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Review
. 2014 Nov 11:5:563.
doi: 10.3389/fimmu.2014.00563. eCollection 2014.

Erythropoietin and cancer: the unintended consequences of anemia correction

Nataša Debeljak  1 , Peter Solár  2 , Arthur J Sytkowski  3
Affiliations
Review

Erythropoietin and cancer: the unintended consequences of anemia correction

Nataša Debeljak et al. Front Immunol. .

Abstract

Until 1990, erythropoietin (EPO) was considered to have a single biological purpose and action, the stimulation of red blood cell growth and differentiation. Slowly, scientific and medical opinion evolved, beginning with the discovery of an effect on endothelial cell growth in vitro and the identification of EPO receptors (EPORs) on neuronal cells. We now know that EPO is a pleiotropic growth factor that exhibits an anti-apoptotic action on numerous cells and tissues, including malignant ones. In this article, we present a short discussion of EPO, receptors involved in EPO signal transduction, and their action on non-hematopoietic cells. This is followed by a more detailed presentation of both pre-clinical and clinical data that demonstrate EPO's action on cancer cells, as well as tumor angiogenesis and lymphangiogenesis. Clinical trials with reported adverse effects of chronic erythropoiesis-stimulating agents (ESAs) treatment as well as clinical studies exploring the prognostic significance of EPO and EPOR expression in cancer patients are reviewed. Finally, we address the use of EPO and other ESAs in cancer patients.

Keywords: angiogenesis; cancer; cell response; clinical trials; erythropoietin; erythropoietin receptor; receptor partners.

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Figures

Figure 1
Figure 1
Erythropoietin receptor and signaling pathways. The structure of the receptor dimer is outlined; docking sites for several intracellular proteins are marked with P and linked with black-dotted arrow to individual pathway components. Positive interactions are presented with full black arrows, negative with dotted red.
Figure 2
Figure 2
EPOR-βcR receptor complex. Proposed structures of tissue-protective complexes are presented: heterotrimer including βcR homodimer with EPOR and heterodimer βcR with EPOR. Adapted from Brines and Cerami (47).
Figure 3
Figure 3
EPOR-tissue-protective erythropoietin receptor (nepor receptor complex). Proposed structure of EPO interacting complexes are presented: homodimer EPHB4, homodimer EPOR, and heterodimer EPHB4 with EPOR. Adapted from Jackson (36).
See this image and copyright information in PMC

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