Erythropoietin Signaling in the Microenvironment of Tumors and Healthy Tissues

Erythropoietin (EPO), the primary cytokine of erythropoiesis, stimulates both proliferation and differentiation of erythroid progenitors and their maturation to red blood cells. Basal EPO levels maintain the optimum levels of circulating red blood cells. However, during hypoxia, EPO secretion and its expression is elevated drastically in renal interstitial fibroblasts, thereby increasing the number of erythroid progenitors and accelerating their differentiation to mature erythrocytes. A tight regulation of this pathway is therefore of paramount importance. The biological response to EPO is commenced through the involvement of its cognate receptor, EPOR. The receptor-ligand complex results in homodimerization and conformational changes, which trigger downstream signaling events and cause activation or inactivation of critical transcription factors that promote erythroid expansion. In recent years, recombinant human EPO (rEPO) has been widely used as a therapeutic tool to treat a number of anemias induced by infection, and chemotherapy for various cancers. However, several studies have uncovered a tumor promoting ability of EPO in man, which likely occurs through EPOR or alternative receptor(s). On the other hand, some studies have demonstrated a strong anticancer activity of EPO, although the mechanism still remains unclear. A thorough investigation of EPOR signaling could yield enhanced understanding of the pathobiology for a variety of disorders, as well as the potential novel therapeutic strategies. In this chapter, in addition to the clinical relevance of EPO/EPOR signaling, we review its anticancer efficacy within various tumor microenvironments.