Erythropoietin Stimulates Tumor Growth via EphB4.
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.
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Sunila
S
Pradeep
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Jie
J
Huang
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.
Edna M
EM
Mora
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Alpa M
AM
Nick
Department of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Min Soon
MS
Cho
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Sherry Y
SY
Wu
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Kyunghee
K
Noh
Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC 27599, USA.
Chad V
CV
Pecot
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Rajesha
R
Rupaimoole
Molecular Health, GmbH, Heidelberg 69115, Germany.
Martin A
MA
Stein
Molecular Health, GmbH, Heidelberg 69115, Germany.
Stephan
S
Brock
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Yunfei
Y
Wen
Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chiyi
C
Xiong
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Kshipra
K
Gharpure
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Jean M
JM
Hansen
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Archana S
AS
Nagaraja
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Rebecca A
RA
Previs
Department of Surgery, University of Puerto Rico, San Juan 00936, Puerto Rico.
Pablo
P
Vivas-Mejia
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.
Hee Dong
HD
Han
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Wei
W
Hu
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.
Lingegowda S
LS
Mangala
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Behrouz
B
Zand
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.
Loren J
LJ
Stagg
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.
John E
JE
Ladbury
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bulent
B
Ozpolat
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
S Neslihan
SN
Alpay
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Masato
M
Nishimura
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Rebecca L
RL
Stone
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Koji
K
Matsuo
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Guillermo N
GN
Armaiz-Peña
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Heather J
HJ
Dalton
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Christopher
C
Danes
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Blake
B
Goodman
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cristian
C
Rodriguez-Aguayo
Molecular Neurology, Sygnis AG, Heidelberg 69120, Germany.
Carola
C
Kruger
Molecular Neurology, Sygnis AG, Heidelberg 69120, Germany.
Armin
A
Schneider
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Shyon
S
Haghpeykar
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Padmavathi
P
Jaladurgam
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.
Mien-Chie
MC
Hung
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
Robert L
RL
Coleman
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jinsong
J
Liu
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.
Chun
C
Li
Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Diana
D
Urbauer
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.
Gabriel
G
Lopez-Berestein
Molecular Health, GmbH, Heidelberg 69115, Germany.
David B
DB
Jackson
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: asood@mdanderson.org.
Anil K
AK
Sood
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D004921:Erythropoietin / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D036224:Receptor, EphB4 / Q000235:genetics* / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D004921:Erythropoietin; D036224:Receptor, EphB4