matrix metalloproteinase (MMP) (8-10) and reactive oxygen species (11). …”

“…Using xenograft and orthotopic models of cancer, we showed that integrin α1-null mice develop less, smaller, and poorly vascularized tumors compared to wild type mice. The reduced angiogenesis in the α1-null mice is due to increased levels of MMP9, which generates angiostatin with consequent inhibition of endothelial cell growth (9, 10, 12, 13). Thus, integrin α1β1 serves as a pro-angiogenic receptor, and loss of its expression by endothelial cells protects the host from tumor growth by reducing pathological angiogenesis.…”