Three N-linked (N24, N38, and N83) and one O-linked (S126) oligosaccharide side chains represent 35–40% of the EPO molecular mass. N Engl J Med 322:: Seidenfeld J, Piper M, Flamm C, et al: Epoetin treatment of anemia associated with cancer therapy: A systematic review and meta-analysis of controlled clinical trials.
Proc Natl Acad Sci U S A (1986) 83(17):6465–9. Furthermore, concurrent administration of EPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer (57).
Cox Regression Analysis of Locoregional Progression-Free Survival. doi:10.1002/dta.1341, 9. (55) confirmed the results of Arcasoy et al. Leuk Res (2011) 35(3):416–8.
Stull DE, Vernon MK, Legg JC, Viswanathan HN, Fairclough D, Revicki DA. (106) revealed that normal human cervix and endometrium, as well as ovary malignant tumors of female reproductive organs produce EPO and EPOR, and that the tumor cells themselves and capillary endothelial cells are sites responsive to the EPO signal. Maxwell PH, Ferguson DJ, Nicholls LG, Iredale JP, Pugh CW, Johnson MH, et al. Erythropoietin receptor expression in human melanoma cells. N glycosylation does not affect hormone function in vitro but is essential for in vivo biological activity like biosynthesis, structural stability, secretion, plasma half-life, and clearance (21–23).
Harris KW, Winkelmann JC. doi:10.1002/stem.156, 74. This rather surprising result received considerable coverage in high-profile medical journals16,18 and in the lay press at the time the data were first released, and caused concern among many patients and physicians who pay attention to such things. Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA. 7. Abbreviations: EpoR, erythropoietin receptor; RT, radiotherapy; AJCC, American Joint Committee on Cancer. The protein encoded by EPHB4 gene binds to ephrin-B2 ligand and plays an essential role in vascular development. Schwartzberg L, Burkes R, Mirtsching B, Rearden T, Silberstein P, Yee L, et al. Cytokine use and survival in the first-line treatment of ovarian cancer: a Gynecologic Oncology Group Study. Interestingly, an EPO analog stimulated neovascularization in colorectal liver metastases of hepatectomized and non-hepatectomized mice (110).
Sytkowski AJ. Cancer 95:: Elliott S, Busse L, Bass MB, et al: Anti-Epo receptor antibodies do not predict Epo receptor expression.
(71) showed that breast cancer stem-like cells (BCSC) isolated from patient tumors express the EPOR and respond to EPO treatment with increased proliferation and self-renewal. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. Results of a combined phase I and II clinical trial. Curr Med Res Opin (2009) 25(7):1689–97. Carlini RG, Dusso AS, Obialo CI, Alvarez UM, Rothstein M. Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. J Cell Biochem (2013) 114(11):2471–8. doi:10.1002/14651858.CD006158.pub2. EPO-EPOR signaling was also critical for survival in vivo, as targeting EPOR expression decreased GSC tumorigenic potential (69).
Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E. Structural characterization of human erythropoietin. A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells. J Clin Oncol 23:: Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. From the Klinik für Strahlenheilkunde Universitätsklinikum; Pathologisches Institut, Universität Freiburg, Freiburg, Germany; Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA; Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, Professional English and Academic Editing Support, Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update, Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline, Prognostic Index for Acute- and Lymphoma-Type Adult T-Cell Leukemia/Lymphoma, Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update, Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update, Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update, Patient-Clinician Communication: American Society of Clinical Oncology Consensus Guideline, Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial, Cost Sharing and Adherence to Tyrosine Kinase Inhibitors for Patients With Chronic Myeloid Leukemia, American Society of Clinical Oncology Statement: A Conceptual Framework to Assess the Value of Cancer Treatment Options. Further, Epo pretreatment of some cancer cell lines render them less sensitive to the cytotoxic effects of the chemotherapy drug, cisplatin, also known as Platinol®.12 However, the degree of influence of the Epo/Epo R system in different types of cancers is highly variable. Med Res Rev (2013) 33(3):637–64. Laryngorhinootologie 83:: Collet D: Modeling Survival Data in Medical Research . This is followed by a more detailed presentation of both pre-clinical and clinical data that demonstrate EPO’s diverse actions on cancer cells as well as possible receptors involved in the response of cancer cells to EPO/ESA therapy. Scand J Med Sci Sports (2011) 21(3):369–77.
In these tissues, EPO was shown to be tissue protective in an anti-apoptotic and/or mitogenic manner. doi:10.1038/bjc.2012.395, 93. doi:10.3816/CLC.2011.n.009, 152.
There has been much discussion of EPO use in cancer patients, and several professional and regulatory organizations and authorities have issued various guidances. Clinical trials with reported adverse effects of chronic erythropoiesis-stimulating agents (ESAs) treatment as well as clinical studies exploring the prognostic significance of EPO and EPOR expression in cancer patients are reviewed. Blood (2010) 115(7):1453–60.
Use of biosimilar epoetin to increase hemoglobin levels in patients with chemotherapy-induced anemia: real-life clinical experience. Küster O, Simon P, Mittelbronn M, Tabatabai G, Hermann C, Strik H, et al.
In non-hematopoietic tissue, some other receptor partners have been proposed, including the beta common receptor (βcR) (35) and the epinephrine B4 receptor (EPHB4) (36). doi:10.1126/stke.3952007pe38. The JAK2-mediated activation of SRC and inactivation of PTEN have been proposed as underlying mechanisms. Szenajch J, Wcislo G, Jeong JY, Szczylik C, Feldman L. The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells from clinic to bench – a critical review. doi:10.1634/theoncologist.2009-0279. We do speculate that one of these receptors and/or possible analogs of these receptors may be involved in the response of cancer cells to EPO/ESA therapy.
Erythropoietin-induced proliferation of cancer cells was associated with the activation of JAK2, JAK3, STAT3, and STAT5 but not JAK1 or STAT1 (78), AKT phosphorylation (77), ERK phosphorylation (87) with hTERT gene transcription by JAK2/STAT5/c-MYC, and hTERT protein phosphorylation by PI3K/AKT (88). Transcription factors involved are stimulatory HIF-2, HNF-4alpha and inhibitory GATA-2, NF-kappaB [reviewed in Ref.
Blood (1990) 76(1):31–5.
Some of the studies indicate a negative outcome (marked in gray). Anticancer Res (2010) 30(9):3721–6. Endogenous biotin was blocked using the DAKO biotin blocking system. Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, et al. doi:10.1073/pnas.92.9.3717, 11.
25 This point may be important because although the mean Hb in each study group was identical (12.5 g/dL), there was a trend for more severe baseline anemia in the treatment arm (Hb < 10.5 g/dL in 14% of those patients v 11% in the placebo arm). 2) : 22–28, 1999). Todaro M, Turdo A, Bartucci M, Iovino F, Dattilo R, Biffoni M, et al. A model with interaction term between receptor status and treatment arm allowed different treatment relative risks for receptor-positive versus -negative patients.
23, no. Table 1. Randomized, double-blind, placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia. Advanced practice providers must understand the risks and benefits when considering ESAs for their patients. In 1977, the protein was isolated from human urine (3) enabling research toward cloning of the gene, its characterization, and in vitro expression (4, 5).
Cancer Cell (2010) 18(5):423–35. Bustos A, Álvarez R, Aramburo PM, Carabantes F, Díaz N, Florián J, et al. Anticancer Res (2014) 34(5):2325–9.
Int J Exp Pathol (2010) 91(6):495–9. Romanowski RR, Sytkowski AJ. Improvement in cancer survival with erythropoietin therapy seemed a lofty goal but did not appear to be too much to ask.
M. Pepe analyzed the data and M. Henke drafted the report. Erythropoietin receptor and signaling pathways. We suggest that the concurrent use of long-termed EPO/ESA and anti-cancer treatment is the main reason for EPO/ESA negative effects on response to anti-cancer therapy, overall survival, and disease recurrence. Clin Hemorheol Microcirc (2010) 44(2):115–23. Pronzato P, Cortesi E, van der Rijt CC, Bols A, Moreno-Nogueira JA, de Oliveira CF, et al. It should be mentioned that, although we applied a simplified scoring system, our results could be confirmed when applying published scoring protocols23 (data not shown). 5865-5868.
McCaffery PJ, Fraser JK, Lin FK, Berridge MV. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. European patent application [EP 2 492 355 A1 (36)] discloses a molecular composition(s) of a novel tissue-protective EPO-binding receptor protein complex, termed NEPOR. Brines M, Patel NS, Villa P, Brines C, Mennini T, De Paola M, et al. Received: 31 July 2014; Accepted: 22 October 2014; Published online: 11 November 2014. (92) discovered that EPO-driven EGR1 and c-FOS gene expression, as well as histone H4 acetylation in breast cancer cells were mediated via polyADP-ribosylation.
Cancer cells are known to express EpoR, 8-12 the expression of which seem to correlate to cellular dedifferentiation. By keeping up to date with the most recent literature and practice guidelines, advanced practice providers will be able to effectively and safely manage their patients with common toxicities such as anemia. Cancer.Net, ASCO.org (102) who found that injection of EPO into the ovariectomized mouse uterine cavity promoted blood vessel formation of the endometrium. Intraperitoneal administration of EPO induced AKT and ERK1/2 signalization followed by peritoneal lymphangiogenesis stimulation. doi:10.1016/j.molonc.2010.01.004, 60. Locoregional progression-free survival of patients randomly assigned to epoetin beta or placebo. Br J Cancer (2011) 105(9):1267–72.
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