Erythropoietin in tumor angiogenesis

Erythropoietin (EPO) is a moonlighting protein since is ability to work as hormone, cytokine and growth factor. Its cardinal function is to regulate erythropoiesis in the bone marrow. However, EPO with his receptor EPOR are expressed also in non-hematopoietic tissues such as endothelium where they exert a protective function. Moreover, it is known EPO-EPOR pathway contribute to neovascularization in the angiogenic switch of tumor, but the mechanism is not completely established. In this article, after a brief introduction on tumor angiogenesis and description of classical and non-classical pro-angiogenic factors, we review the role of EPO in tumor angiogenesis highlighting the different mechanisms activated by it to promote tumor growth and progression. Finally, we analyze the controversy between the beneficial and the harmful effects of EPO. We suppose that the accurate characterization of EPO variants and their downstream pathways will allow to develop specific inhibition strategies to block only EPOR expressed by tumor cells without inducing signalling in hematopoietic cells to avoid side effects.