Erythropoietin: Good or Bad for Cancer?

Figure 1. Erythropoietin (Epo) binds its receptor (Epo R) on the surface of red blood cell progenitors in the bone marrow causing proliferation, maturation, and differentiation, thereby preventing or correcting anemia. Epo may also bind Epo R expressed on the surface of cancer cells and may elicit tumor growth via cell proliferation, protection from apoptosis, and/or angiogenesis. [Note: figure adapted from Brower, V. (2003) Nat. Med. 9:1439.]

Anemia is a common clinical problem experienced by nearly 75% of cancer patients. Anemia results in fatigue, weakness and often depression, which may severely reduce the quality of life of patients living with cancer. Further, there is some evidence that anemia may impair the efficacy of cancer therapies.^1,2 Hence, under the clinical practice guidelines set out by the American Society of Clinical Oncology and the American Society of Hematology in 2002,³ patients with cancer-related anemia have commonly been prescribed recombinant human Erythropoietin (Epo) in the form of epoetin alfa, under the tradenames Procrit^® (also known as Eprex^®) and Epogen^®, and epoetin beta, under the tradename NeoRecormon^®.⁴

Natural mature Epo is a 30 kDa glycoprotein characterized by four anti-parallel alpha helices and both N- and O-linked glycosylations. In vivo, Epo is produced primarily by the kidney and is regulated by oxygen tension such that under conditions of hypoxia, circulating Epo levels increase. Epo binds the Epo receptor (Epo R) on erythroid progenitors in bone marrow eliciting proliferation, maturation, and differentiation of red blood cells and Epo deficiency is associated with a reduction in red blood cell number and anemia.^1,2 Administration of recombinant human Epo has been shown to increase hemoglobin levels, improve hematocrit, reduce blood transfusion requirements, and enhance the quality of life of cancer patients suffering from anemia.^1,2

Recent studies, however, suggest that the guidelines for prescribing Epo to cancer patients may need to be reviewed. A 2003 Epo trial conducted by Johnson & Johnson investigated the effects of Epo treatment for the prevention of anemia on the survival of non-anemic, metastatic breast cancer patients. Due to an observed higher mortality rate among the group treated with Eprex, concerns were raised that Epo may have an adverse effect on survival and the study was terminated.⁵ A subsequent study conducted by Hoffman-La Roche on anemic head-and-neck cancer patients found that while epoetin beta was successful in correcting anemia, it failed to improve, and may even impair, cancer control and survival.⁶

It appears that the problems surrounding Epo treatment of cancer patients stem from the biology of Epo itself.⁴ Once thought to act solely on the erythroid compartment, it is now becoming increasingly clear that Epo has pleiotropic effects.¹ High levels of Epo and Epo R are found in many different cell types and the Epo/Epo R system is known to induce proliferation, chemotaxis, and angiogenesis, and inhibit apoptosis.^1,2 Epo and Epo R are expressed in head-and-neck tumors,⁶ breast, colon, lung, prostate,⁷ ovary,^7,8 uterine,⁸ and cervical⁹ cancer cells, neuroblastomas, astrocytomas, and other solid nervous system tumors,¹⁰ and numerous malignant cell lines.^11,12 Additionally, the Epo/Epo R system appears to be functioning in these cells and tissues.^8,10-12 Epo added to cancer cell lines in vitro elicits secretion of angiogenic growth factors and promotes proliferation and chemotaxis of endothelial cells.¹⁰ Neutralizing anti-Epo monoclonal antibody and soluble Epo R antagonist injected into ex vivo cultured tumor tissue blocks,⁸ and soluble Epo R antagonist injected into mice possessing cancer cell xenografts,¹¹ reduce angiogenesis and tumor cell survival. 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. A thorough re-examination of the biology of Epo as well as its clinical application for cancer patients is urgently needed.

References

1. Lappin, T.R. et al. (2002) Stem Cells 20:485.
2. Weiss, M.J. (2003) Oncologist 8:18.
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4. Brower, V. (2003) Nat. Med. 9:1439.
5. Leyland-Jones, B. (2003) Lancet Oncol. 4:459.
6. Henke, M. et al. (2003) Lancet 362:1255.
7. Arcasoy, M.O. et al. (2003) Biochem.
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10. Acs, G. et al. (2003) Am. J. Physiol. 162:1789.
11. Batra, S. et al. (2003) Lab. Invest. 83:1477
12. Yasuda, Y. et al. (2003) Carcinogenesis 24:1021.
13. Liu, W.M. et al. (2004) Oncogene 23:981.