Erythropoietin Stimulates Tumor Growth via EphB4

Sunila Pradeep; Jie Huang; Edna M Mora; Alpa M Nick; Min Soon Cho; Sherry Y Wu; Kyunghee Noh; Chad V Pecot; Rajesha Rupaimoole; Martin A Stein; Stephan Brock; Yunfei Wen; Chiyi Xiong; Kshipra Gharpure; Jean M Hansen; Archana S Nagaraja; Rebecca A Previs; Pablo Vivas-Mejia; Hee Dong Han; Wei Hu; Lingegowda S Mangala; Behrouz Zand; Loren J Stagg; John E Ladbury; Bulent Ozpolat; S Neslihan Alpay; Masato Nishimura; Rebecca L Stone; Koji Matsuo; Guillermo N Armaiz-Peña; Heather J Dalton; Christopher Danes; Blake Goodman; Cristian Rodriguez-Aguayo; Carola Kruger; Armin Schneider; Shyon Haghpeykar; Padmavathi Jaladurgam; Mien-Chie Hung; Robert L Coleman; Jinsong Liu; Chun Li; Diana Urbauer; Gabriel Lopez-Berestein; David B Jackson; Anil K Sood

doi:10.1016/j.ccell.2015.09.008

Erythropoietin Stimulates Tumor Growth via EphB4

Cancer Cell. 2015 Nov 9;28(5):610-622. doi: 10.1016/j.ccell.2015.09.008. Epub 2015 Oct 17.

Authors

Sunila Pradeep¹, Jie Huang¹, Edna M Mora², Alpa M Nick¹, Min Soon Cho³, Sherry Y Wu¹, Kyunghee Noh¹, Chad V Pecot⁴, Rajesha Rupaimoole¹, Martin A Stein⁵, Stephan Brock⁵, Yunfei Wen¹, Chiyi Xiong⁶, Kshipra Gharpure¹, Jean M Hansen¹, Archana S Nagaraja¹, Rebecca A Previs¹, Pablo Vivas-Mejia⁷, Hee Dong Han⁸, Wei Hu¹, Lingegowda S Mangala⁸, Behrouz Zand¹, Loren J Stagg⁹, John E Ladbury⁹, Bulent Ozpolat¹⁰, S Neslihan Alpay¹⁰, Masato Nishimura¹, Rebecca L Stone¹, Koji Matsuo¹, Guillermo N Armaiz-Peña¹, Heather J Dalton¹, Christopher Danes¹, Blake Goodman¹, Cristian Rodriguez-Aguayo¹⁰, Carola Kruger¹¹, Armin Schneider¹¹, Shyon Haghpeykar¹, Padmavathi Jaladurgam¹, Mien-Chie Hung¹², Robert L Coleman¹, Jinsong Liu¹³, Chun Li⁹, Diana Urbauer¹⁴, Gabriel Lopez-Berestein¹⁵, David B Jackson⁵, Anil K Sood¹⁶

Affiliations

¹ Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
² Department of Surgery, University of Puerto Rico, San Juan 00936, Puerto Rico; University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
³ Department of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
⁴ Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Molecular Health, GmbH, Heidelberg 69115, Germany.
⁶ Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Surgery, University of Puerto Rico, San Juan 00936, Puerto Rico.
⁸ Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Molecular Neurology, Sygnis AG, Heidelberg 69120, Germany.
¹² Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 402, Taiwan.
¹³ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁵ Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

Receptors, Erythropoietin
Recombinant Proteins
STAT3 Transcription Factor
Erythropoietin
Receptor, EphB4

Abstract

Publication types

MeSH terms

Substances

Grants and funding