Integrins as signaling molecules and targets for tumor therapy

Abstract

Adhesion molecules include ligands and receptors. Together they provide cells with anchorage and traction for migration, and the receptors also mediate signals that control cell polarity, survival, growth, differentiation and gene expression. Integrins are a major group of versatile adhesion receptors that serve both adhesive and signaling functions. They possess shared and unique specificies both outside and inside the cell. Many of the integrins share an affinity toward the RGD recognition sequence in their extracellular matrix ligands, but are still capable of distinguishing different RGD-containing proteins. The shared signaling pathways are likely to include changes in intracellular Ca2+ and PIP2 concentrations, and the activation of protein kinase C and focal adhesion kinase. Examples of integrin-specific signaling include that the α(v)β3 integrin (vitronectin receptor) can potentiate the effects of insulin and certain other growth factors and that the α5β1 integrin (fibronectin receptor) supports cell survival in serum-free cultures by up-regulating the anti-apoptosis protein Bcl-2. Another integrin function is that some integrins, in particular α5β1, are necessary for fibronectin matrix formation. Overexpression of α5β1, which results in the assembly of additional fibronectin matrix, reduces tumorigenicity of cultured tumor cells. Systemic treatment of tumor- bearing mice with an artificially generated fibronectin matrix suppresses metastasis. These and other findings indicate that the ligand binding and signaling functions of integrins offer targets for new therapeutic approaches.