Integrins and their various ECM ligands play essential roles in virtually every aspect of physiological and pathological microvasculature formation. This is controlled largely through integrin-mediated signal transduction and involves extensive cross talk with other signaling cascades, including those involving growth factor receptor tyrosine kinases (Figure 2). Additionally, ECM proteolysis regulates integrin functions, in many cases switching integrin regulation of neovascularization from a positive to a negative state. These various data highlight microvascular integrins and their ECM ligands as attractive candidates for therapeutic intervention to selectively enhance or repress various forms of physiological or pathological neovascularization.
Cell Adhesion: The process by which cells adhere to each other and to components of the extracellular environment. Precise regulation of cell adhesion is necessary for normal developmental and physiologic mainte nance. Abnormal regulation of cell adhesion events can lead to various disease states, including cancer.
Extracellular matrix: A complex mixture of secreted macromole-cules that comprise the noncellular material of all tissues. Besides providing structural support, the extracellular matrix is biologically active and influences a host of dynamic cellular responses.
Integrin: Heterodimeric cell surface molecules composed of a and b subunits. Integrins serve as the cell's primary adhesion receptors for extracellular matrix ligands and play important roles in regulating cellular functions, ranging from differentiation to proliferation and migration.
1. Hynes, R. O. (2002). Integrins: Bidirectional, allosteric signaling machines. Cell 110(6), 673-87. A review of the molecular models for integrin adhesion, activation, and signaling.
2. Hynes, R. O., Lively, J. C., McCarty, J. H., Taverna, D., Francis, S. E., Hodivala-Dilke, K., and Xiao, Q. (2002). The diverse roles of integrins and their ligands in angiogenesis. Cold Spring Harbor Symp Quantitat. Biol. 67, 143-153. A detailed summary of the molecular genetic data supporting roles for different integrins in angiogenesis.
3. Kim, S., Bell, K., Mousa, S. A., and Varner, J. A. (2000). Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am. J. Pathol. 156(4), 1345-1362.
4. Bouvard, D., Brakebusch, C., Gustafsson, E., Aszodi, A., Bengtsson, T., Berna, A., and Fassler, R. (2001). Functional consequences of integrin gene mutations. Circ. Res. 89(3), 211-223.
5. Hynes, R. O. (2002). A reevaluation of integrins as regulators of angio-genesis. Nat. Med. 8(9), 918-921.
6. McCarty, J. H., Monahan-Earley, R. A., Brown, L. F., Keller, M., Gerhardt, H., Rubin, K., Shani, M., Dvorak, H. F., Wolburg, H., Bader, B. L., Dvorak, A. M., and Hynes, R. O. (2002). Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol. Cell. Biol. 22(21), 7667-7677.
7. Stupack, D. G., and Cheresh, D. A. (2002). Get a ligand, get a life: Integrins, signaling and cell survival. J. Cell Sci. 115(Part 19), 3729-3738.
8. Giancotti, F. G., and Ruoslahti, E. (1999). Integrin signaling. Science 285(5430), 1028-1032. This article provides an excellent summary of the complexity of integrin signaling and how these events regulate cell proliferation, differentiation, and migration.
9. Hood, J. D., Frausto, R., Kiosses, W. B., Schwartz, M. A., and Cheresh, D. A. (2003). Differential av integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J. Cell Biol. 162(5), 933-943.
10. Hanahan, D., and Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3), 353-364.
11. Kalluri, R. (2003). Basement membranes: Structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer 3(6), 422-433. This article describes in detail the importance of various basement membrane components and their cryptic fragments in regulating different aspects of developmental and pathological angiogenesis.
12. Lawler, J. (2000). The functions of thrombospondin-1 and -2. Curr. Opin. Cell Biol. 12(5), 634-640.
Dr. Joseph McCarty was a postdoctoral researcher in the Center for Cancer Research at MIT. He is currently an Assistant Professor in the Department of Cancer Biology at the University of Texas MD Anderson Cancer Center. His research focuses on the development and maturation of the brain vasculature.
Dr. Richard Hynes was a Daniel K. Ludwig Professor of Biology at MIT and an Investigator of the Howard Hughes Medical Institute. His research interests concern the role of cell adhesion in physiology and pathology.
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