Erythropoietin promotes the growth of pituitary adenomas by enhancing angiogenesis

Abstract

RhEPO is frequently used in clinical practice to treat anemia. However, recently rhEPO has been reported to accelerate tumor growth, progression and metastasis. Many pituitary adenoma patients, particularly those with macroprolactinomas, tend to have anemia and may need rhEPO therapy. To date, whether rhEPO has deleterious effects on pituitary adenomas has not been defined. Here we demonstrated for the first time that human pituitary adenomas are EPOR negative tumors and rhEPO accelerated the tumor growth of MMQ pituitary adenoma xenografts via enhancement of angiogenesis in vivo, whereas rhEPO displayed no direct effect on MMQ cells in vitro. Our mechanistic study showed that rhEPO administration increased phosphorylation of JAK2, STAT3 and VEGF expression in human umbilical vein endothelial cells (HUVECs) in vitro and in MMQ cell xenografts in vivo. Furthermore, VEGF inhibitor attenuated rhEPO induced angiogenesis and delayed tumor growth in MMQ pituitary adenoma xenografts in vivo. JAK2 inhibitor AG490 attenuated EPO induced HUVECs proliferation, phosphorylation of JAK2, STAT3 and VEGF upregulation in vitro and inhibited EPO induced vessel formation in Chicken chorioallantoic membrane (CAM) angiogenesis model in vivo. These results suggest that rhEPO administration may promote the growth of pituitary adenomas by enhancing angiogenesis through EPO-JAK2-STAT3-VEGF signaling pathway. rhEPO should be used with caution in anemia patients bearing pituitary adenoma due to its potential deleterious effects.