The role of the tumor microenvironment in regulating angiogenesis.

The tumor-associated stroma has been shown to play a significant role in cancer formation. Paracrine signaling interactions between epithelial tumor cells and stromal cells are a key component in the transformation and proliferation of tumors in several organs. Whereas the intracellular signaling pathways regulating the expression of several pro- and antiangiogenic proteins have been well characterized in human cancer cells, the intercellular signaling that takes place between tumor cells and the surrounding tumor-associated stroma has not been as extensively studied with regard to the regulation of angiogenesis. In this chapter we define the key players in the regulation of angiogenesis and examine how their expression is regulated in the tumor-associated stroma. The resulting analysis is often seemingly paradoxical, underscoring the complexity of intercellular signaling within tumors and the need to better understand the environmental context underlying these signaling mechanisms.