Erythropoietin Promotes the Growth of Tumors Lacking Its Receptor and Decreases Survival of Tumor-Bearing Mice by Enhancing Angiogenesis 1

Erythropoietin (Epo), a known hematopoietic growth factor, has been reported to promote tumor growth and angiogenesis in Epo receptor (EpoR)–positive tumors, but its effects on EpoR-negative tumors have not been clearly shown. Here, we show that Epo accelerates the growth of EpoR-negative tumors by promoting tumor angiogenesis. Mice were inoculated with Lewis lung carcinoma cells and treated with Epo. Erythropoietin accelerated tumor growth and increased intratumoral microvessel density, although it did not accelerate Lewis lung carcinoma cell tumor proliferation in vitro. To observe the direct effect of Epo on endothelial cells, we examined human dermal microvascular endothelial cells (HMVECs) that expressed EpoR. Erythropoietin induced the proliferation of HMVECs and protected them from H2O2-induced cell death. Erythropoietin activated the extracellular signal–regulated kinase signaling pathway and up-regulated the expression of the downstream antiapoptotic protein Bcl-xL in HMVECs. Moreover, in both the absence and presence of tumors, in vivo treatment of mice with Epo increased circulating endothelial progenitor cells. To investigate the role of Epo in a primary tumor model, we inoculated the chemical carcinogen methylcholanthrene (MCA) subcutaneously into mice at two doses, a high or a low dose, which induced fibrosarcoma, and treated them with Epo. Erythropoietin promoted tumor growth after MCA inoculation at both doses and decreased the overall survival of the mice inoculated with the high-dose MCA. However, Epo did not increase the incidence of fibrosarcoma at either dose. Lewis lung carcinoma cells and MCA-induced fibrosarcomas did not express EpoR. These results suggest that Epo accelerates the growth of tumors that lack EpoR expression by promoting tumor angiogenesis.