Erythropoietin promotes the growth of tumors lacking its receptor and decreases survival of tumor-bearing mice by enhancing angiogenesis

Tatsuma Okazaki, Satoru Ebihara, Masanori Asada, Shinsuke Ymanda, Kaijun Niu and Hiroyuki Arai

Year 2008, Volume 10, Issue 9

Abstract

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 (LLCs) and treated with Epo. Epo accelerated tumor growth and increased intratumoral microvessel density, while it did not accelerate LLC tumor cell proliferation in vitro. To observe direct effect of Epo on endothelial cells, we examined human dermal microvascular endothelial cells (HMVECs), which expressed EpoR. Epo induced proliferation of HMVECs and protected them from H2O2-induced cell death. Epo activated the extracellular signal-regulated kinase (ERK) signaling pathway and up-regulated the expression of the downstream anti-apoptotic protein Bcl-xL in HMVECs. Moreover, in both 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 2 doses, a high or a low doses, which induced fibrosarcoma, and treated them with Epo. Epo 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 incidence of fibrosarcoma at either dose. LLCs and MCA-induced-fibrosarcomas did not express EpoR. These results suggest that Epo accelerates growth of tumors that lack EpoR expression by promoting tumor angiogenesis, and decreases overall survival in our mouse models of cancer.

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