Skip to main content
SpringerLink
Log in

Erythropoietin Signaling in the Microenvironment of Tumors and Healthy Tissues

  • Chapter
  • First Online:
Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1223))

Abstract

Erythropoietin (EPO), the primary cytokine of erythropoiesis, stimulates both proliferation and differentiation of erythroid progenitors and their maturation to red blood cells. Basal EPO levels maintain the optimum levels of circulating red blood cells. However, during hypoxia, EPO secretion and its expression is elevated drastically in renal interstitial fibroblasts, thereby increasing the number of erythroid progenitors and accelerating their differentiation to mature erythrocytes. A tight regulation of this pathway is therefore of paramount importance. The biological response to EPO is commenced through the involvement of its cognate receptor, EPOR. The receptor–ligand complex results in homodimerization and conformational changes, which trigger downstream signaling events and cause activation or inactivation of critical transcription factors that promote erythroid expansion. In recent years, recombinant human EPO (rEPO) has been widely used as a therapeutic tool to treat a number of anemias induced by infection, and chemotherapy for various cancers. However, several studies have uncovered a tumor promoting ability of EPO in man, which likely occurs through EPOR or alternative receptor(s). On the other hand, some studies have demonstrated a strong anticancer activity of EPO, although the mechanism still remains unclear. A thorough investigation of EPOR signaling could yield enhanced understanding of the pathobiology for a variety of disorders, as well as the potential novel therapeutic strategies. In this chapter, in addition to the clinical relevance of EPO/EPOR signaling, we review its anticancer efficacy within various tumor microenvironments.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF (1993) Structure, function, and activation of the erythropoietin receptor. Blood 81:2223–2236

    Article  CAS  Google Scholar 

  2. Yasuda Y, Nagao M, Okano M, Masuda S, Sasaki R et al (1993) Localization of erythropoietin and erythropoietin-receptor in post-implantation mouse embryos. Dev Growth Differ 35(6):711–722. https://doi.org/10.1111/j.1440-169X.1993.00711.x

    Article  CAS  Google Scholar 

  3. Snow MHL (1977) Gastrulation in the mouse: growth and regionalization of the epiblast. J Embryol Exp Morphol 42:293–303. https://dev.biologists.org/content/42/1/293

    Google Scholar 

  4. Yasuda Y, Fujita Y, Musha T, Tanaka H, Shiokawa S, Nakamatsu K et al (2001) Expression of erythropoietin in human female reproductive organs. Ital J Anat Embryol 106:215–222

    CAS  PubMed  Google Scholar 

  5. Acs G, Zhang PJ, Rebbeck TR, Acs P, Verma A (2002) Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Cancer 95:965–981. https://doi.org/10.1002/cncr.10787

    Article  CAS  Google Scholar 

  6. Arcasoy MO, Amin K, Karayal AF, Chou SC, Raleigh JA et al (2002) Functional significance of erythropoietin receptor expression in breast cancer. Lab Investig 82:911–918. https://doi.org/10.1097/01.LAB.0000020415.72863.40

    Article  CAS  PubMed  Google Scholar 

  7. Feldman L, Wang Y, Rhim JS, Bhattacharya N, Loda M, Sytkowski AJ (2006) Erythropoietin stimulates growth and STAT5 phosphorylation in human prostate epithelial and prostate cancer cells. Prostate 66:135–145. https://doi.org/10.1002/pros.20310

    Article  CAS  PubMed  Google Scholar 

  8. Lopez TV, Lappin TRJ, Maxwell P, Shi Z, Lopez-Marure R, Aguilar C et al (2011) Autocrine/paracrine erythropoietin signaling promotes JAK/STAT-dependent proliferation of human cervical cancer cells. Int J Cancer 129:2566–2576. https://doi.org/10.1002/ijc.25935

    Article  CAS  PubMed  Google Scholar 

  9. Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A et al (2003) Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 24:1021–1029. https://doi.org/10.1093/carcin/bgg060

    Article  CAS  PubMed  Google Scholar 

  10. Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N (2003) Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci U S A 98(9):5181–5186. https://www.ncbi.nlm.nih.gov/pubmed/?term=Erythropoietin+induces+tumor+regression+and+antitumor+immune+responses+in+murine+myeloma+models

    Article  CAS  Google Scholar 

  11. Cervi D, Shaked Y, Haeri M, Usenko T, Lee CR et al (2007) Enhanced natural-killer cell and erythropoietic activities in VEGF-A-overexpressing mice delay F-MuLV-induced erythroleukemia. Blood 109(5):2139–2146. https://doi.org/10.1182/blood-2005-11-026823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cervi D, Truong AH, Lee JS, Sukhai N, Li YJ, Koki A, Ben-David Y (2004) Phosphorylation status of c-kit and EPO receptors, and the presence of wild-type p53 confer in vitro resistance of murine erythroleukemic cells to Celecoxib. Oncogene 23(13):2305–2314. https://doi.org/10.1038/sj.onc.1207400

    Article  CAS  PubMed  Google Scholar 

  13. Deshet-Unger N, Hiram-Bab S, Haim-Ohana Y, Mittelman M, Gabet Y, Neumann D (2016) Erythropoietin treatment in murine multiple myeloma: immune gain and bone loss. Sci Rep 6:30998. https://doi.org/10.1038/srep30998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Katz O, Gil L, Lifshitz L, Prutchi-Sagiv S, Gassmann M, Mittelman M, Neumann D (2007) Erythropoietin enhances immune responses in mice. Eur J Immunol 37(6):1584–1593. https://doi.org/10.1002/eji.200637025

    Article  CAS  PubMed  Google Scholar 

  15. Lamanuzzi A, Saltarella I, Ferrucci A, Ria R, Ruggieri S, Racanelli V et al (2016) Role of erythropoietin in the angiogenic activity of bone marrow endothelial cells of MGUS and multiple myeloma patients. Oncotarget 7(12):14510–14521. https://doi.org/10.18632/oncotarget.7587

    Article  PubMed  PubMed Central  Google Scholar 

  16. Vatsveen TK, Sponaas AM, Tian E, Zhang Q, Misund K, Sundan A et al (2016) Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro. Hematol Oncol 9(1):75. https://doi.org/10.1186/s13045-016-0306-x

    Article  CAS  Google Scholar 

  17. Miyake T, Kung CK, Goldwasser E (1977) Purification of human erythropoietin. J Biol Chem 252(15):5558–5564

    CAS  PubMed  Google Scholar 

  18. Obara N, Imagawa S, Nakano Y, Suzuki N, Yamamoto M, Nagasawa T (2003) Suppression of erythropoietin gene expression by cadmium depends on inhibition of HIF-1, not stimulation of GATA-2. Arch Toxicol 77(5):267–273. https://doi.org/10.1007/s00204-003-0444-0

    Article  CAS  PubMed  Google Scholar 

  19. Tabata M, Tarumoto T, Ohmine K, Furukawa Y, Hatake K, Ozawa K et al (2003) Stimulation of GATA-2 as a mechanism of hydrogen peroxide suppression in hypoxia-induced erythropoietin gene expression. J Cell Physiol 186(2):260–267. https://doi.org/10.1002/1097-4652(200002)186:2<260::AID-JCP1025>3.0.CO;2-K

    Article  Google Scholar 

  20. Haase VH (2013) Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 27(1):41–53. https://doi.org/10.1016/j.blre.2012.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ebert BL, Bunn HF (1999) Regulation of the erythropoietin gene. Blood 94(6):1864–1877

    Article  CAS  Google Scholar 

  22. Fisher JW (2003) Erythropoietin: physiology and pharmacology update. Exp Biol Med 228(1):1–14. https://doi.org/10.1177/153537020322800101

    Article  CAS  Google Scholar 

  23. Lacombe C, Mayeux P (1998) Biology of erythropoietin. Haematologica 83(8):724–732

    CAS  PubMed  Google Scholar 

  24. Sasaki R, Masuda S, Nagao M (2000) Erythropoietin: multiple physiological functions and regulation of biosynthesis. Biosci Biotechnol Biochem 64:1775–1793. https://doi.org/10.1271/bbb.64.1775

    Article  CAS  PubMed  Google Scholar 

  25. Jelkmann W (2003) Erythropoietin. J Endocrinol Investig 26:832–837. https://doi.org/10.1007/BF03345232

    Article  CAS  Google Scholar 

  26. Maiese K, Chong ZZ, Hou J, Shang YC (2008) Erythropoietin and oxidative stress. Curr Neurovasc Res 5:125–142

    Article  CAS  Google Scholar 

  27. Toyoda T, Itai T, Arakawa T, Aoki KH, Yamaguchi H (2000) Stabilization of human recombinant erythropoietin through interactions with the highly branched N-glycans. J Biochem 128:731–737. https://doi.org/10.1093/oxfordjournals.jbchem.a022809

    Article  CAS  PubMed  Google Scholar 

  28. Singbartl G (1994) Adverse events of erythropoietin in long-term and in acute/short-term treatment. Clin Investig 72(6):36–43

    Google Scholar 

  29. Vazquez-Mellado MJ, Monjaras-Embriz V, Rocha-Zavaleta L (2017) Erythropoietin, stem cell factor, and cancer cell migration. Vitam Horm 105:273–291. https://doi.org/10.1016/bs.vh.2017.02.008

    Article  CAS  PubMed  Google Scholar 

  30. D’Andrea AD, Zon LI (1990) Erythropoietin receptor. Subunit structure and activation. J Clin Invest 86(3):681–687. https://doi.org/10.1172/JCI114763

    Article  PubMed  PubMed Central  Google Scholar 

  31. Huang LJ, Constantinescu SN, Lodish HF (2001) The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell 8(6):1327–1338. https://doi.org/10.1016/S1097-2765(01)00401-4

    Article  CAS  PubMed  Google Scholar 

  32. Kuhrt D, Wojchowski DM (2015) Emerging EPO and EPO receptor regulators and signal transducers. Blood 125(23):3536–3541. https://doi.org/10.1182/blood-2014-11-575357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Temkin SM, Hellmann M, Serur E, Lee YC, Abulafia O (2006) Erythropoietin administration during primary treatment for locally advanced cervical carcinoma is associated with poor response to radiation. Int J Gynecol Cancer 16:1855–1861. https://doi.org/10.1111/j.1525-1438.2006.00709.x

    Article  CAS  PubMed  Google Scholar 

  34. Rankin EB, Wu C, Khatri R, Wilson TL, Andersen R, Araldi E et al (2012) The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 149(1):63–74. https://doi.org/10.1016/j.cell.2012.01.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McGee SJ, Havens AM, Shiozawa Y, Jung Y, Taichman RS (2012) Effects of erythropoietin on the bone microenvironment. Growth Factors 30(1):22–28. https://doi.org/10.3109/08977194.2011.637034

    Article  CAS  PubMed  Google Scholar 

  36. Munugalavadla V, Kapur R (2005) Role of c-kit and erythropoietin receptor in erythropoiesis. Crit Rev Oncol Hematol 54:63–75. https://doi.org/10.1016/j.critrevonc.2004.11.005

    Article  PubMed  Google Scholar 

  37. Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O et al (1993) JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74:227–236. https://doi.org/10.1016/0092-8674(93)90414-l

    Article  CAS  PubMed  Google Scholar 

  38. Kirito K, Nakajima K, Watanabe T, Uchida M, Tanaka M et al (2002) Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation. Blood 99:102–110. https://doi.org/10.1182/blood.v99.1.102

    Article  CAS  PubMed  Google Scholar 

  39. Klingmuller U, Bergelson S, Hsiao JG, Lodish HF (1996) Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. Proc Natl Acad Sci U S A 93:8324–8328. https://doi.org/10.1073/pnas.93.16.8324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bao H, Jacobs-Helber SM, Lawson AE, Penta K, Wickrema A, Sawyer ST (1999) Protein kinase B (c-Akt), phosphatidylinositol 3-kinase, and STAT5 are activated by erythropoietin (EPO) in HCD57 erythroid cells but are constitutively active in an EPO-independent, apoptosis-resistant sub clone (HCD57-SREI cells). Blood 93:3757–3773

    Article  CAS  Google Scholar 

  41. Damen JE, Wakao H, Miyajima A, Krosl J, Humphries RK, Cutler RL et al (1995) Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. EMBO J 14:5557–5568. https://doi.org/10.1002/j.1460-2075.1995.tb00243.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lin JS, Chen YS, Chiang HS, Ma MC (2008) Hypoxic preconditioning protects rat hearts against ischaemia-reperfusion injury: role of erythropoietin on progenitor cell mobilization. J Physiol 586:5757–5769. https://doi.org/10.1113/jphysiol.2008.160887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu N, Tian J, Cheng J, Zhang J (2013) Effect of erythropoietin on the migration of bone marrow-derived mesenchymal stem cells to the acute kidney injury microenvironment. Exp Cell Res 319:2019–2027. https://doi.org/10.1016/j.yexcr.2013.04.008

    Article  CAS  PubMed  Google Scholar 

  44. Satoh K, Kagaya Y, Nakano M, Ito Y, Ohta J, Tada H et al (2006) Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 113:1442–1450. https://doi.org/10.1161/CIRCULATIONAHA.105.583732

    Article  CAS  PubMed  Google Scholar 

  45. Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C et al (2003) Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 102:1340–1346. https://doi.org/10.1182/blood-2003-01-0223

    Article  CAS  PubMed  Google Scholar 

  46. Hoch M, Fischer P, Stapel B, Missol-Kolka E, Sekkali B, Scherr M et al (2011) Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies. Cell Stem Cell 9(2):131–143. https://doi.org/10.1016/j.stem.2011.07.001

    Article  CAS  PubMed  Google Scholar 

  47. Ropers HH, Craig IW (1989) REPOrt of the committee on the genetic constitution of chromosomes 12 and 13. Cytogenet Cell Genet 51:259–279. https://doi.org/10.1159/000132794

    Article  CAS  PubMed  Google Scholar 

  48. Hsu YR, Wu GM, Mendiaz EA, Syed R, Wypych J, Toso R et al (1997) The majority of stem cell factor exists as monomer under physiological conditions. Implications for dimerization mediating biological activity. J Biol Chem 272:6406–6415. https://doi.org/10.1074/jbc.272.10.6406

    Article  CAS  PubMed  Google Scholar 

  49. Langley KE, Bennett LG, Wypych J, Yancik SA, Liu XD, Westcott KR et al (1993) Soluble stem cell factor in human serum. Blood 81:656–660

    Article  CAS  Google Scholar 

  50. Liu H, Chen X, Focia PJ, He X (2007) Structural basis for stem cell factor-kit signaling and activation of class III receptor tyrosine kinases. EMBO J 26:891–901. https://doi.org/10.1038/sj.emboj.7601545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ronnstrand L (2004) Signal transduction via the stem cell factor receptor/c-kit. Cell Mol Life Sci 61:2535–2548. https://doi.org/10.1007/s00018-004-4189-6

    Article  CAS  PubMed  Google Scholar 

  52. Matsui Y, Zsebo KM, Hogan BL (1990) Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. Nature 347:667–669. https://doi.org/10.1038/347667a0

    Article  CAS  PubMed  Google Scholar 

  53. Matsui J, Wakabayashi T, Asada M, Yoshimatsu K, Okada M (2004) Stem cell factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial cells. J Biol Chem 279:18600–18607. https://doi.org/10.1074/jbc.M311643200

    Article  CAS  PubMed  Google Scholar 

  54. Guo J, Jie W, Shen Z, Li M, Lan Y, Kong Y et al (2014) SCF increases cardiac stem cell migration through PI3K/AKT and MMP-2/−9 signaling. Int J Mol Med 34:112–118. https://doi.org/10.3892/ijmm.2014.1773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brown WM, Maxwell P, Graham AN, Yakkundi A, Dunlop EA, Shi Z et al (2007) Erythropoietin receptor expression in non-small cell lung carcinoma: a question of antibody specificity. Stem Cells 25:718–722. https://doi.org/10.1634/stemcells.2006-0687

    Article  CAS  PubMed  Google Scholar 

  56. Elliott S, Busse L, Bass MB, Lu H, Sarosi I, Sinclair AM et al (2006) Anti-EPO receptor antibodies do not predict EPO receptor expression. Blood 107:1892–1895. https://doi.org/10.1182/blood-2005-10-4066

    Article  CAS  PubMed  Google Scholar 

  57. Doleschel D, Mundigl O, Wessner A, Gremse F, Bachmann J, Rodriguez A et al (2012) Targeted near-infrared imaging of the erythropoietin receptor in human lung cancer xenografts. J Nucl Med 53:304–311. https://doi.org/10.2967/jnumed.111.091124

    Article  CAS  PubMed  Google Scholar 

  58. Fuge F, Doleschel D, Rix A, Gremse F, Wessner A, Winz O et al (2015) In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography. Eur Radiol 25:472–479. https://doi.org/10.1007/s00330-014-3413-5

    Article  PubMed  Google Scholar 

  59. Shi Z, Hodges VM, Dunlop EA, Percy MJ, Maxwell AP, El-Tanani M et al (2010) Erythropoietin-induced activation of the JAK2/STAT6, PI3K/Akt, and Ras/ERK pathways promotes malignant cell behaviour in a modified breast cancer cell line. Mol Cancer Res 8:615–626. https://doi.org/10.1158/1541-7786.MCR-09-0264

    Article  CAS  PubMed  Google Scholar 

  60. Um M, Gross AW, Lodish HF (2007) A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastomaSH-SY5Y and pheochromocytoma PC-12 cells. Cell Signal 19:634–645. https://doi.org/10.1016/j.cellsig.2006.08.014

    Article  CAS  PubMed  Google Scholar 

  61. Liang K, Qiu S, Lu Y, Fan Z (2014) Autocrine/paracrine erythropoietin regulates migration and invasion potential and the stemness of human breast cancer cell. Cancer Biol Ther 15:89–98. https://doi.org/10.4161/cbt.26717

    Article  CAS  PubMed  Google Scholar 

  62. Pradeep S, Huang J, Mora EM, Nick AM, Cho MS, Wu SY et al (2015) Erythropoietin stimulates tumor growth via EphB4. Cancer Cell 28(5):610–622. https://doi.org/10.1016/j.ccell.2015.09.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jeong JY, Feldman L, Solar P, Szenajch J, Sytkowski J (2008) Characterization of erythropoietin receptor and erythropoietin expression and function in human ovarian cancer cells. Int J Cancer 122:274–280. https://doi.org/10.1002/ijc.23068

    Article  CAS  PubMed  Google Scholar 

  64. Solar P, Hrckova G, Varinska L, Solarova Z, Kriska J, Uhrinova I et al (2012) Location and the functionality of erythropoietin receptor(s) in A2780 cells. Oncol Rep 28:141–146. https://doi.org/10.3892/or.2012.1795

    Article  CAS  PubMed  Google Scholar 

  65. Rozsas A, Berta J, Rojko L, Horvath LZ, Keszthelyi M, Kenessey I et al (2013) Erythropoietin receptor expression is a potential prognostic factor in human lung adenocarcinoma. PLoS One 8:e77459. https://doi.org/10.1371/journal.pone.0077459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N (2001) Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci U S A 98(9):5181–5186. https://doi.org/10.1073/pnas.081275298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Howard JC, Berger L, Bani MR, Hawley RG, Ben-David Y (1996) Activation of the erythropoietin gene in the majority of F-MuLV induced erythroleukemias results in growth factor independence and enhanced tumorigenicity. Oncogene 12:1405–1415

    CAS  PubMed  Google Scholar 

  68. Howard JC, Yosefi S, Cheong G, Bernstein A, Ben-David Y (1993) Temporal order of the mutation of Fli-1, p53 and erythropoietin genes during the multistep erythroleukemias induced by F-MuLV. Oncogene 8:2721–2729

    CAS  PubMed  Google Scholar 

  69. Shaked Y, Cervi D, Neuman M, Klement G, Michaud CR, Haeri M et al (2005) The splenic microenvironment is a source of angiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells. Blood 105:4500–4507. https://doi.org/10.1182/blood-2004-08-3210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Vecchiarelli-Federico LM, Cervi D, Haeri M, Li Y, Nagy A, Ben-David Y (2010) Vascular endothelial growth factor--a positive and negative regulator of tumor growth. Cancer Res 70(3):863–867. https://doi.org/10.1158/0008-5472.CAN-09-3592

    Article  CAS  PubMed  Google Scholar 

  71. Usenko T, Li YJ, Haeri M, Li Y, Vecchiarelli-Federico LM, Zhao X et al (2009) Enrichment of Sca1+ hematopoietic progenitors in polycythemic mice inhibits leukemogenesis. Blood 114:1831–1841. https://doi.org/10.1182/blood-2008-11-187419

    Article  CAS  PubMed  Google Scholar 

  72. Cui JW, Li YJ, Sarkar A, Brown J, Tan YH et al (2007) Retroviral insertional activation of the Fli-3 locus in erythroleukemias encoding a cluster of microRNAs that convert EPO-induced differentiation to proliferation. Blood 110:2631–2640. https://doi.org/10.1182/blood-2006-10-053850

    Article  CAS  PubMed  Google Scholar 

  73. Li Y, Luo H, Liu T, Zachsenhaus E, Ben-David Y (2015) The transcription factor Fli-1 in development, cancer and disease. Oncogene 35:2022–2031. https://doi.org/10.1038/onc.2014.162

    Article  CAS  Google Scholar 

  74. Knight K, Wade S, Balducci L (2004) Prevalence and outcomes of anemia in cancer: a systematic review of the literature. Am J Med. 116:11S–26S. https://www.ncbi.nlm.nih.gov/pubmed/15050883

    Article  Google Scholar 

  75. Debeljak N, Solár P, Sytkowski AJ (2014) Erythropoietin and cancer: the unintended consequences of anemia correction. Front Immunol 5:563. https://doi.org/10.3389/fimmu.2014.00563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Moebus V, Jackisch C, Schneeweiss A, Huober J, Lueck HJ, du Bois A et al (2013) Adding EPOetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer: randomized clinical trial. J Natl Cancer Inst 105(14):1018–2610. https://doi.org/10.1093/jnci/djt145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tonia T, Mettler A, Robert N, Schwarzer G, Seidenfeld J, Weingart O et al (2012) Erythropoietin or darbEPOetin for patients with cancer. Cochrane Database Syst Rev 12:CD003407. https://doi.org/10.1002/14651858.CD003407.pub5

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Wuling Liu and Krishnapriya M. Varier contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, China

    Wuling Liu, Babu Gajendran & Yaacov Ben-David

  2. The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China

    Wuling Liu, Babu Gajendran & Yaacov Ben-David

  3. Department of Medical Biochemistry, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, India

    Krishnapriya M. Varier

  4. Central Laboratory, Guizhou Provincial People’s Hospital, The Affiliated Hospital of Guizhou University, Guiyang, Guizhou, China

    Klarke M. Sample

  5. Department of Medicine, University of Toronto, Toronto, ON, Canada

    Eldad Zacksenhaus

  6. Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, Canada

    Eldad Zacksenhaus

Authors
  1. Wuling Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krishnapriya M. Varier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klarke M. Sample
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eldad Zacksenhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Babu Gajendran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yaacov Ben-David
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Columbia University Medical Center, Department of Radiology, New York, NY, USA, Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Liu, W., Varier, K.M., Sample, K.M., Zacksenhaus, E., Gajendran, B., Ben-David, Y. (2020). Erythropoietin Signaling in the Microenvironment of Tumors and Healthy Tissues. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1223. Springer, Cham. https://doi.org/10.1007/978-3-030-35582-1_2

Download citation

Publish with us

Policies and ethics

Search

Navigation