Inhibition of angiogenesis by tissue inhibitor of metalloproteinase

Abstract

Matrix proteases play a critical role in cell invasion and migration, including the process of angiogenesis. The ability of specific factors to induce angiogenic responses correlates with their stimulation of matrix protease synthesis and release. Using an in vivo angiogenesis assay, the endothelial cell response to known angiogenic factors, basic fibroblast growth factor (bFGF) and adipocyte conditioned medium, was blocked by an inhibitor of matrix metalloproteinase activity, TIMP-1. The TIMP effect was mediated, at least in part, through the inhibition of endothelial cell migration, as determined by the ability of TIMP to block chemotaxis in a Boyden chamber assay. These results indicate that the inhibition of migration is a direct effect on the endothelial cells and does not require accessory cells. An additional observation was that the RNA levels for TIMP were significantly reduced in differentiated adipocytes, compared to undifferentiated F442A controls. Therefore, the acquisition of an angiogenic phenotype may involve not only the induction of positive factors, but also the suppression of angiogenesis inhibitors.

The anti-angiogenic herbal composition Ob-X inhibits adipose tissue growth in obese mice

“…MMP inhibitors, both synthetic and endogenous, inhibit angiogenic responses both in vivo and in vitro. [37][38][39][40] Moreover, MMPdeficient mice show delayed or diminished angiogenic responses during development or in response to tumor xenograft. 41 But on the other hand, it was reported that MMP-based proteolysis of the ECM proteins releases cryptic fragments, which are very potent anti-antiogenic substances such as angiostatin 42 and endostatin.…”

Effect of timing of surgery on survival after preoperative hyperfractionated accelerated radiotherapy (HART) for locally advanced rectal cancer (LARC): Is it a matter of days?

“…These zinccontaining enzymes are actively involved in the degradation of the extracellular matrix, and hence act as key-players in tumor invasion and spread. Moreover, there is evidence that these enzymes play a role in the angiogenesis process [46]. Kumar et al advanced the hypothesis that radiotherapy leads to overexpression of type-IV collagenases in rectal cancer (especially MMP-2 and MMP-9) [44].…”

Correlation between basic fibroblast growth factor immunostaining of stromal cells and stromelysin-3 mRNA expression in human breast carcinoma

“…A number of studies have suggested that the ability of specific factors to induce angiogenic responses correlates with their stimulation of matrix protease synthesis in endothelial cells (Gross et al, 1982;Montesano and Orci, 1985). For example, antibodies to interstitial collagenase inhibit endothelial cell invasion (Montesano and Orci, 1985), and metalloprotease inhibitors, such as TIMP, inhibit the angiogenic process (Johnson et al, 1994). We have previously shown that microvessel density and ST3 expression do not correlate in breast cancer (Linder et al, 1997), suggesting that the mechanisms that induce ST3 expression are distinct from those that induce angiogenesis.…”