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.

Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6-methylguanine-DNA methyltransferase expression

“…Cell viability assay, western blot analysis, mitotic catastrophe assessment, flow cytometry, bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In the present study, the protocols and the reagents of the cell counting kit (CCK)8 cell viability assay, western blot analysis, mitotic catastrophe assessment and flow cytometry were identical to those described in previous studies by our group (23)(24)(25)(26)(27). For the CCK8 assay, the Cell Counting Kit (CCK-8/WST-8) was used (AR1160-500; Wuhan Boster Biological Technology, Ltd.).…”

“…The mice were kept on a 12-hour reversed light/dark cycle, the temperature was maintained at 25˚C, they were fed with SPF pellet diet (Beijing Huafukang Company, Beijing, China) and water was supplied. As described in previous studies by our group (23)(24)(25)27), in order to increase the tumor formation rate, the tissues were dissociated and then implanted subcutaneously into the three nude mice. Once the tumors were formed after two weeks, the mice were sacrificed by cervical dislocation and tumors from nude mice were dissociated and equally implanted subcutaneously into the lower rear flank of twelve six-week-old nude mice again.…”

Erythropoietin and its derivatives: from tissue protection to immune regulation

“…Notably, when CD131 was knockdown by small interfering RNA (siRNA) transfection, the effect of EPO on endothelial cells was abolished, indicating the critical role of TPR signaling in angiogenesis 81 . EPO also significantly increased the expression of vascular endothelial growth factor (VEGF) both in endothelial cells and macrophages, which in turn stimulated angiogenesis 84,85 . In addition, lymphangiogenesis and lymph node tumor metastasis were also reported to be induced by EPO through PI3K-and ERKdependent pathway 86 .…”

Hypoxia-Independent Angiogenesis in Adipose Tissues during Cold Acclimation

“…In addition, rhEpo administration to cancer-induced anemic patients caused thromboembolism 168 . With evidence that the use of Epo in patients may lead to the stimulation of underlying small tumor masses, we proposed the use of anti-Epo to cancer patients 169 . However, due to unknown adverse effects that may be caused by anti-Epo delivery in cancer patients, the use of anti-Epo as a treatment requires more investigation 53,170 .…”