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  • br Acknowledgments br Significance The mechanisms underlying


    Significance The mechanisms underlying the adverse effects of Epo-stimulating agents on the reduced survival of cancer patients are not well understood. Here, we identified EphB4 as an alternative Epo receptor, which triggers Src/Stat3 signaling via EphB4. We also showed that rhEpo-mediated tumor growth can be abrogated by targeting EphB4 in vivo. In our study, evaluation of human ovarian and breast cancer samples revealed that EphB4, but not the canonical EpoR, correlated with a clinical outcome in Epo-treated patients. Overall, we present converging evidence from in vitro, in vivo, and clinical studies that EphB4 is a critical mediator of Epo-induced cancer growth. Our study provides an important and clinically significant dimension to the biology of erythropoietin.
    Introduction Erythropoiesis-stimulating agents (ESAs), such as recombinant human epoetin (rhEpo) and darbepoetin, are recombinant glycosylated analogs of erythropoietin (Epo) that have been used to relieve chemotherapy-induced anemia in cancer patients (Glaspy, 2009a, Sytkowski, 2007). Epo is a pleiotropic cytokine that regulates erythropoiesis, angiogenesis, cytoprotection, and proliferation (Foley, 2008, Glaspy, 2009b). Alarmingly, a growing number of studies have demonstrated that ESA-based treatment can compromise the overall survival of cancer patients (Crouch and DeSantis, 2009, Kumar et al., 2012, Tóvári et al., 2008, Wang et al., 2011), raising the possibility of growth-stimulatory effects on cancer 5-Hydroxy-CTP and via the canonical Epo receptor (EpoR) (Aapro et al., 2012, Chateauvieux et al., 2011, Hedley et al., 2011, McKinney and Arcasoy, 2011, Rathod and Salahudeen, 2011). However, EpoR expression on cancer cells has largely failed to explain the effects of rhEpo on tumor growth. For example, rhEpo can affect proliferative and survival responses in cancer cells without EpoR expression (Okazaki et al., 2008), while failing to induce proliferation in EpoR-positive tumor cells (Belda-Iniesta et al., 2007). Other explanations (e.g., EpoR variants) have also been inadequate in explaining the effects of rhEpo on tumor growth (Foley, 2008). Evidence from other therapeutic areas has also suggested the existence of an alternative Epo receptor. For example, carbamylated Epo (cEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in response to hypoxic conditions (Chen et al., 2009, Leist et al., 2004, Zamora et al., 2005) in an EpoR-independent manner (Leist et al., 2004). Such observations, combined with a lack of a convincing molecular explanation underlying the effects of rhEpo on cancer growth, prompted us to consider the existence of an alternative Epo receptor. Using 5-Hydroxy-CTP and a hypothesis-driven in silico strategy, we further explored ephrin-type B receptor 4 (EphB4) as an alternative candidate Epo receptor that accounts for many of the growth-stimulatory effects of rhEpo in tumors.
    Discussion Administration of exogenous Epo in patients with cancer has been linked with tumor progression (Crouch and DeSantis, 2009, Kumar et al., 2012, Tóvári et al., 2008, Wang et al., 2011), but the mechanism remained elusive until now. Although the interaction between Epo and the canonical EpoR can explain tumor progression in some models, mounting evidence indicates that this interaction is not involved in most Epo-induced tumor growth (Sturm et al., 2010, Kassem and Yassin, 2010). A possible explanation to this puzzle is the concept that alternative EpoRs (e.g., EpoR-IL3 heterodimer and soluble EpoR) can account for non-hematological effects, but these alternative receptors have not explained Epo-induced tumor progression. Our results have broad implications for understanding Epo biology. For example, the Epo-EphB4 pathway could potentially explain some of the non-hematologic functions of Epo. EphB4 is present and tends to colocalize with EpoR in a subset of cortical neurons (Figure S6J) (Uhlén et al., 2015). Pharmacological doses of cEpo have neuroprotective effects that have been shown to be independent of EpoR function (Sturm et al., 2010). Epo has been shown to prevent chemotherapy-induced neurotoxicity in cancer patients (Kassem and Yassin, 2010). Administration of Epo after a stroke can reduce the extent of damage and accelerate patient recovery (Chang et al., 2005, Noguchi et al., 2007).