Integrins are transmembrane receptors that mediate cell adhesion to neighboring cells and to the extracellular matrix. Here, the various modes in which integrin-mediated adhesion regulates intracellular signaling pathways impinging on cell survival, proliferation, and differentiation are considered. Subsequently, evidence that integrins also control crucial signaling cascades in cancer cells is discussed. Lastly, the important role of integrin signaling in tumor cells as well as in stromal cells that support cancer growth, metastasis, and therapy resistance indicates that integrin signaling may be an attractive target for (combined) cancer therapy strategies. Current approaches to target integrins in this context are reviewed. 1. Integrin-Mediated Cell Adhesion 1.1. Cell Adhesion Cells within multicellular organisms are typically attached to each other and to the extracellular matrix (ECM). ECM is a meshwork of various glycoproteins that exists in many forms, including laminin-rich basement membranes that align tissues, pliable matrices made from fibrilar networks of collagens, rigid collagen-based bone matrices, and provisional fibronectin-containing matrices associated with active processes such as wound healing and angiogenesis [1]. Various adhesion molecules, such as those belonging to the cadherin family, mediate cell-cell contacts. Likewise, interactions with the ECM also occur through a variety of receptors, including syndecans, dystroglycans, and integrins. 1.2. Integrins Integrin cell adhesion receptors participate in cell-cell and cell-ECM interactions [2]. This large family of heterodimeric transmembrane receptors recognizes a plethora of extracellular ligands, including transmembrane receptors on other cells and ECM proteins. The common integrin-binding motif, Arg-Gly-Asp (RGD), is shared by several ECM proteins, including fibronectin, vitronectin, and fibrinogen. Integrin binding to laminins and collagens occurs at other recognition motifs. Integrins participating in cell-cell adhesion bind counter receptors such as a disintegrin and metalloproteases (ADAMs), or immunoglobulin-type receptors such as intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecules (VCAMs) that are expressed on leukocytes and endothelial cells. 1.3. Integrin Evolution Clearly, integrins are essential receptors in mammalian development, and adult life. Studies in mice have attributed roles to certain integrins already at very early stages of development while others play specific roles later in the adult. In fact, integrins are found throughout
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