EPHB4 is an erythropoietin (EPO) receptor associated with poor survival in rhEPO-treated patients.

  • Major finding: EPHB4 is an erythropoietin (EPO) receptor associated with poor survival in rhEPO-treated patients.

  • Mechanism: rhEPO signals through EPHB4 to activate downstream SRC and STAT3, leading to tumor progression.

  • Impact: Anti-EPHB4 therapies have the potential to reduce the tumor-promoting effects of rhEPO treatment.

Erythropoietin (EPO) is a cytokine involved in multiple cellular functions, including erythropoiesis, angiogenesis, cytoprotection, and proliferation. Recombinant human EPO (rhEPO) has been used to treat chemotherapy-induced anemia in cancer patients; however, rhEPO has been reported to reduce the overall survival of cancer patients, indicating that it may enhance tumor growth. The expression of the canonical EPO receptor EPOR largely fails to explain the tumor-promoting effects of EPO, suggesting the possibility of an alternative EPO receptor. Pradeep, Huang, Mora, and colleagues used in silico strategies to identify EPHB4 as a potential alternative EPO receptor, and confirmed the ability of rhEPO to bind to EPHB4, albeit less strongly than to EPOR. Stimulation of the EPHB4 receptor by rhEPO resulted in the activation of SRC and STAT3, whereas rhEPO stimulation of EPOR resulted in JAK2/STAT5 activation. Additionally, the rhEPO-induced increases in proliferation, migration, and invasion of cancer cells required EPHB4-mediated SRC/STAT3 signaling, but not EPOR. These results were confirmed in vivo in mouse models of ovarian and breast cancer, in which EPO-induced tumor growth was dependent on EPHB4. Furthermore, in human patients with breast or ovarian cancer, increased expression of EPHB4, but not the canonical receptor EPOR, was associated with a poor clinical outcome in patients treated with erythropoiesis-stimulating agents such as rhEPO. Taken together, these findings indicate that EPHB4 is an EPO receptor that functions through the activation of SRC and STAT3 to promote tumor growth in response to treatment with rhEPO. These results explain the harmful effects of EPO treatment on the survival of patients with cancer, and suggest that inhibition of EPHB4 may be a promising therapeutic strategy to reduce the tumor-promoting effects of EPO treatment.

Pradeep S, Huang J, Mora EM, Nick AM, Cho MS, Wu SY, et al. Erythropoietin stimulates tumor growth via EphB4. Cancer Cell 2015;28:610–22.

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