Cell Adhesion Is a Key Determinant in de Novo Multidrug Resistance (MDR): New Targets for the Prevention of Acquired MDR

Clinical circumvention of multidrug resistance (MDR) is a Sisyphian task faced in the treatment of many cancers. Identification of several mechanisms of acquired MDR has led to the development of chemosensitizing agents that counter specific mechanisms of MDR. Initial successes in therapy using “chemosensitizers” often culminate in relapse due to the multifactorial nature of acquired MDR. Therefore, it may be important to design therapeutic strategies that focus on mechanisms that allow for cell survival after initial treatments, before the acquisition of MDR. It has been proposed that extracellular effectors such as cytokines, matrix components, and adjacent cells may provide sanctuary to cancer cells by preventing stress-induced cell death. This review focuses on research implicating the cancer cell environment as a particularly important determinant in the emergence of drug resistance. More specifically, we will discuss the role of direct contact between cancer cells and the extracellular matrix or with adjacent cells as extrinsic effectors of de novo MDR. Cell adhesion has been demonstrated to prevent cell death through a number of mechanisms. Identification of cell adhesion-mediated drug resistance as an initial or de novo effector of MDR suggests that therapies targeting interactions between cancer cells and their environment may lead to the sensitization of cancer cells to chemotherapy or radiotherapy before the emergence of acquired mechanisms of MDR.