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In Reply

Klinik für Strahlenheilkunde Universitätsklinikum, Freiburg, Germany

Frank Pajonk

Department of Radiation Oncology, David Geffen School of Medicine, UCLA, Los Angeles, CA

We appreciate Dr Sizer's correspondence. He shifts the current discussion to the potential action of erythropoietin in cancer cells. Understanding these mechanisms may eventually help to improve treatment for our cancer patients.

We recently demonstrated the dismal outcome of erythropoietin treatment to be confined to patients with cancer reacting with the C-20 antibody.¹ This antibody was widely used to detect erythropoietin receptors (EpoR) and, in fact, discriminates well between medium and high-level EpoR expression but it cross-reacts with heat-shock protein (HSP)-70.² The limited specificity of C20 raised questions whether erythropoietin may directly act on cancer cells.^3-5 Considering, however, that only patients with C-20–positive cancer do badly when given erythropoietin, we still feel that signaling downstream of EpoR⁶ may happen in these cells.

Dr Sizer suggests that HSP-70 expression in our samples will explain the clinical observations: HSP-70 is known to relocate to the nucleus and to protect the antiapoptotic transcription factor GATA-1 from cleavage by caspase-3 if cells are exposed to erythropoietin.⁷ Although this mechanism regulates erythropoiesis its role in cancer biology might be debated: GATA-1 is not reported to be expressed in solid cancer and erythropoietin promotes cancer growth of functionally caspase-3–deleted breast cancer cells in vitro.^8,9 If, however, GATA-1 controls in fact cancer cell survival EpoRs should be present to mediate the relocation of HSP-70 on erythropoietin.

We are confident that improved methodologies will allow us in the near future to more precisely investigate EpoR and HSP-70 expression and their mutual interactions in cancer cells. Given a sensitivity of C20 for EpoR and the fact that erythropoietin did not influence the course of C-20–negative patients, we would expect even more pronounced effects in truly EpoR-positive cancer patients.

AUTHORS' 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[Abstract/Free Full Text]

2. Brown WM, Maxwell P, Graham AN, et al: Erythropoietin receptor expression in non-small cell lung carcinoma: A question of antibody specificity. Stem Cells 25:718-722, 2007[CrossRef][Medline]

3. Della Ragione F, Cucciolla V, Borriello A, et al: Erythropoietin receptors on cancer cells: A still open question. J Clin Oncol 25:1812-1813, 2007[Free Full Text]

4. Agarwal N, Gordeuk VR, Prchal JT: Are erythropoietin receptors expressed in tumors? Facts and fiction–more careful studies are needed. J Clin Oncol 25:1813-1814, 2007[Free Full Text]

5. Jelkmann W, Laugsch M: Problems in identifying functional erythropoietin receptors in cancer tissue. J Clin Oncol 25:1627-1628, 2007[Free Full Text]

6. Hardee ME, Cao Y, Fu P, et al: Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression. PLoS ONE 2:e549, 2007[CrossRef]

7. Ribeil JA, 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]

8. 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[Abstract/Free Full Text]

9. Janicke RU, Sprengart ML, Wati MR, et al: Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273:9357-9360, 1998

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Related Correspondence

• Heat Shock Protein 70, Erythropoietin, and Cancer
  Kurt C. Sizer
  JCO 2007 25: 4326 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Henke, M. Articles by Pajonk, F. Search for Related Content PubMed Articles by Henke, M. Articles by Pajonk, F. Related Articles Related Correspondence Social Bookmarking                            What's this?