Erythropoietin Stimulates Tumor Growth via EphB4

• Published in: Cancer cell Vol. 28; no. 5; pp. 610 - 622
• Main Authors: Pradeep, Sunila, Huang, Jie, Mora, Edna M., Nick, Alpa M., Cho, Min Soon, Wu, Sherry Y., Noh, Kyunghee, Pecot, Chad V., Rupaimoole, Rajesha, Stein, Martin A., Brock, Stephan, Wen, Yunfei, Xiong, Chiyi, Gharpure, Kshipra, Hansen, Jean M., Nagaraja, Archana S., Previs, Rebecca A., Vivas-Mejia, Pablo, Han, Hee Dong, Hu, Wei, Mangala, Lingegowda S., Zand, Behrouz, Stagg, Loren J., Ladbury, John E., Ozpolat, Bulent, Alpay, S. Neslihan, Nishimura, Masato, Stone, Rebecca L., Matsuo, Koji, Armaiz-Peña, Guillermo N., Dalton, Heather J., Danes, Christopher, Goodman, Blake, Rodriguez-Aguayo, Cristian, Kruger, Carola, Schneider, Armin, Haghpeykar, Shyon, Jaladurgam, Padmavathi, Hung, Mien-Chie, Coleman, Robert L., Liu, Jinsong, Li, Chun, Urbauer, Diana, Lopez-Berestein, Gabriel, Jackson, David B., Sood, Anil K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.11.2015
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Blotting, Western; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Disease Progression; Erythropoietin - genetics; Erythropoietin - pharmacology; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Kaplan-Meier Estimate; MCF-7 Cells; Mice, Inbred C57BL; Mice, Nude; Middle Aged; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Protein Binding - drug effects; Receptor, EphB4 - genetics; Receptor, EphB4 - metabolism; Receptors, Erythropoietin - genetics; Receptors, Erythropoietin - metabolism; Recombinant Proteins - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Young Adult
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.09.008

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo’s effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin. [Display omitted] •EphB4 functions as a canonical Epo receptor•rhEpo-mediated EphB4 activation triggers downstream signaling via STAT3•rhEpo induces EphB4-mediated functional and biological effects•EphB4 expression negatively correlates with clinical outcome Pradeep et al. identify EphB4 as an erythropoietin (Epo) receptor promoting rhEpo-induced tumor growth and progression via Stat3 signaling. In human ovarian and breast cancer samples, expression of EphB4 rather than of the canonical EpoR correlates with decreased disease-specific survival in rhEpo-treated patients.