Erythropoietin and cancer: the unintended consequences of anemia correction.

Nataå¡A Debeljak,Arthur J Sytkowski,Peter Solã¡R

doi:10.3389/fimmu.2014.00563

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.

Highlights

The presence of a circulating hemopoietic factor controlling the red blood cell (RBC) production was first suggested in 1906 [1]
We suggest that the concurrent use of long-termed EPO/erythropoiesis-stimulating agents (ESAs) and anti-cancer treatment is the main reason for EPO/ESA negative effects on response to anti-cancer therapy, overall survival, and disease recurrence
A plethora of scientific evidence demonstrates a growthpromoting, anti-apoptotic action of EPO and other ESAs on non-hematopoietic cells, both normal and malignant, and this is supported by numerous clinical observations showing adverse effects of EPO administration on the clinical management of tumor growth and progression

Summary

INTRODUCTION

The presence of a circulating hemopoietic factor controlling the red blood cell (RBC) production was first suggested in 1906 [1]. Trošt et al [55] confirmed the results of Arcasoy et al [91] with positive response of breast cancer cells to EPO They demonstrated time- and concentration-dependent manner of EPO-induced MCF-7 proliferation and EGR1, FOS, and EPOR as transcription targets of the EPO-EPOR signaling loop [55]. In this regard, Inbar et al [92] discovered that EPO-driven EGR1 and c-FOS gene expression, as well as histone H4 acetylation in breast cancer cells were mediated via polyADP-ribosylation. EPO antagonized trastuzumab-induced therapeutic effects through JAK2-mediated activation of SRC and inactivation of PTEN protein, so combined therapy of HER2-positive cancer cells with EPO and trastuzumab reduced the response of these cells to trastuzumab both in vitro and in vivo. The authors suggest that EPO administration may promote the growth of pituitary adenomas by enhancing angiogenesis through EPO-JAK2-STAT3-VEGF signaling pathway and should be used with caution in anemia patients www.frontiersin.org

Terminated early

Other observations

CONCLUSION