The tumor microenvironment as a determinant of drug response and resistance

Classically, studies of drug resistance in cancer have focused on the molec ular biology of single cancer cells. These types of studies have provided i mportant information regarding certain drug resistance mechanisms, includin g mechanisms that reduce intracellular drug accumulation, alter or repair d rug-induced damage, and reduce drug-induced apoptosis. While these cellular mechanisms undoubtedly contribute to the overall phenomenon of drug resist ance, it is now evident that the tumor cell microenvironment also influence s how a tumor cell behaves and responds to cytotoxic drugs or radiation. Tw o different forms of tumor cell-environmental interaction may explain how s ome tumor cells survive initial drug exposure and eventually express classi cal mechanisms of drug resistance. The first form involves soluble mediator s, such as interleukins, that are secreted by non-tumor, stromal cells. Int erleukin-6 (IL-6) is a classical example of how a soluble mediator secreted by the tumor microenvironment is capable of enhancing tumor cell survival and perhaps blocking apoptosis. The second form of tumor cell-environment i nteraction requires direct cell contact and has been given the term cell-ad hesion-mediated drug resistance (CAM-DR). In this case, binding extracellul ar matrix ligands in the tumor microenvironment may activate cell adhesion molecules, such as the integrins, and these interactions result in the acti vation of signal transduction pathways that block drug-induced apoptosis. I nterrupting the tumor cell-environment interactions or the associated signa l transduction pathways may represent a new approach for the treatment of c ancer.