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Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp. 1813-1814 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.7253
Are Erythropoietin Receptors Expressed in Tumors? Facts and Fiction—More Careful Studies Are NeededDivisions of Hematology and Oncology, University of Utah, Salt Lake City, UT
Center for Sickle Cell Disease, Howard University, Washington, DC
Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT To the Editor: The October 10, 2006, issue of the Journal of Clinical Oncology includes a report by Henke and colleagues of a retrospective study1 that examined the effect of erythropoietin beta on locoregional progression-free survival in patients with advanced carcinoma of the head and neck according to expression of erythropoietin receptors (EpoR) on cancer cells. The investigators concluded that erythropoietin might adversely affect the prognosis of patients with head and neck cancer if the cancer cells express EpoR. If this conclusion was supported by convincing experimental evidence, it would have far-reaching practical consequences as underscored in the accompanying editorial.2 However, the suggestion that Henke and colleagues report of a casual relationship of erythropoietin supplementation with poor patient outcome in patientswhose tumors express EpoR on cancer cells is open to debate because the C-20 antibody used for the detection of EpoR lacks specificity and the administration of intravenous iron as part of the erythropoietin protocol may have had an adverse effect unrelated to the erythropoietin itself. Elliot and colleagues3 found that the C-20 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) detects, in addition to EpoR, a peptide of different molecular weight—heat shock protein 70 (HSP70). HSP70 expression is upregulated in rapidly proliferating cells and is therefore likely to be expressed by head and neck tumor cells.3 Furthermore, HSP70 exerts an antiapoptotic effect by interacting with apoptotic protease activation factor-1. This interaction prevents formation of a functional apoptosome, which in turn results in inhibition of caspase-9 and caspase-3 activation, crucial steps in apoptosis induced by ischemia, doxorubicin, and UV-B radiation.4 More recently, Della Ragione and colleagues confirmed the detection of HSP70 by C20 antibody when used on extracts of K562 and megakaryoblastic leukemia cells (F. Della Ragione, personal communication, October 2006; manuscript submitted). The studies of Henke and colleagues would have been more compelling if they had used an antibody with proven EpoR mono-specificity. The clinical protocol followed by Henke and colleagues included the administration of 200 mg iron (III) saccharate (Ferrum Hausmann, Vifor, St Gallen, Switzerland) intravenously once weekly if the transferrin saturation was lower than 25%, but apparently regardless of iron stores or the serum ferritin concentration. Stimulation of erythropoiesis by erythropoietin would be expected to be accompanied by a decrease in transferrin saturation, and therefore, one wonders if the patients receiving erythropoietin were given intravenous iron more frequently than patients receiving placebo. The body's natural response to malignancy, infection, and other inflammatory stimuli is to reduce iron absorption and transferrin saturation. Because iron chelators have been demonstrated to have an antitumor effect,5,6 it would be appropriate to consider whether the administration of intravenous iron could have a tumor-promoting effect or other adverse consequences.
The extensive use of recombinant human erythropoietin raises important issues as to its benefits and risks in view of the widespread existence of EpoR in nonerythroid tissues. We have observed that patients with familial polycythemia who have a gain of function EpoR mutation7 and patients with Chuvash polycythemia8 who overexpress erythropoietin because of a homozygous germline von Hippel Lindau mutation (VHL 598C The risks of erythropoietin therapy should be weighed against the potential beneficial effects of improving anemia, quality of life, and neurocognitive performance, and of decreasing the size of ischemic damage in brain, heart, and other organs exposed to interrupted blood flow.9 As to the effect of erythropoietin on tumor progression, further studies with more specific detection of EpoR expression will be needed to clarify this important issue. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Victor R. Gordeuk, Amgen; Josef T. Prchal, Astra Zeneca, Amgen Stock: N/A Honoraria: Victor R. Gordeuk, Amgen; Josef T. Prchal, Astra Zeneca, Amgen Research Funds: N/A Testimony: N/A Other: N/A ACKNOWLEDGMENTS Supported in part by National Institutes of Health research Grants No. UH1-HL03679 (V.R.G.), MO1-RR10284 (V.R.G.), R01HL66333-01 (J.T.P.,V.R.G.), and R01HL5007-09 (J.T.P.). REFERENCES
1. 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 2. Lai SY, Grandis JR: Understanding the presence and function of erythropoietin receptors on cancer cells. J Clin Oncol 24:4675-4676, 2006 3. Elliott S, Busse L, Bass MB, et al: Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 107:1892-1895, 2006 [Erratum in: Blood 107:3454, 2006] 4. Komarova EY, Afanasyeva EA, Bulatova MM, et al: Downstream caspases are novel targets for the antiapoptotic activity of the molecular chaperone hsp70. Cell Stress Chaperones 9:265-275, 2004[CrossRef][Medline] 5. Whitnall M, Howard J, Ponka P, et al: A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci U S A 103:14901-14906, 2006 6. Necas E, Prchal JT: The diverse functions of Lipocalin: A recently-recognized mediator of transferrin independent iron transport, innate immunity, and cancer signaling. Hematologist 3:3, 2006 7. Prchal JT, Semenza GL, Prchal J, et al: Familial polycythemia. Science 268:1831-1832, 1995 8. Gordeuk VR, Sergueeva AI, Miasnikova GY, et al: Congenital disorder of oxygen sensing: Association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 103:3924-3932, 2004 9. Brines M, Cerami A: Discovering erythropoietin's extra-hematopoietic functions: Biology and clinical promise. Kidney Int 70:246-250, 2006[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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T) are at risk for complications (eg, thromboembolic events) that may be due to aberrant EpoR stimulation in nonerythroid tissues. VHL 598C
, elevated plasma vascular endothelial growth factor concentrations, and approximately 10-fold higher hemoglobin-adjusted serum erythropoietin concentrations. However, elevated serum erythropoietin level in this context is not associated with increased incidence of cancer.
