Angiogenesis

David A. Cheresh P.C. Brooks, S. Strömblad, L.C. Sanders, T.L. von Schalscha, R.T. Aimes, W.G. Stetler-Stevenson, J.P. Quigley, D.A. Cheresh, "Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha-vß3," Cell, 85:683-93, 1996. (Cited in more than 155 papers since publication) Comments by David A. Cheresh, professor of immunology and vascular biology at the Scripps Research Institute in La Jolla, Calif. Much in the news of late, angiogenesis, the formation of blood vessels during embryogenesis, tissue repair, and the spread of tumors, has been billed as an excellent target for cancer-fighting therapies. Recent studies by the authors of this paper have identified the integrin alpha-vß3 --one of a family of cell-adhesion molecule receptors--as a therapeutic target on angiogenic blood vessels. As part of as-yet-unpublished studies, they've also gone on to evaluate antagonists of this integrin in Phase I and Phase II clinical trials in cancer patients. This 1996 paper provided the first evidence that alpha-vß3 works with an enzyme called matrix metalloproteinase 2 (MMP-2) in a functionally active form on the surface of angiogenic blood vessels; this finding provided insight into alpha-vß3's role in angiogenesis and laid the foundation for subsequent studies that targeted the complex for anti-angiogenesis therapies. By demonstrating that these two classes of molecules, integrins and proteinases (or proteases), work together on the same pathway, senior author David Cheresh and his colleagues were, according to Cheresh, the first to show how the direct interaction of an integrin and an MMP regulate the migration and invasive behavior of blood vessels, and, as a result, among the first to link the two previously distinct areas of cell biology: one that centers on cell adhesion and another that centers on cell invasion. "It brings many fields together in that so much of biology depends on the ability of cells to, in an orchestrated way, move from one point in the body to another," Cheresh says of the research. He adds that this mechanism affects not only the cell's capacity to migrate, but also its ability to remodel the extracellular matrix. The Scripps researchers knew that alpha-v integrins were involved in angiogenesis because specific integrin inhibitors had been shown in several studies to stymie new blood vessel growth and cause regression of tumors in disease models. Based on those studies, they began to examine the mechanisms by which alpha-vß3 may be contributing to angiogenesis. Since they knew that alpha-vß3 was involved in adhesion mechanisms and in the cell migration of endothelial cells, they began to study proteolytic events, events that cause protein degradation, which had also previously been linked to angiogenesis. One such event was the expression of MMP-2, inhibitors of which had also been shown to stop blood vessel growth. After examining alpha-vß3 and MMP-2 in histological sections of tumors and other neovascular sites, Cheresh's team determined that most places where blood vessels expressed the integrin also had on their surface MMP-2--no alpha-vß3, little if any MMP-2. "We were able to conclude that alpha-vß3 and MMP-2 actually function as an adhesion-invasion complex," explains Cheresh. When blood vessels are, for example, invading a collagenous matrix, MMP-2 does its part by degrading or creating a cleavage in the collagens, the high tensile strength proteins that form the bulk of the connective tissue in all animals. That cleaving then opens up adhesive sites for alpha-vß3 and, in so doing, facilitates endothelial cell survival. The research that culminated in the 1996 Cell paper enabled the Scripps investigators to construct a model integral to more recent follow-up research (P.C. Brooks et al., Cell, 92:391-400, Feb. 6, 1998). In this most recent study, Cheresh, working with his then postdoc Peter C. Brooks, now at the University of Southern California, demonstrated that angiogenesis could be blocked in vivo by using a naturally occurring fragment of MMP-2, a C-terminal hemopexin-like domain called PEX, to prevent intact MMP-2 from binding to alpha-vß3. Like the recent work of angiogenesis pioneer Judah Folkman (see news story, page 1), the recipient of a good deal of media attention recently for his controversial studies heralding the proteins endostatin and angiostatin as antitumor agents, Cheresh's work may be an example of how a naturally occurring breakdown fragment of a protein that's normally involved in angiogenesis actually suppresses the process. "It actually represents a potential way that we can reverse the invasive behavior of blood vessels," notes Cheresh. He hopes several small molecules that he and his team have singled out for their ability to block the binding of alpha-vß3 to MMP-2 will some day be useful for preventing angiogenesis and tumor growth. Cheresh also points out that the complex may be implicated in many invasive cell interactions that not only regulate angiogenesis, but also inflammatory events, embryonic development, and cancer metastasis. "What we hope to do is to extend some of our approaches to block the MMP-2/alpha-vß3 interaction more selectively," says Cheresh. He and his coworkers believe there might be other examples of MMPs and integrins working together.

Angiogenesis

The Scientist Staff

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