Promalignant effects of antiangiogenics in the tumor microenvironment.

Antiangiogenic therapies are considered a promising strategy against solid tumors. Their aim is to inhibit the formation of new blood vasculature, thereby reducing the oxygen and nutrient supply to prevent further tumor growth and spreading. However, the strategy has seen limitations, as survival benefits are modest and often accompanied with increased tumor aggressiveness in form of invasion and metastasis. Antiangiogenic induced changes in the tumor microenvironment, such as hypoxia, mechanical stress or extracellular acidification can activate different receptors of tumoral and stromal cells and induce an extensive remodeling of the entire tumor microenvironment, with the overall goal to invade nearby tissues and regain access to the vasculature. In this regard, receptor tyrosine kinases have been studied intensively and especially the inhibition of c-Met has given promising results, characterized by a reduction in invasiveness and prolonged survival. Receptors that sense changes in the extracellular matrix like integrins or proteoglycans can also induce downstream signaling that stimulates the expression of remodeling factors such as new matrix components, enzymes or chemoattractants. Targeting multiple receptors and sensors of cancer cells simultaneously might represent an effective second line treatment that prevents the formation of malignant side effects.