Regulation of tumor dormancy as a function of tumor-mediated paracrine regulation of stromal Tsp-1 and VEGF expression

Tumor dormancy is a critical yet poorly understood phenomenon affecting both the diagnosis and treatment of human cancers. This is due in large part to the lack of model systems available to study dormant tumor cells and the length of time needed to adequately examine the models that do exist. It has been demonstrated in several types of human cancer that tumor dormancy is a function of an impairment in angiogenesis. The intracellular signaling pathways regulating the expression of several pro- and anti-angiogenic 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, and as a result dormancy. In this review 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.