Integrin-mediated adhesion: tipping the balance between chemosensitivity and chemoresistance

The integrin family of extracellular matrix receptors plays an important role in normal development, epithelial morphogenesis, angiogenesis, and in tumor progression and metastasis. Integrins cooperate with growth factor receptors to control many cellular functions including proliferation and cell survival. Integrin-mediated adhesion regulates many of the cell cycle checkpoints including activation of cyclin D/cdk4/6 complexes, expression of cyclin D genes, and regulation of levels of cyclin-dependent kinase inhibitors. In addition, integrin-mediated cell adhesion regulates apoptosis by modulating the activity of both the mitochondrial pathway and the death receptor pathways. Therefore, integrin-mediated adhesion modulates the decision of life or death. A role for tumor-matrix interactions in the acquisition of drug resistance has been reported for many cancers including breast cancer. Recent evidence suggests that integrin-mediated adhesion to the ECM may undermine the response of tumors to chemotherapeutic agents. Integrins have been shown to be readily accessible drug targets and are therefore attractive potential targets for combined modality chemotherapy.