Role of the tumor stroma in resistance to anti-angiogenic therapy

Several angiogenesis inhibitors are currently used in the clinic for treatment of cancer. While anti-angiogenesis treatment can improve treatment outcome, the overall benefit on patient survival is still rather limited. This is partially explained by intrinsic or acquired resistance of tumor cells to angiostatic drugs. In addition, it has become evident that extrinsic mechanisms are also involved in resistance to angiostatic therapy. Most of these extrinsic mechanisms reside in the tumor stroma, which is composed of different cell types, including endothelial (progenitor) cells, smooth muscle cells, pericytes, (myo)fibroblasts, immune cells and platelets. In the current review, we describe the role of these stromal cells in the resistance to anti-angiogenic drugs and discuss possible strategies to overcome resistance and enhance the efficacy of angiostatic therapy.