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Journal of Clinical Oncology, Vol 24, No 29 (October 10), 2006: pp. 4675-4676 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.1190
Understanding the Presence and Function of Erythropoietin Receptors on Cancer CellsUniversity of Pittsburgh School of Medicine, Department of Otolaryngology, University of Pittsburgh Cancer Center, Pittsburgh, PA
University of Pittsburgh School of Medicine, Departments of Otolaryngology and Pharmacology, University of Pittsburgh Cancer Institute, Pittsburgh, PA The expression of erythropoietin (EPO) and the EPO receptor (EPOR) have been recognized in a variety of human cancers, including breast, prostate, colon, ovary, uterine, cervical, glioblastoma, and head and neck squamous cell carcinoma (HNSCC).1 A growing number of studies demonstrate functional EPO/EPOR signaling events in cancer cells that contribute to disease progression. These findings have been difficult to reconcile with the current clinical practice of treating or preventing anemia in cancer patients with recombinant EPO (rEPO).2 Anemia is a well-recognized negative prognostic factor for cancer patients treated with radiation therapy and chemotherapy.3-5 EPO has been an appealing alternative to blood transfusion for these patients to increase hemoglobin levels and to improve quality of life by decreasing fatigue. In addition to the identification of EPO and EPOR on cancer cells, a number of recent clinical trials have heightened concerns regarding the potential effects of EPO on cancer progression. The Breast Cancer Erythropoietin Trial (BEST) examined rEPO treatment in nonanemic, metastatic breast cancer patients.6 This study was terminated early when a higher mortality rate was observed among the rEPO treatment group. In a previous report, Henke and colleagues7 performed a randomized, double-blind, multi-institutional trial comparing anemic head and neck cancer patients receiving radiation therapy with or without rEPO treatment. These authors reported that rEPO treatment corrected hemoglobin levels, but was associated with decreased locoregional cancer control and patient survival. Although there was some concern regarding study design and methodology, that study and the BEST trial raised legitimate concerns regarding current recommendations for the routine use of rEPO in cancer patients.8 In the study reported in this issue of the Journal of Clinical Oncology, Henke and colleagues examined the expression of EPOR in a subset of 154 patients from a single clinical center derived from their original multicenter population (351 patients).9 Expression of EPOR was assessed by immunohistochemistry and reviewed by two independent, blinded pathologists. Within their patient population, 104 patients (67.5%) demonstrated EPOR expression. Their findings demonstrated that decreased locoregional progression-free survival due to treatment with rEPO was significant only in patients with HNSCC that expressed EPOR. rEPO treatment did not impact outcome in patients who had tumors that did not express EPOR. Although originally identified as a cytokine that promoted RBC progenitor survival and differentiation, the role of EPO in normal cells has been dramatically redefined within the past decade.10 EPO/EPOR signaling regulates physiologic cyclic uterine angiogenesis.11 In the CNS, EPO is produced by astrocytes and EPOR is expressed by neurons. EPO appears to have a neuroprotective effect against ischemic injury.12 Similarly, rEPO protects cardiac myocytes against ischemic injury in preclinical studies.13
The ability of cancer cells to subvert the EPO/EPOR system should not be surprising. A significant number of oncogenes represent signaling molecules that have been appropriated by cancer cells to facilitate proliferation and survival. The overexpression of the epidermal growth factor receptor in HNSCC is crucial for growth, invasion, metastasis, and angiogenesis.14 A number of preclinical studies have demonstrated EPO-mediated activation of the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)–Akt, JAK-STAT (Janus kinase-Signal Transducer and Activator of Transcription), and nuclear factor-kappa B (NF The contribution of the EPO/EPOR signaling axis to cancer progression is not completely straightforward. The influence of EPO/EPOR on different cancer types appears to be quite variable and remains incompletely understood. A number of different tumor cell lines do not demonstrate any proliferation response to rEPO.25 Similarly, certain cancer types undergo increased apoptosis or are more sensitive to fluorouracil treatment.26,27 Clearly, the complex biology of EPO/EPOR signaling in normal and cancer cells requires continued research. Understanding the role of EPO in normal cellular function and tumor progression will improve our ability to use rEPO rationally in the clinical setting. Additional well-controlled studies in vitro and in xenograft models are necessary to define the contribution of EPO to tumor growth, apoptosis, angiogenesis, and chemoradiotherapy sensitivity in different types of cancer. Recognition of the presence of paracrine and autocrine EPO/EPOR signaling within cancer cells may also redefine the present understanding of anemia in cancer patients. Indeed, the development of anemia in cancer patients may not be due to the burden of chronic disease. Rather, the ability of cancer cells to subvert the EPO/EPOR signaling mechanism to promote tumor progression may create a tumor sink for endogenous and exogenous EPO, thus depriving the hematopoietic system of the necessary stimulatory cues for RBC production. Such a model is consistent with the observation that the hematopoietic response to rEPO is not as robust in anemic cancer patients as would be predicted.28 The mounting evidence regarding the role of EPO/EPOR signaling in certain cancer cell types can no longer be simply dismissed. EPO/EPOR signaling will result in varied effects in different types of healthy and cancer cells. As the role of EPO/EPOR in cancer cells continues to be elucidated, serious deliberation is required in regard to the current clinical guidelines for the use of rEPO in cancer patients.2 Given our current understanding of the potential benefits and risks, rEPO treatment should probably continue in cancer patients with severe anemia (hemoglobin < 10 g/dL). More complex issues need to be resolved with regard to rEPO treatment in patients with less severe anemia (hemoglobin < 12 g/dL), specific target hemoglobin levels, and titration of rEPO to achieve those levels. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. ACKNOWLEDGMENTS This work was supported by the Flight Attendant Medical Research Institute Young Clinical Scientist Award (S.Y.L.), the Thyroid Head and Neck Cancer Foundation Young Investigator Award (S.Y.L.), the University of Pittsburgh Cancer Institute Head and Neck Specialized Program of Research Excellence Career Development Award (S.Y.L.), and National Institutes of Health Grant No. P50 CA097190-01A1 (J.R.G.). REFERENCES
1. Hardee M, Arcasoy M, Blackwell K, et al: Erythropoietin biology in cancer. Clin Cancer Res 12:332-339, 2006 2. Rizzo JD, Lichtin AE, Woolf SH, et al: Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20:4083-4107, 2002 3. Shasha D: The negative impact of anemia on radiotherapy and chemoradiation outcomes. Semin Hematol 38:8-15, 2001[CrossRef][Medline] 4. Caro JJ, Salas M, Ward A, et al: Anemia as an independent prognostic factor for survival in patients with cancer: A systemic, quantitative review. Cancer 91:2214-2221, 2001[CrossRef][Medline] 5. Spivak JL: The anaemia of cancer: Death by a thousand cuts. Nat Rev Cancer 5:543-555, 2005[CrossRef][Medline] 6. Leyland-Jones B, Semiglazov V, Pawlicki M, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 23:5960-5972, 2005 7. 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. Lancet 362:1255-1260, 2003[CrossRef][Medline] 8. Correspondences: Lancet 363:78-82; 992-994, 2004[Medline] 9. Henke M, Mattern D, Pepe M, et al: Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol 24:4708-4713, 2006 10. Maiese K, Li F, Chong ZZ: New avenues of exploration for erythropoietin. JAMA 293:90-95, 2005 11. Yasuda Y, Masuda S, Chikuma M, et al: Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem 273:25381-25387, 1998 12. Sakanaka M, Wen TC, Matsuda S, et al: In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 95:4635-4640, 1998 13. Hanlon PR, Fu P, Wright GL, et al: Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: Role of protein kinase C and phosphatidylinositol 3-kinase signaling. FASEB J 19:1323-1325, 2005 14. Kalyankrishna S, Grandis JR: Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 24:2666-2672, 2006 15. Lester RD, Jo M, Campana WM, et al: 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. J Biol Chem 280:39273-39277, 2005 16. Kumar S, Yu H, Fong D, et al: Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells. Melanoma Res 16:275-283, 2006[CrossRef][Medline] 17. Mohyeldin A, Lu H, Dalgard C, et al: Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. Neoplasia 7:536-543, 2005 18. Lai SY, Childs EE, Xi S, et al: Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene 24:4442-4449, 2005[CrossRef][Medline] 19. Bittorf T, Buchse T, Sasse T, et al: Activation of the transcription factor NF-kappaB by the erythropoietin receptor: Structural requirements and biological significance. Cell Signal 13:673-681, 2001[CrossRef][Medline] 20. Pajonk F, Weil A, Sommer A, et al: The erythropoietin-receptor pathway modulates survival of cancer cells. Oncogene 23:8987-8991, 2004[CrossRef][Medline] 21. Acs G, Zhang PJ, McGrath CM, et al: 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. Am J Path 162:1789-1806, 2003 22. Anagnostou A, Lee ES, Kessimian N, et al: Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 87:5978-5982, 1990 23. Yasuda Y, Fujita Y, Matsuo T, et al: Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 24:1021-1029, 2003 24. Belenkov AI, Shenouda G, Rizhevskaya E, et al: Erythropoietin induces cancer cell resistance to ionizing radiation and to cisplatin. Mol Cancer Ther 3:1525-1532, 2004 25. Wesphal G, Niederberger E, Blum C, et al: Erythropoietin and G-CSF receptors in human tumor cells: Expression and aspects regarding functionality. Tumori 88:150-159, 2002[Medline] 26. Mittelman M, Neumann D, Peled A, et al: Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci U S A 98:5181-5186, 2001 27. Tovari J, Gilly R, Raso E, et al: Recombinant human erythropoietin alpha targets intratumoral blood vessels, improving chemotherapy in human xenograft models. Cancer Res 65:7186-7193, 2005 28. Miller CB, Jones RJ, Piantadosi S, et al: Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 322:1689-1692, 1990[Abstract]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B) signaling pathways in a variety of human cancers.
