ISSN: 2469-2778 HTIJ

Hematology & Transfusion International Journal
Review Article
Volume 4 Issue 1 - 2017
A Systematic Review on the Erythropoietin Receptors Expression in Various Cancers and Importance of Recombinant Erythropoietin in Chemotherapy Induced Anaemia
Jayant Kumar1*, Isabella reccia1, Tomokazu Kusano1 and Swati Agrawal2
1Department of hepato-pancreato-biliary surgery (HPB), Imperial College, UK
2John Radcliff Hospitals, UK
Received: January 05, 2017 | Published: January 29, 2017
*Corresponding author: Jayant Kumar, Department of Surgery & Cancer, Imperial College, London, W120HS, UK, Email:
Citation: Kumar J, reccia I, Kusano T, Agrawal S (2017) A Systematic Review on the Erythropoietin Receptors Expression in Various Cancers and Importance of Recombinant Erythropoietin in Chemotherapy Induced Anaemia. Hematol Transfus Int J 4(1): 00072. DOI: 10.15406/htij.2017.04.00072

Abstract

Erythropoietin (EPO) is the primary and influential mediator of red cell synthesis. Its action is mediated by various pathways as JAK2-STAT5, Ras-Raf-MAP kinase, PI-3K-Akt and protein kinase C and adaptor protein CrkL following interaction between EPO and erythropoietin receptors (EPOR) in the various cells. Apart from erythropoiesis it also regulates neuronal functioning and angiogenesis etc. Nevertheless, the pathological presence of these EPOR receptors is seen in various tumour cells that have raised concerns regarding enhanced tumour growth and impaired overall survival. Though the expression of these receptors and its function varies in tumour types and individuals. The recombinant EPO plays an important role in the treatment of cancer-related anemia. However, it must be used judiciously according to individual needs and may be in future EPOR status assessment should help in assessing response and predicting any unwanted adverse effects.

Keywords: Erythropoietin; JAK2-STAT5; Glycoprotein; Paracrine

Abbreviations

EPORs: Erythropoietin Receptors; RBC: Red Blood Cell; HIF: Hypoxia-Inducible Transcription Factors; RHuEPO: Recombinant Human EPO

Introduction

Erythropoietin (EPO) discovered in 1906 is a circulatory hemopoietic glycoprotein hormone involved in the red blood cell (RBC) production. Later it was found that it has multitude of actions apart from erythropoiesis as affecting endothelial cell growth, nerve cells and tumour cells expressing erythropoietin receptors (EPORs) [1]. The human EPO gene is located on chromosome 7q22 translates 193 amino acid proteins (Figure 1). Its expression in interstitial cells of kidney and liver is regulated by oxygen level through hypoxia via hypoxia-inducible transcription factors (HIF). There are certain other transcription factors also involved in this process as HNF-4 alpha (Hepatocyte nuclear factor 4-alpha), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and inhibitory GATA-2. The presence of normal oxygen tension hydroxylated the HIF alpha subunits, leading to its proteasomal. Degradation while in cases of hypoxia, as the HIF molecule cannot be hydroxylated and therefore stabilized. Post-translational modification as glycosylation and disulphide bond formation plays an important role in affecting synthesis, structural stability, secretion, plasma half-life and degradation [2]. Renal cortex is the principal site of EPO production in an adult human, while the liver is main production site in the fetus. Following it’s secretion into blood EPO travels to bone marrow to bind with the EPOR present on the surface of the erythroid precursor cells, thus helps in their differentiation, proliferation and survival. Along with that it also influences other body tissues as neurons, endothelial cells and tumour cells through endocrine, autocrine and paracrine pathways.

Figure 1: Schematic diagram showing EPO role in erythropoiesis.

Figure 2: Showing EPOEPOR interaction and signal transduction pathways inside cell. The most common pathways are JAK2-STAT5 pathway, Ras-Raf-MAP kinase pathway, PI-3K-Akt pathway and protein kinase C pathway and adaptor protein CrkL pathway.

EPOR in hemopoietic tissues

The Structure and function of EPOR were primarily studied in erythropoietic tissue. Initial identification of EPOR and its binding sites were done by incorporation of radio labeled thymidine into EPO. Development of recombinant human EPO (RHuEPO) has added new dimensions in the discovery of EPOR in various cells. The density of these receptors varies with the cell types as erythroid colony forming cells have highly enriched receptor number of approx. 1000 receptors per cell. Interestingly enough EPOR shows two different types of affinity influencing the inherent activity of these receptors [3]. The EPOR gene is approximately 6kb in size and located on chromosome 19q12. Its expression in erythropoietic and neuronal tissues are modulated by the factors as anemia and hypoxia predominantly however, other factors such as stem cell factors, interleukin-1, interferon, ionomycin and phorbol also play important role. The EPOR, protein made of 508 amino acids is owned to a cytokine receptor super family. It has an extracellular region containing 225 amino acids, the Trans membrane region of 22 amino acids and cytoplasmic region of 236 amino acids [4]. 

Signal transduction

The interaction of EPO with EPOR induces many important signal transduction pathways with are worth mentioning here. The binding of EPO with EPOR induces a conformational change that caused activation of various kinases and other molecules of information waves towards nucleus. This takes place through phosphorylation of numerous kinases following activation of EPOR. The most common pathways are JAK2-STAT5 pathway, Ras-Raf-MAP kinase pathway, PI-3K-Akt pathway and protein kinase C pathway and adaptor protein CrkL pathway. Apart from directing signal to the nucleus and promoting erythropoiesis, they play convey other important signals. JAK2-STAT5 pathway has anti-apoptotic role in erythropoietic cells and other tissues [4,5,6] (Figure 2).

EPOR in non-hemopoietic tissues

EPO and EPOR induced tissue protective effect has been noted in various non- hemopoietic tissues as neuronal tissues, blood vessels, heart, liver, kidney, gastrointestinal epithelium, pancreatic tissues, ovaries, uterine tissues, placenta [3,7-13]. EPOR mRNA and EPOR protein present in central and peripheral nervous system induces both neurotrophic and neuroprotective effect by promoting proliferation and differentiation of neuronal stem and progenitor cells [14-18]. Therefore, of major importance are the seminal studies are by Sakanaka, et al. [19] who reported prevention of neuronal ischemia and learning disability following introduction of EPO into the lateral brain ventricles of rodents [19,20]. This might be because EPO up regulates Bcl-xl expression in neuronal and maintain mitochondrial function [21-24]. The increased expression of EPOR activates PI-3 and the MAP kinase in endothelial cells of blood vessels and cardiac myocytes. Studies in animal model proved its role in revascularization, cardio-protective against ischemic injury whereas at high doses it showed anti-apoptotic effect and causes vasoconstriction [25-30].

EPOR in tumour tissues

As seen in other tissue type EPOR are also expressed in various tumour tissue as prostate, colorectal, pancreas, breast, renal, hepatic cellular carcinoma, head and neck, melanoma, lung, endometrial, ovarian and uterine carcinomas are some important ones [31-37]. The present essay is aimed to review the structural and functional aspects of expression of erythropoietin receptors (EPOR) in tumor cells and their possible influence on tumour growth. Along with, that further analysis has been to drawn regarding clinical significance of these receptors and effect of recombinant EPO on various tumors expressing these receptors.

Discussion

In the landmark study by Sinclair, et al. [38] they demonstrated no evidence towards amplification of EPOR in various biopsy samples of tumour tissues as brain, colon, kidney, breast, lymphoma, prostate and lung. Although certain studies showed amplified EPOR expression based on the detection rate of polyclonal antibody C-20, M-20 but later studies refuted these results because of non-specific ability of these antibody to cross react with other proteins too [38-44].

Clinical importance of EPO in EPOR expressing tumors

Various studies have shown the presence EPOR mRNA in culture lines of human cancer cells [44,45,46], used reverse transcriptase PCR techniques to demonstrate these receptors in different human cancer lines (HeLa, HEK293T, RCC4, SW 480, MCF-7, HepG2). However, they didn't contemplate any quantitative alterations in spite of hypoxia or EPO therapy [46]. Certain scientists demonstrated hypoxia and EPO induced increase in expression of EPOR mRNA results in increased survival of MCF-7 breast cancer cell lines and SiHa cervical cancer lines in a paracrine manner and promoting angiogenesis [47,48]. The effect of EPO in tumour cells are not straight forward as many tumour displayed no change in cancer cells while some tumour cell lines such as human neuroblastoma cells showed growth inhibition; however, administration of high doses EPO (≥10 U/mL) has been found to be associated with significant protein phosphorylation and angiogenesis in breast cancer cell lines [49,50]. Contrary to this cell lines of prostate and renal cancer cells showed increase growth with relatively lower concentration of EPO [35,41,51,52]. Having said that, there is critical doubt over clinical relevance of these results in the real clinical world regarding assessing the tumour response. The discrepancy in results have been noted in between tumour cell lines and laboratories, a typical example could be study by Kokhaie, et al. [53] where they reported no response to EPO congeners in different cell lines of lymphoid and myeloma cells [53]. How Bauer, et al. [54] studied the effect of EPO on 53 primary human renal and colorectal tumor cell lines. They demonstrated enhanced growth in 2 specimen and inhibition of growth in 5, while no effect in rest specimens [54]. The conflicting behavior of this tumour cell could be due to the lack of growth synergy between tumour cells in culture lines, difference in culture conditions as absence or presence of cell lines, preparation of cell lines [55-57]. Nevertheless, researchers tried to find out the role EPO in conjunction of other chemotherapeutic drugs though results are far from any fruitful surmise and consensus of clinician validates it as double edge sword. Carvalho, et al. [58] reported increased frequency of apoptosis on exposure of daunorubicin or vinblastine and EPO combination drugs in the renal carcinoma cell lines, whereas, Gewirtz et al. failed to exemplify any interference in MDA-MB231 and MCF-7 breast cancer cell lines [58]. In antithesis to the above results few studies have reported resistance to chemotherapy in conjunction of very high threshold of EPO in HT 100 cervical cancer, U87 glioma, melanoma and HeLa cell line by inducing tyrosine phosphorylation of GM-CSF receptor and abatement of pro-apoptotic proteins Bcl-2 and Bcl-10 [59,60].

In presence of great uncertainty with in vitro studies scientist tried to withdraw conclusion of EPO-EPOR response in preclinical animal models. In a landmark study of ovarian and uterine transplanted nude mice by Yashuda, et al. [32] exhibited tumour downgrading following the application of soluble EPOR or anti-EPO antibodies. Likewise, they also demonstrated anti-angiogenesis and anti-apoptotic effect following imposition of EPOR blocking peptides in human melanoma and choriocarcinoma xenograft models. The possible explanation of these could be EPO mediated anti-apoptotic effect causing tumor growth [1,32]. The RHuEPO therapy in cancer patients have been given to treat or prevent chemotherapy or radiotherapy induced anemia and to curtail the need of blood transfusion, nevertheless, they also increase the efficacy of chemotherapeutic drugs and radiotherapy through improved oxygenation. Reported increased efficacy of cyclophosphamide than carboplatin in rat models in presence of RHuEPO, as maintained hematocrit and improved oxygenation aids in sensitization of cytotoxic effect of chemotherapy in animal tumor models [61,62]. At the same time these effect alter with tumour type as noted reduction in tumor growth with cisplatin and RHuEPO though couldn't produce similar effect with mitomycin C or cyclophosphamide [63]. McKinney, et al. [64] and Debeljak, et al. [65] proposed three possible theory mechanisms regarding tumor progression and reduces survival in some cancer types following RHuEPO therapy for cancer chemotherapy induced anemia. First due to local effects in tumour microenvironment affecting tumor cells or other as blood vessel endothelium and tumor-associated macrophages; second is direct or indirect systemic effect that impairs survival; third could be direct effect of EPO on stem cells leading to tumour progression and poor survival in some cancer patients. Recombinant EPO has been in successfully used in clinical practice for treatment of anemia in the cancer patients along with increase effectiveness of chemo-radio therapy though by contrast theoretical possibility of tumour growth is not denied. Mutiple randomized trials and subsequent analysis gave apt evidence towards its beneficence in treatment of cancer related anemia [66-68]. In a meta-analysis demonstrated only 0.64 relative risk for blood transfusion following recombinant EPO therapy [59,69]. The most perilous adverse events causing mortality risk were increased risk for cardiovascular and thromboembolic events, tumour growths and pure red cell aplasia. The detailed analysis various studies according to tumour response and patient survival have been under taken. Antonadou, et al. [70] reported statistically significant disease free survival in patients with pelvic malignancies undertaking radiotherapy with recombinant EPO. Similarly, Blohmer, et al. [71] demonstrated significantly better disease free survival in high risk cervical carcinoma patients receiving combined recombinant EPO with chemo-radiotherapy. In the same line Leyland, et al. [72] in Breast cancer and Henke, et al. [73] in Head and Neck cancer and Wright, et al. [74] in lung cancer have found the negative influence of erythropoietin Several other studies, showed increased tumour growth and reduced tumour survival, where increased EPOR expression in these tumors contributes towards the poor survival, tumor growth or disease recurrence [12,75]. The expression of EPOR acts as an important prognostic factor i.e. intensified expression is inversely related with prognosis and reduced response to chemo-radio therapy [76,77,78]. Further studies based on EPOR subtypes are needed in order to better understand the tumour biology and substantiate the treatment justification in cancer chemotherapy induced anemia.

Conclusion

In the midst of the present evidences there is no doubt that EPO has detrimental influence in cancer producing EPOR, leading to increase tumour growth and poor survival. The main concern for its use is chemotherapy induced anemia in cancer patients which needs attention, having said that there is no clear cut guideline regarding initiation of EPO in anemic cancer patients. The consensus is towards assessing the EPOR receptors status in tumors like estrogen-progesterone receptors in breast cancers. So that EPO simulating agents could be prescribed in patients with EPOR negative tumors. In 2008, American Society of Clinical Oncology laid its guidelines regarding treatment of anemia in cancer patients and fixed the upper limit of treatment at hemoglobin level of 12g/dl [79].

References

  1. Yasuda Y, Musha T, Tanaka H, Fujita Y, Fujita H, et al. (2001) Inhibition of erythropoietin signalling destroys xenografts of ovarian and uterine cancers in nude mice. British journal of cancer 84(6): 836-843.
  2. Jelkmann W, Wagner K (2004) Beneficial and ominous aspects of the pleiotropic action of erythropoietin. Annals of Hematology 83(11): 673-686.
  3. Hitomi K, Fujita K, Sasaki R, Chiba H, Okuno Y, et al. (1988) Erythropoietin receptor of a human leukemic cell line with erythroid characteristics. Biochemical and biophysical research communications 154(3): 902-909.
  4. Rane SG, Reddy EP (2002) JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21(21): 3334-3358.
  5. Zouein FA, Duhé RJ, Booz GW (2011) JAKs go nuclear: Emerging role of nuclear JAK1 and JAK2 in gene expression and cell growth. Growth Factors 29(6): 245-252.
  6. Oshea JJ, Holland SM, Staudt LM (2013) Mechanisms of Disease JAKs and STATs in Immunity, Immunodeficiency, and Cancer. N Engl J Med 368: 161-170.
  7. Li F, Chong ZZ, Maiese K (2004) Erythropoietin on a tightrope: Balancing neuronal and vascular protection between intrinsic and extrinsic pathways. NeuroSignals 13(6): 265-289.
  8. Chong ZZ, Kang JQ, Maiese K (2003) Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. British journal of pharmacology 138(6): 1107-1118.
  9. Marti HH (2004) Erythropoietin and the hypoxic brain. The Journal of experimental biology 207(Pt 18): 3233-3242.
  10. Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW (2006) Erythropoietin biology in cancer. Clinical Cancer Research 12(2): 332-339.
  11. Pajonk F, Weil A, Sommer A, Suwinski R, Henke M (2004) The erythropoietin-receptor pathway modulates survival of cancer cells. Oncogene 23(55): 8987-8991.
  12. Chabowska AM, Sulkowska M, Chabowski A, Wincewicz A, Koda M, et al. (2008) Erythropoietin and erythropoietin receptor in colorectal cancer. International journal of surgical pathology 16: 269-276.
  13. Blau CA (2007) Erythropoietin in cancer: presumption of innocence? Stem cells. 25(8): 2094-2097.
  14. Studer L, Csete M, Lee SH, Kabbani N, Walikonis J, et al. (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. The Journal of neuroscience : the official journal of the Society for Neuroscience 20(19): 7377-7383.
  15. Noguchi CT, Asavaritikrai P, Teng R, Jia Y (2007) Role of erythropoietin in the brain. Critical Reviews in Oncology/Hematology 64(2): 159-171.
  16. Brines ML, Ghezzi P, Keenan S, Agnello D, De Lanerolle NC, et al. (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proceedings of the National Academy of Sciences of the United States of America 97(19): 10526-10531.
  17. Rangarajan V, Juul SE (2014) Erythropoietin: Emerging role of erythropoietin in neonatal neuroprotection. Pediatric Neurology 51(4): 481-488.
  18. Alnaeeli M, Li Wang, Piknova B, Rogers H, Xiaoxia Li, et al. (2012) Erythropoietin in Brain Development and Beyond. Anatomy Research International 2012: 1-15.
  19. Sakanaka M, Matsuda S, Chun WT, Masaya N, Morishita E, et al. (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proceedings of the National Academy of Sciences of the United States of America 95(8): 4635-4640.
  20. Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, et al. (1998) Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 253(1): 26-32.
  21. Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R, et al. (1996) Erythropoetin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76(1): 105-116.
  22. Sirén AL, Fratelli M, Brines M, Goemans C, Casagrande S, et al. (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proceedings of the National Academy of Sciences of the United States of America 98(7): 4044-4049.
  23. Wen TC, Sadamoto Y, Tanaka J, Zhu PX, Nakata K, et al. (2002) Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. Journal of Neuroscience Research 67(6): 795-803.
  24. Kumral A, Genc S, Ozer E, Yilmaz O, Gokmen N, et al. (2006) Erythropoietin downregulates bax and DP5 proapoptotic gene expression in neonatal hypoxic-ischemic brain injury. Biology of the Neonate 89(3): 205-210.
  25. Tramontano AF, Muniyappa R, Black AD, Blendea MC, Cohen I, et al. (2003) Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochemical and Biophysical Research Communications 308(4): 990-994.
  26. Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, et al. (2003) A novel protective effect of erythropoietin in the infarcted heart. Journal of Clinical Investigation 112(7): 999-1007.
  27. Garg K, Harlokesh NY, Manjeet S, Sharma P L, et al. (2010) Mechanism of cardioprotective effect of erythropoietin-induced preconditioning in rat heart. Indian journal of pharmacology 42(4): 219-223.
  28. Bagla AG, Ertugrul E, Halil FM, Askin K, et al. (2013) Experimental acute myocardial infarction in rats: HIF-1??, caspase-3, erythropoietin and erythropoietin receptor expression and the cardioprotective effects of two different erythropoietin doses. Acta Histochemica 115(7): 658-668.
  29. Huang CH, Hsu CY, Tsai MS, Wang TD, Chang WT, et al. (2008) Cardioprotective effects of erythropoietin on postresuscitation myocardial dysfunction in appropriate therapeutic windows. Critical Care Medicine 36(11): S467-473.
  30. Parsa CJ, Kim J, Riel RU, Pascal LS, Thompson RB, et al. (2004) Cardioprotective Effects of Erythropoietin in the Reperfused Ischemic Heart. Journal of Biological Chemistry 279(20): 20655-20662.
  31. Lambin P, Ramaekers BL, van Mastrigt GA, Van den EP, de Jong J, et al. (2009) Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. Cochrane database of systematic reviews (3):CD006158.
  32. Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, et al. (2003) Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 24(6): 1021-1029.
  33. Morais C, Johnson DW, Vesey DA, Gobe GC (2013) Functional significance of erythropoietin in renal cell carcinoma. BMC cancer 13: p.14.
  34. Fuge F, Doleschel D, Rix A, Gremse F, Wessner A, et al. (2014) In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography. European Radiology 25(2): 472-479.
  35. Arcasoy MO, Amin K, Vollmer RT, Jiang X, Demark-Wahnefried W, et al. (2005) Erythropoietin and erythropoietin receptor expression in human prostate cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 18(3): 421-430.
  36. Mannello F, Tonti GM (2008) Erythropoietin and its receptor in breast cancer: putting together the pieces of the puzzle. The oncologist 13(7): 761-768.
  37. Ribatti D, Marzullo A, Gentile A, Longo V, Nico B, et al. (2007) Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma. Histopathology 50(5): 591-596.
  38. Sinclair AM, Rogers N, Busse L, Archibeque I, Brown W, et al. (2008) Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. British journal of cancer 98(6): 1059-1067.
  39. Acs G, Zhang PJ, Rebbeck TR, Acs P, Verma A (2002) Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Cancer 95(5): 969-981.
  40. LaMontagne KR, Butler J, Marshall DJ, Tullai J, Gechtman Z, et al. (2006) Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor-positive breast carcinoma models. Molecular cancer therapeutics 5(2): 347-355.
  41. Lee YS, Vortmeyer AO, Lubensky IA, Vogel TW, Ikejiri B, et al. (2005) Coexpression of erythropoietin and erythropoietin receptor in von Hippel-Lindau disease-associated renal cysts and renal cell carcinoma. Clin Cancer Res 11(3): 1059-064.
  42. Batra S, Perelman N, Luck LR, Shimada H, Malik P (2003) Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival. Lab Invest 83(10): 1477-1487.
  43. Okazaki T, Ebihara S, Asada M, Yamanda S, Yamanda S, et al. (2008) Erythropoietin promotes the growth of tumors lacking its receptor and decreases survival of tumor-bearing mice by enhancing angiogenesis. Neoplasia 10(9): 932-939.
  44. Acs G, Zhang PJ, McGrath CM, Acs P, McBroom J, et al. (2003) Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. The American journal of pathology 162(6): 1789-1806.
  45. Arcasoy MO, Jiang X, Haroon Z (2003) Expression of erythropoietin receptor splice variants in human cancer. Biochem Biophys Res Commun 307(4): 999-1007.
  46. Laugsch M, Metzen E, Svensson T, Depping R, Jelkmann W (2008) Lack of functional erythropoietin receptors of cancer cell lines. International Journal of Cancer 122(5): 1005-1011.
  47. Lester RD, Jo M, Campana WM, Gonias SL (2005) Erythropoietin promotes MCF-7 breast cancer cell migration by an ERK/mitogen-activated protein kinase-dependent pathway and is primarily responsible for the increase in migration observed in hypoxia. The Journal of biological chemistry 280(47): 39273-39277.
  48. Barbera L, Thomas G (2010) Erythropoiesis stimulating agents, thrombosis and cancer. Radiotherapy and Oncology 95(3): 269-276.
  49. Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, et al. (2001) Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 61(9): 3561-3565.
  50. Shi Z, Hodges VM, Dunlop EA, Percy MJ, Maxwell AP, et al. (2010) Erythropoietin-induced activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK pathways promotes malignant cell behavior in a modified breast cancer cell line. Molecular cancer research : MCR 8(4): 615-626.
  51. Balogova S, Huchet V, Egrot C, Michaud L, Paycha F, et al. (2013) Effect of erythropoietin on bone marrow uptake of 18F-fluorocholine in prostate cancer: comparison with 18F-fluoride uptake. Clinical nuclear medicine 38(3): 200-202.
  52. Wu P, Ning Z, Xi Wang, Chi Z, Teng L, et al. (2012) The Erythropoietin/Erythropoietin Receptor Signaling Pathway Promotes Growth and Invasion Abilities in Human Renal Carcinoma Cells. PLoS ONE 7(9).
  53. Kokhaei P, Abdalla AO, Hansson L, Mikaelsson E, Kubbies M, et al. (2007) Expression of erythropoietin receptor and in vitro functional effects of epoetins in B-cell malignancies. Clinical Cancer Research 13(12): 3536-3544.
  54. Bauer E, Danhauser RS, Riese DW, Raab HR, Sandner S, et al. (1992) Effects of Recombinant Human Erythropoietin on Clonogenic Growth of Primary Human Tumor Specimens in Vitro. Cytokines in Hemopoiesis, Oncology, and AIDS II, pp: 115-125.
  55. Spyridonidis A (1999) Proliferation and Survival of Mammary Carcinoma Cells Are Influenced by Culture Conditions Used for Ex Vivo Expansion of CD34<sup>+</sup>Blood Progenitor Cells. Blood 93(2): 746 LP-755 LP.
  56. Westenfelder C, Baranowski R L (2000) Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney international 58(2): 647-657.
  57. Westenfelder C, Biddle D L, Baranowski R L (1999) Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney international 55(3): 808-820.
  58. Carvalho G, Lefaucheur C, Cherbonnier C, Métivier D, Chapel A, et al. (2005) Chemosensitization by erythropoietin through inhibition of the NF-kappaB rescue pathway. Oncogene 24(5): 737-745.
  59. Hedley BD, Allan AL, Xenocostas A (2011) The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression. Clinical cancer research : an official journal of the American Association for Cancer Research 17(20): 6373-6380.
  60. Belenkov AI, Shenouda G, Rizhevskaya E, Cournoyer D, Belzile JP, et al. (2004) Erythropoietin induces cancer cell resistance to ionizing radiation and to cisplatin. Molecular cancer therapeutics 3(12): 1525-1532.
  61. Vaupel P, Dunst J, Engert A, Fandrey J, Feyer P, et al. (2005) Effects of recombinant human erythropoietin (rHuEPO) on tumor control in patients with cancer-induced anemia. Onkologie 28(4): 216-221.
  62. Blackwell K, Kirkpatrick JP, Snyder SA, Broadwater G, Farrell F, et al. (2003) Human recombinant erythropoietin significantly improves tumor oxygenation independent of its effects on hemoglobin. Cancer Res 63(19): 6162-6165.
  63. Sigounas G, Sallah S, Sigounas VY (2004) Erythropoietin modulates the anticancer activity of chemotherapeutic drugs in a murine lung cancer model. Cancer Letters 214(2): 171-179.
  64. McKinney M, Arcasoy MO (2011) Erythropoietin for oncology supportive care. Experimental cell research 317(9): 1246-1254.
  65. Debeljak N, Solár P, Sytkowski A J (2014) Erythropoietin and cancer: The unintended consequences of anemia correction. Frontiers in Immunology 5: 563.
  66. Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, et al. (2007) A systematic review and economic evaluation of epoetin alpha, epoetin beta and darbepoetin alpha in anaemia associated with cancer, especially that attributable to cancer treatment. Health technology assessment 11(13): 1-202.
  67. Glaspy JA, Jadeja JS, Justice G, Kessler J, Richards D, et al. (2002) Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. British journal of cancer 87(3): 268-276.
  68. Senecal FM, Yee L, Gabrail N, Charu V, Tomita D, et al. (2005) Treatment of chemotherapy-induced anemia in breast cancer: results of a randomized controlled trial of darbepoetin alfa 200 microg every 2 weeks versus epoetin alfa 40,000 U weekly. Clinical breast cancer 6(5): 446-454.
  69. Bohlius J, Weingart O, Trelle S, Engert A et al. (2006) Cancer-related anemia and recombinant human erythropoietin--an updated overview. Nature clinical practice. Oncology 3(3): 152-64.
  70. Antonadou D, Cardamakis E, Puglisi E, Malamos N, Throuvalas N (2001) Erythropoietin enhances radiation treatment efficacy in patients with pelvic malignancies. final results of a randomized phase III study. European Journal of Cancer 37: S144.
  71. Blohmer JU, Paepke S, Sehouli J, Boehmer D, Kolben M, et al. (2011) Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin alfa in patients with high-risk cervical cancer: Results of the NOGGO-AGO intergroup study. Journal of Clinical Oncology 29(28):3791-3797.
  72. Jones BL, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, et al. (2005) Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. Journal of Clinical Oncology 23(25): 5960-5972.
  73. Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, et al. (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362(9392): 1255-1260.
  74. Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, et al. (2007) Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 25(9): 1027-1032.
  75. Devon KM, McLeod RS (2009) Pre and peri-operative erythropoietin for reducing allogeneic blood transfusions in colorectal cancer surgery. Cochrane database of systematic reviews (1): CD007148.
  76. Ceelen W, Boterberg T, Smeets P, Van Damme N, Demetter P, et al. (2007) Recombinant human erythropoietin alpha modulates the effects of radiotherapy on colorectal cancer microvessels. British journal of cancer 96(5): 692-700.
  77. Selzer E, Wacheck V, Kodym R, Schlagbauer WH, Schlegel W, et al. (2000) Erythropoietin receptor expression in human melanoma cells. Melanoma Res 10(5): 421-426.
  78. Mirmohammadsadegh A, Marini A, Gustrau A, Delia D, Nambiar S, et al. (2010) Role of erythropoietin receptor expression in malignant melanoma. The Journal of investigative dermatology 130(1): 201-210.
  79. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Somerfield MR, et al. (2010) American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol 28(33): 4996-5010.
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