title: Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival.
abstract: Erythropoietin was traditionally considered an erythroid-restricted cytokine, but recent evidence indicates a broader role for it in nonhematopoietic tissues, specifically in neural development. Pediatric solid tumors are mostly developmental in origin, and more than 50% of the solid tumors are neural in origin. We found erythropoietin receptor and erythropoietin expression in common pediatric tumor cells: neuroblastomas, Ewing's sarcoma family of tumors, pediatric brain tumors (medulloblastoma, astrocytoma, and ependymoma), Wilms tumors, rhabdomyosarcomas, and hepatoblastomas (n = 24), and in cell lines derived from some of these tumors (n = 25). Expression of erythropoietin in tumor cell lines was hypoxia-inducible. Addition of exogenous erythropoietin to tumor cell lines expressing erythropoietin receptor increased nuclear DNA binding activity of nuclear factor kappa B and increased the expression of the antiapoptotic genes bcl-1, bcl-xL, and mcl-1. Additionally, exogenous erythropoietin increased production and secretion of angiogenic growth factors, vascular endothelial growth factor, or placenta growth factor from the tumor cell lines, which promoted endothelial cell proliferation and chemotaxis. Erythropoietin receptor expression that promotes tumor cell survival and releases angiogenic growth factors in pediatric tumors has not been previously described. Therefore, a careful evaluation of the impact of erythropoietin is warranted in vivo, in xenograft models of pediatric tumors, followed by evaluation in pediatric patients with cancer.
authors.affiliation: Division of Hematology-Oncology, Childrens Hospital Los Angeles, California, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Batra
authors.forename: Natalya
authors.initials: N
authors.lastname: Perelman
authors.forename: Lori R
authors.initials: LR
authors.lastname: Luck
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Punam
authors.initials: P
authors.lastname: Malik
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017467:Receptors, Erythropoietin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin; D000072483:Placenta Growth Factor