Disruption of matrix metalloproteinase 2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo

Abstract

Matrix metalloproteinase 2 (MMP2) can associate with integrin ␣v␤3 on the surface of endothelial cells, thereby promoting vascular invasion. Here, we describe an organic molecule (TSRI265) selected for its ability to bind to integrin ␣v␤3 and block ␣v␤3 interaction with MMP2. Although disrupting ␣v␤3͞MMP2 complex formation, TSRI265 has no effect on ␣v␤3 binding to its extracellular matrix ligand vitronectin and does not influence MMP2 activation or catalytic activity directly. However, TSRI265 acts as a potent antiangiogenic agent and thereby blocks tumor growth in vivo. These findings suggest that activated MMP2 does not facilitate vascular invasion during angiogenesis unless it forms a complex with ␣v␤3 on the endothelial cell surface. By disrupting endothelial cell invasion without broadly suppressing cell adhesion or MMP function, the use of compounds such as TSRI265 may provide a novel therapeutic approach for diseases associated with uncontrolled angiogenesis.

Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies

“…A current paradigm postulates that irradiation in a dosedependent manner promotes migration and invasiveness of glioma cells (Wild-Bode et al, 2001). This effect involves remodelling and the growth of experimental tumours (Brooks et al, 1996;Silletti et al, 2001;Wild-Bode et al, 2001;Wick et al, 2002). The recent demonstration that irradiation increases circulating levels of TGF-b, circulating cancer cells and tumour metastases by a direct effect of the TGF-b on the cancer cells may also contribute to explain that unexpected biological effect of radiotherapy (Biswas et al, 2007).…”

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

“…An integrin receptor strongly involved in angiogenesis and tumor growth is ␣ v ␤ 3 -integrin [67][68][69]. This integrin can bind vitronectin and fibronectin and various other proteins with an arginine-glycine-aspartic acid (RGD) (Arg-Gly-Asp) sequence, like fibrinogen, von Willebrand factor and denatured collagen [62,66].…”

Matrix Metalloproteinase 2-Integrin αvβ3 Binding Is Required for Mesenchymal Cell Invasive Activity but Not Epithelial Locomotion: A Computational Time-Lapse Study

“…Moreover, the treated mesenchymal cells tend to exhibit a less persistent, more diffusive, motile behavior. The PEX polypeptide does not affect endocardial-like cell velocity, persistence of motility, or protrusive activity.The second inhibitory reagent TSRI265 is an organic compound designed to mimic the hemopexin polypeptide and to thus prevent MMP2-integrin ␣v␤3 binding (Brooks et al, 1996;Silletti et al, 2001). When endocardial cushions were incubated in the presence of compound TSRI265, mesenchymal cell motility (Figure 5bЈ) is significantly reduced compared with a control organic compound, TSRI359 ( Figure 5b).…”

“…Furthermore, Brooks et al (1996) showed that the ␣v␤3 integrin and MMP2 form a complex on motile endothelial cells; and that MMP2 is proteolytically active. Related studies demonstrate that a specifically-truncated, noncatalytic fragment of MMP2 (the hemopexin-like domain) prevents binding of MMP2 to integrin ␣v␤3, and thereby disrupts angiogenesis (Brooks et al, 1998).Similarly, an organic reagent (TSRI265) that prevents binding of MMP2 to the ␣v␤3 integrin, in vitro, inhibits tumor angiogenesis (Silletti et al, 2001). Pfeifer and colleagues demonstrated that viral delivery of PEX suppressed neovascularization by specifically blocking MMP2 activation (Pfeifer et al, 2000).…”