INVOLVEMENT OF INTEGRINS IN CELL-SURVIVAL

Apoptosis is a regulated process of cell death by which cells actively participate in their own destruction. In multicellular organisms, the balance between cell proliferation and apoptosis provides homeostatic control, and a regulatory failure of either event can contribute to oncogenesis. The extracellular matrix (ECM) is known to play a regulatory role in cellular growth and differentiation, but only more recently has it been recognized as a regulator of apoptosis. In these processes the major transmitters of ECM-derived signals to the cell are members of the integrin family, although the mechanical process of cell spreading also plays a role. Both in vivo and in vitro the loss of adhesion to specific components of the ECM can lead to cell death, and such apoptosis can be induced experimentally by blocking integrin binding. Heterotypic and homotypic cell-cell adhesion can also protect from adhesion-dependent apoptosis and there is evidence to suggest that this too is integrin mediated. In addition, some integrin mediated signaling appears to promote apoptosis. The downstream mechanisms of integrin signaling causing cell death have not been greatly explored, but there is evidence from two different systems that the induction of ICE transcription and nuclear translocation of p53 are candidate processes. Alterations in integrin expression or signaling therefore are likely to contribute to tumor development by enabling escape from apoptosis. Also, the recognition of the importance of cell-cell adhesion in tumor cell survival offers the potential of developing improved drug regimes for the treatment of malignancy.