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Journal of Clinical Oncology, Vol 25, No 27 (September 20), 2007: pp. 4326 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.0419
Heat Shock Protein 70, Erythropoietin, and CancerThe University of Texas M.D. Anderson Cancer Center, Houston, TX To the Editor: Henke et al1 recently reported that erythropoietin receptor (EpoR) tumor status correlated with progression-free survival outcomes for patients with head and neck cancer scheduled for radiotherapy, who were randomly assigned to receive erythropoietin or placebo. A primary criticism of this study has been the controversy regarding the specificity of the EpoR antibody (C-20; Santa Cruz Biotechnologies, Santa Cruz, CA) used for immunohistochemical staining.2-7 Interestingly, C-20 has been reported to recognize heat shock protein 70 (HSP-70) almost exclusively,7 due to cross-reactivity of the EpoR immunizing peptide.2,7 The significance of HSP-70 staining in the study by Henke et al1 should be re-examined, in light of recent data. Although overexpression of HSPs, and HSP-70 in particular, in a wide variety of human tumors and their potential associations with clinical outcomes have been reported,8 a direct link between HSP-70 and erythropoietin exposure had not been previously established. However, Ribeil et al, recently reported that in the presence of erythropoietin, HSP-70 protects nuclear transcription factor GATA-1 from caspase-mediated proteolysis, resulting in erythroid differentiation. In contrast, in the absence of erythropoietin, HSP-70 is exported out of the nucleus, GATA-1 is cleaved, and erythroid precursors undergo apoptosis.9 These results evoke several relevant questions, including: what is the relationship between HSP-70 and erythropoietin in tumor cells? In particular, does erythropoietin differentially promote tumor cell survival based on HSP-70 expression? With regard to tumor biopsy study by Henke et al,1 was the C-20 antibody used in this study actually distinguishing HSP-70–positive and –negative tumors (rather than, or in addition to EpoR)? Was it HSP-70 expression that correlated with progression-free survival outcomes for patients exposed to eryth-ropoietin or placebo? Re-examining these tumors with an HSP-70–specific antibody would address this issue directly. Future prospective and retrospective studies designed to further examine the relationship between erythropoietin exposure and tumor progression and survival, should consider HSP-70 tumor expression status in those trials that include tumor biopsies. Such studies, coupled with emerging biologic data, such as the study by Ribeil et al,9 will guide rational treatment recommendations for the use of erythroid stimulating agents in patients with cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. 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. Elliott S, Busse L, Bass MB, et al: Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 107:1892-1895, 2006 3. Verdier F, Gomez S, Lacombe C, et al: Selected anti-Epo receptor antibodies predict Epo receptor expression. Blood 108:1106, 2006 4. Elliott S, Sinclair AM, Begley CG: Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 108:1107, 2006 5. Henke M, Verma A, Acs G: Erythropoietin receptors on cancer cells: Exciting perspectives, difficult to appreciate. Blood 108:1107-1108, 2006 6. Elliott S, Busse L, Spahr C, et al: Anti-EpoR antibodies detect a 59-kDa protein. Blood 108:1108-1109, 2006 7. Ragione FD, Cucciolla V, Borriello A, et al: Erythropoietin receptors on cancer cells: A still open question. J Clin Oncol 25:1812-1813, 2007 8. Ciocca DR, Calderwood SK: Heat shock proteins in cancer: Diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86-103, 2005[CrossRef][Medline] 9. Ribeil J-A, Zermati Y, Vandekerckhove J, et al: Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature 445:102-105, 2007[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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