Skip to main content
NCBI home page
Environmental Health and Preventive Medicine logoLink to Environmental Health and Preventive Medicine
. 2003 Jan;7(6):239–245. doi: 10.1007/BF02908882

Pleiotrophic actions of erythropoietin

Laurie Feldman 1, Arthur J Sytkowski 1,✉
PMCID: PMC2723462  PMID: 21432392

Abstract

Erythropoietin is the prime regulator of red blood cell production. However, recent evidence suggests that the hormone has multiple effects outside the hematopoietic system. Functional receptors have been identified on a wide variety of normal and malignant cell types, and numerous biologic effects of the hormone on these cells have been observed both in vitro and in vivo. These findings are causing a reassessment of the understanding of erythropoietin physiology. Moreover, there are important implications for the use of recombinant erythropoietin in the clinical setting.

Key words: cancer, angiogenesis, brain, gut, reproductive system

References

  • (1).Shingo T, Sorokan ST, Shimazaki R, Weiss S. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian neural stem cells. J. Neuroscience 2001; 21(24): 9733–9743. [DOI] [PMC free article] [PubMed]
  • (2).Dame C, Bartmann P, Wolber E, Fahnenstich H, Hofmann D, Fandry J. Erythropoietin gene expression in different areas of the developing human central nervous system. Brain Research-Developmental Brain Research 2000; 125(1–2): 60–74. [DOI] [PubMed]
  • (3).Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immunohistochemical localization of Erythropoietin and its receptor in the developing human brain. Pediatric and Developmental Pathology 1999; 2(2): 148–158. [DOI] [PubMed]
  • (4).Carami A, Brines ML, Ghezzi P, Cerami CJ. Effects of epoetin alpha on the central nervous system. Seminars in Oncology 2001, 28 (2 Suppl 8): 66–70. [DOI] [PubMed]
  • (5).Brines ML, Ghezzi P, Keenan S, Agnello D, deLanerolle NC, Cerami C, Itri LM, Cerami A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. USA 2001; 97(19): 10527–10531. [DOI] [PMC free article] [PubMed]
  • (6).Siren AL, Ehrenreich H. Erythropoietin—a novel concept in neuroprotection. European Archives of Psychiatry & Clinical Neuroscience 2001; 251(4): 179–184. [DOI] [PubMed]
  • (7).Calapai G, Marciano MC, Corica F, Allegra A, Parisi A, Frisina N, Caputi AP, Buermi M. Erythropoietin protects against brain ischemic injury by inhibition of nitric oxide formation. Eur. J. Pharmacol. 2000; 410(3): 349–356. [DOI] [PubMed]
  • (8).Studer L, Csete M, Lee SH, Kabbani N, Walikonis J, Wold B, McKay R. Enhanced proliferation, survival and dopaminergic differentiation of CNS precursors in lowered oxygen. J. Neuroscience 2000; 20(19): 7377–7783. [DOI] [PMC free article] [PubMed]
  • (9).Chin K, Yu X, Beleslin-Cokie B, Liu C, Shen K, Mohrenweiser HW, Noguchi CT. Production and processing of Erythropoietin transcripts in brain. Brain Research-Molecular Brain Research 2000; 82(1–2): 29–42. [DOI] [PubMed]
  • (10).Alafaci C, Salpietro F, Grasso G, Sfacteria A, Passalacqua M, Morabito A, Tripodo E, Calapai G, Buemi M, Tomasello F. Effect of recombinant human Erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage. Eur. J. Pharmaco. 2000; 416(2): 219–225. [DOI] [PubMed]
  • (11).Renzi MJ, Thirumalai N, Jolliffe LK, Farrell FX. Erythropoietin downregulates SHP1 and induces a sustained activation of ERK1/ERK2 in primary cortical neurons. Blood 2001; 98(11): 77a.
  • (12).Juul SE, Ledbetter DJ, Joyce AE, Dame C, Christensen RD, Zhao Y, DeMarco V. Erythropoietin acts as a trophic factor in neonatal rat intestine. Gut 2001; 49(2): 182–189. [DOI] [PMC free article] [PubMed]
  • (13).Juul SE, Joyce AE, Zhao Y, Ledbetter DJ. Why is Erythropoietin present in human milk? Studies of erythropoietin receptors in enterocytes of human and rat neonates. Pediatric Res. 1999; 46(3): 263–268. [DOI] [PubMed]
  • (14).Ledbetter DJ, Juul SE. Erythropoietin and the incidence of necrotizing enterocolitis in infants with very low birth weight. J. Pediat. Surgery 2000; 35(2): 178–181. [DOI] [PubMed]
  • (15).Masuda S, Kobayashi T, Chikuma M, Nagao M, Sasaki R. The oviduct produces Erythropoietin in an estrogen- and oxygen-dependent manner. American Journal of Physiology—Endocrinology & Metabolism 2000; 278(6)E: 1038–1044. [DOI] [PubMed]
  • (16).Yasuda Y, Masuda S, Chikuma M, Inioue K, Nagao M, Sasaki R. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J. Biol. Chem. 1998; 273(39): 25381–25387. [DOI] [PubMed]
  • (17).Yasuda Y, Fujita Y, Musha T, Tanaka H, Shiokawa S, Nakamatsu K, Moir S, Matsuo T, Nakamura Y. Expression of erythropoietin in human female reproductive organs. In Motta PM, Nottola SA, Macchiarelli G, Correr S (eds). Molecular, Cellular and Developmental Biology of Reproduction: Basic and Clinical Aspects P 215–222, 2001. [PubMed]
  • (18).Matsuzaki S, Murakami T, Uehara S, Yokomizo R, Noda T, Kimura Y, Okamura K. Erythropoietin concentrations are elevated in the peritoneal fluid of women with endometriosis. Human Reproduction 2001; 16(15): 945–948. [DOI] [PubMed]
  • (19).Fairchild Benyo D, Canrad KP. Expression of the erythropoietin receptor by trophoblast cells in the human placenta. Biology of Reproduction 1999; 60(4): 861–870. [DOI] [PubMed]
  • (20).Magnanti M, Gandini O, Giulani L, Gazzaniga P, Marti HH, Gradilone A, Frati L, Agliano AM, Gassmann M. Erythropoietin expression in primary rat Sertoli and peritubular myoid cells. Blood 2001; 98(9): 2872–2874. [DOI] [PubMed]
  • (21).Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc. Natl. Acad. Sci. USA 1990; 87(15): 5978–5982. [DOI] [PMC free article] [PubMed]
  • (22).Anagnostou A, Liu Z, Steiner M, Chin K, Lee ES, Kessimian N, Noguchi CT. Erythropoietin receptor mRNA expression in human endothelial cells. Proc. Natl. Acad. Sci. USA 1994; 91(9): 3974–3978. [DOI] [PMC free article] [PubMed]
  • (23).Choi K. The hemangioblast: a common progenitor of hematopoietic and endothelial cells. J. Hematother. Stem Cell Res. 2000; 11(1): 91–101. [DOI] [PubMed]
  • (24).Ribatti D, Vacca A, Roncali L, Dammacco F. Hematopoiesis and angiogenesis: a link between two apparently independent processes. J. Hematother. Stem Cell Res. 2000; 9(1): 13–19. [DOI] [PubMed]
  • (25).Carlini RG, Reyes AA, Rothstein M. Recombinant human erythropoietin stimulates angiogenesis in vivo. Kidney Int. 1995; 47(3): 740–745. [DOI] [PubMed]
  • (26).Banerjee D, Rodrigueez M, Nag M, Adamson JW. Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide activity. Kidney Int. 2000; 57(5): 1895–1904. [DOI] [PubMed]
  • (27).Carlini RG, Alonzo EJ, Dominguez J, Blanca I, Weisinger JR, Rothstein M, Bellorin-Font E. Effect of recombinant human erythropoietin on endothelial cell apoptosis. Kidney Int. 1999; 55(2): 546–553. [DOI] [PubMed]
  • (28).Ribatti D, Presta M, Vacca A, Ria R, Giuliani R, Dell'Ezra P, Nico B, Roncali L, Dammacco F. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates angiogenesis in vivo. Blood 1999; 93(8): 2627–2636. [PubMed]
  • (29).Fodinger M, Fritsche-Polanz R, Buchmayer H, Skoupy S, Sengoelge G, Horl WH, Sunder-Plassmann G. Erythropoeitin-inducible immediate-early genes in human vascular endothelial cells. J. Invest. Med. 2000; 48(2): 137–149. [PubMed]
  • (30).Arcasoy M, Amin K, Haroon Z. Erythropoietin (EPO) stimulates angiogenesis and promotes wound healing. Blood 2001; 98(11): 822a.
  • (31).Selzer E, Wacheck V, Kodym R, Schlagbauer-Wadl H, Schlegel W, Pehamberger H, Jansen B. Erythropoietin receptor expression on human melanoma cells. Melanoma Res. 2000; 10(5): 421–426. [DOI] [PubMed]
  • (32).Westenfelder C, Biddle DE, Baranowski RL. Human, rat and mouse kidney cells express functional erythropoietin receptors. Kidney Int. 1999; 55(3): 808–820. [DOI] [PubMed]
  • (33).Ogilvie M, Yu X, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT, Noguchi CT. Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J. Biol. Chem. 2000; 275(50): 39754–39761. [DOI] [PubMed]
  • (34).Iverson PO. Blood flow to the haemopoietic bone marrow. Acta Physiol Scand. 1997; 159(4): 269–276. [DOI] [PubMed]
  • (35).Davis TA, Black AT, Kidwell WR, Lee KP. Conditioned medium from primary porcine endothelial cells alone promotes the growth of primitive haematopoietic progenitor cells with a high replating potential: evidence for a novel early haematopoietic activity. Cytokine 1997; 9(4): 263–275. [DOI] [PubMed]
  • (36).Pelletier L, Regnard J, Fellman D, Charbord P. An in vitro model for the study of human bone marrow angiogenesis: role of hematopoietic cytokines. Lab. Invest. 2000; 80(4): 501–511. [DOI] [PubMed]
  • (37).Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applciations of research on angiogenesis. N. Engl. J. Med. 1995; 333(26): 1757–1763. [DOI] [PubMed]
  • (38).Moses MA, Klagsbrun M, Shing Y. The role of growth factors in vascular cell development and differentiation. Int. Rev. Cytol. 1995; 161: 1–48. [DOI] [PubMed]
  • (39).Ribatti D, Vacca A, DeFalco G, Roccaro A, Roncali K, Dammacco F. Anticancer Res. 2001; 21(6B): 4333–4339. [PubMed]
  • (40).Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407(6801): 249–257. [DOI] [PubMed]
  • (41).Steinbrech DS, Mehrara BJ, Saadeh PB, Greenwald JA, Spector JA, Gittes GK, Longaker MT. VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism. Am. J. Physiol. Cell Physiol. 2000; 278(4): C853–860. [DOI] [PubMed]
  • (42).Minet E, Michel G, Remacle J, Michiels C. Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review). Int. J. Mol. Med. 2000; 5(3): 253–259. [DOI] [PubMed]
  • (43).Dunst J, Stadler P, Becker A, Kuhnt T, Lautenschlager C, Molls M. Tumor hypoxia and systemic levels of vascular endothelial growth factor (VEGF) in head and neck cancers. Strahlenther Onkol. 2001; 177(9): 469–473. [DOI] [PubMed]
  • (44).Dunst J, Pigorsch S, Hansgen G, Hintner I, Lautenschlager C, Becker A. Low hemoglobin is associated with increased levels of vascular endothelial growth factor (VEGF) in cancer patients. Does anemia stimulate angiogenesis? Strahlenther Onkol. 1999; 175(3): 93–96. [DOI] [PubMed]
  • (45).Bachtiary B, Selzer E, Knocke TH, Potter R, Obermair A. Serum VEGF levels in patients undergoing primary radiotherapy for cervical cancer: impact on progression-free survival. Cancer Lett. 2002; 179(2): 197–203. [DOI] [PubMed]
  • (46).Foekens JA, Peters HA, Grebenchtchikov N, Look MP, Meijervan Gelder ME, Geurts-Moespot A, van der Kwast TH, Sweep CG, Klijn JG. High tumor levels of vascular endothelial growth factor predict poor response to systemic therarpy in advanced breast cancer. Cancer Res. 2001; 61(14): 5407–5414. [PubMed]
  • (47).Kunikane H, Watanabe K, Fukuoka M, Saijo M, Furuse K, Ikegame H, Ariyoshi Y, Kishimoto S. Double-blind randomized control trial of the effect of recombinant human erythropoietin on chemotherapy-induced anemia in patients with non-small cell lung cancer. Int. J. Clin. Oncol. 2001; 6(6): 296–301. [DOI] [PubMed]
  • (48).Cazzola M. Mechanisms of anaemia in patients with malignancy: implications for the clinical use of recombinant human erythropoietin. Med. Oncol. 2000; 17 Suppl 1: S11–16. [PubMed]
  • (49).Horiguchi H, Kayama F, Oguma E, Willmore WG, Hradecky P, Bunn HF. Cadmium and platinum suppression of erythropoietin production in cell culture: clinical implications. Blood 2000; 96(12): 3742–3747. [PubMed]
  • (50).Thatcher N, DeCampos ES, Bell DR, Steward WP, Varghese G, Morant R, Vansteenkiste JF, Rosso R, Ewers SB, Sundal E, Schatzmann E, Stocker H. Epoietin alpha prevents anemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br. J. Cancer 1999; 80(3–4): 396–402. [DOI] [PMC free article] [PubMed]
  • (51).Quirt I, Robeson C, Lau CY, Kovacs M, Burdette-Radoux S, Dolan S, Tang SC, MeKenzie M, Couture F. Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J. Clin. Oncol. 2001; 19(21): 4126–4134. [DOI] [PubMed]
  • (52).Bottomley A, Thomas R, van SK, Flechtner H, Djulbegovic B. Human recombinant erythropoietin and quality of life: a wonder drug or something to wonder about? Lancet Oncol. 2002; 3(3): 145–153. [DOI] [PubMed]
  • (53).Dempke W, Von Poblozki A, Grothey A, Schmoll HJ. Human hematopoietic growth factors: old lessons and new perspectives. Anticancer Res. 2000; 20(6D): 5155–5164. [PubMed]
  • (54).Henke M. Correction of cancer anemia—impact on disease course, prognosis and treatment efficiency, particularly for patients undergoing radiotherapy. Onkologie 2001; 24(5): 450–454. [DOI] [PubMed]
  • (55).Shasha D. the negative impact of anemia on radiotherapy and chemoradiation outcomes. Seminars in Hematology 2001; 38(3 Suppl 7): 8–15. [DOI] [PubMed]
  • (56).Littlewood TJ. The impact of hemoglobin levels on treatment outcomes in patients with cancer. Seminars in Oncology 2001; 28 (2 Suppl 8): 49–53. [DOI] [PubMed]
  • (57).Henke M, Guttenberger R. Erythropoietin in radiation oncology—a review. Oncology 2000; 58(2): 175–182. [DOI] [PubMed]
  • (58).Shasha D, Harrison LB. Anemia treatment and the radiation oncologist. Oncology (Huntingt) 2001; 15: 1486–1491 (discussion 149401496). [PubMed]
  • (59).Stuben G, Thews O, Pottgen C, Knuhmann K, Vaupel P, Stuschke M. Recombinant human erythropoietin increases the radiosensivitity of xenografted human tumors in anaemic nude mice. J. Cancer Res Clin, Oncol 2001; 127(6): 346–350. [DOI] [PMC free article] [PubMed]
  • (60).Thews O, Leonig R, Kelleher DK, Kutzner J, Vaupel P. Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br. J. Cancer 1998; 78(6): 752–756. [DOI] [PMC free article] [PubMed]
  • (61).Oettle H, Riess H, Raguse JD, Bier J, Gath HJ. Recombinant human erythropoeitin in the treatment of head and neck tumour anaemia. Int. J. Oral Maxillofac. Surg. 2001; 30(2): 148–155. [DOI] [PubMed]
  • (62).Glaser CM, Millesi W, Kornek GV, Lang S, Schull B, Watzinger F, Selzer E, Lavey RS. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int. J. Radat. Oncol. Biol. Phys. 2001; 50(3): 705–715. [DOI] [PubMed]
  • (63).Henke M, Guttenberger R, Barke A, Pajonk F, Potter R, Frommhold H. Erythropoietin for patients undergoing radiotherapy: a pilot study. Radiotherr. Oncol. 1999; 50(2): 185–190. [DOI] [PubMed]
  • (64).Sweeney PJ, Nicolae D, Ignacio L, Chen L, Roche M 3rd, Wara W, Marcus KC, Vijayakumar S. Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: a final report of a randomized, open-labelled, phase II trial. Br. J. Cancer 1998; 77(11): 1996–2002. [DOI] [PMC free article] [PubMed]
  • (65).Huinink WWT, deSwart CAM, vanToorn DW, Morack G, Breed WPM, Hillen HFP, vanderHoeven JJM, et al. Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy. Med. Oncol. 1998; 15: 141–144. [DOI] [PubMed]
  • (66).Grogan M, Thomas GM, Melamed I, Wong FL, Pearcey RG, Joseph PK, Portelance L, Crook J, Jones KD. The importance of hemoglbin levels during radiotherapy for carcinoma of the cervix. Cancer 1999; 86(8): 1528–1536. [DOI] [PubMed]
  • (67).Sigounas G, Salleng K, Mehlhop P, Sallah S, Collins M, Kardatos A, Sigounas D. Erythropoietin inhibits drug-induced fibrosis and improves pulmonary function. Blood 2001; 98(11): 798a.
  • (68).Mittlman M, Neumann D, Peled A, Kanter P, Haran-Ghera N. Erythropoietin induces tumor regression and antitumor immune response in murine myeloma cells. Proc. Natl. Acad. Sci. USA 2001; 98(9): 5181–5186. [DOI] [PMC free article] [PubMed]
  • (69).Lissoni P, Rovelli F, Baiocco N, Tangini G, Fumagalli L. A phase II study of subcutaneous low-dose interleukin-2 plus erythropoietin in metastatic renal cell carcinoma progressing on interleukin-2 alone. Anticancer Res. 2001; 21(1B): 777–779. [PubMed]
  • (70).Bunworassate U, Arnouk H, Minderman H, O'Loughlin KL, Sait SNJ, Barcos M, Stewart CC, Baer MR. Erythropoietin-dependent transformation of myelodysplastic syndrome to acute monoblastic leukemia. Blood 2001; 98(12): 3492–3494. [DOI] [PubMed]
  • (71).Westenfelder C, Baranowski RL. Erythropoietin stimulates proliferation of renal carcinoma cells. Kidney International 2000; 58(2): 647–657. [DOI] [PubMed]
  • (72).Arendt BK, Griepp PR, Ahmann G, Jelinek B. Myeloma cells express the erythropoietin receptor. Blood 2001; 98(11): 643a. 11468162
  • (73).Okumo Y, Takahashi T, Susuki A, Ichiba S, Nakamura K, Hitomi K, Sasaki R, Imura H. Expression of the erythropoietin receptor on a human myeloma cell line. Biochem. Biophys. Research Comm. 1990; 170(3): 1128–1134. [DOI] [PubMed]
  • (74).Olujohungbe A, Handa S, Holmes J. Does erythropoietin accelerate malignant transformation in multiple myeloma? Postgraduate Medicine 1977; 73(857): 163–164. [DOI] [PMC free article] [PubMed]
  • (75).Yasuda Y, Musha T, Tanaka H, Fujita Y, Fujita H, Utsumi H, Matsuo T, Masuda S, Nagao M, Sasaki R, Nakamura Y. Inhibition of erythropoietin signaling destroys xenografts of ovarian and uterine tumors in mice. Br. J. Cancer 2001; 84(6): 836–843. [DOI] [PMC free article] [PubMed]
  • (76).Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K, Verma A. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 2001; 61(9): 3561–3565. [PubMed]
  • (77).Haroon Z, Amin K, Karayal A, Cho S-C, Raleigh JA, Varia MA, Arcasoy MO. Functional significance of erythropoietin receptor expression on breast cancer cells. Blood 2001; 98(11): 300–301a. [DOI] [PubMed]
  • (78).Juul SE, Zhao Y, Dame JB, Du Y, Hutson AD, Christensen RD. Origin and fate of erythropoietin in human milk. Pediatr. Res. 2000; 48(5): 660–667. [DOI] [PubMed]
  • (79).Feldman L, Wang Y, Rhim JS, Sytkowski AJ. Human prostate epithelial cells and prostate cancer cells express functional erythropoietin receptors and respond to erythropoietin in vitro. Exp. Hematol. 2002; 30(6, suppl 1): 61.

Articles from Environmental Health and Preventive Medicine are provided here courtesy of The Japanese Society for Hygiene

RESOURCES