Integrins in invasive growth

Abstract

Interactions between tumor cells and the ECM strongly influence tumor development, affecting cell proliferation and survival, as well as the ability to migrate beyond the original location into other tissues to form metastases. Many of these interactions are mediated by integrins, a ubiquitously expressed family of adhesion receptors. Integrins are essential for cell attachment and control cell migration, cell cycle progression, and programmed cell death, responses that they regulate in synergy with other signal transduction pathways.This large group of transmembrane proteins is formed from 18 α and 8 β subunits, which dimerize to yield at least 24 different integrin heterodimers, each with distinct ligand binding and signaling properties. With their extracellular domain, integrins can bind to different ECM molecules, such as collagens and laminins, or to cellular receptors, such as VCAM-1. Their intracellular domains connect directly or indirectly to the actin cytoskeleton, thus linking the cytoskeleton to the ECM. Integrins also serve as bidirectional signaling receptors, inducing changes in protein activities or gene expression in response to ligand binding, while also modulating adhesive affinity on the cell surface in response to changes in cellular physiology. Here, we describe how integrins affect migration, proliferation, and survival of both transformed and normal cells, and we discuss how they modulate invasive growth in vivo. Throughout, we stress that many of these functions are restricted to particular cell types and may be altered upon transformation. Integrin avidity and affinity changes in cell migrationCell migration is essential not only for tissue infiltration and the formation of metastases, but also for nonpathological processes, such as angiogenesis and leukocyte extravasation. In order to migrate, a cell has to pass through a sequence of distinct processes. Migration is initiated by cell polarization and the formation of membrane protrusions at the leading edge. Integrins fix cellular protrusions to the ECM, interact with the actin cytoskeleton, and trigger the association of many different signaling molecules at the so-called focal contacts. Thereafter, integrin signals stimulate cell contraction, which allows the movement of the cell body on the adhesive contacts. Finally, the rear of the cell detaches from the substratum by inactivation of the integrins and disassembly of the adhesion complexes. Integrins further facilitate cell movement through the tissue by activating ECM-degrading enzymes. Although these basic mechanisms are considered to be similar among the various types of migratory cells, there are also clear distinctions, since, for example, fibroblasts are about 3-20 times more adhesive than nonactivated leukocytes, move 10-60 times more slowly, and have a different cytoskeletal organization. These differences in the migration mechanism might explain at least some of the known cell-specific effects of integrins on cell migration.Integrin-mediated cell attachment depends not jus...

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