Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer

Abstract

Erythropoiesis-stimulating agents (ESAs) increase red blood cell (RBC) production in bone marrow by activating the erythropoietin receptor (EpoR) on erythrocytic-progenitor cells. Erythropoiesis-stimulating agents are approved in the United States and Europe for treating anaemia in cancer patients receiving chemotherapy based on randomised, placebo-controlled trials showing that ESAs reduce RBC transfusions. Erythropoiesis-stimulating agent-safety issues include thromboembolic events and concerns regarding whether ESAs increase disease progression and/or mortality in cancer patients. Several trials have reported an association between ESA use and increased disease progression and/or mortality, whereas other trials in the same tumour types have not provided similar findings. This review thoroughly examines available evidence regarding whether ESAs affect disease progression. Both clinical-trial data on ESAs and disease progression, and preclinical data on how ESAs could affect tumour growth are summarised. Preclinical topics include (i) whether tumour cells express EpoR and could be directly stimulated to grow by ESA exposure and (ii) whether endothelial cells express EpoR and could be stimulated by ESA exposure to undergo angiogenesis and indirectly promote tumour growth. Although assessment and definition of disease progression vary across studies, the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients, and preclinical data indicate a direct or indirect effect of ESAs on tumour growth is not strongly supported.

Figure 1

Schematic presentation of the signalling pathways activated by the EpoR on erythrocytic progenitor cells in response to Epo. When the surface of an erythrocytic progenitor cell is exposed to Epo, the pre-formed EpoR dimer undergoes a conformational change that stimulates autophosphorylation of JAK2 kinase, which is associated with the EpoR intracellular domains. In turn, JAK2 kinases phosphorylate tyrosine residues on the EpoR intracellular domains, which then serve as docking sites for various cytoplasmic signalling proteins such as the transcription factor STAT5 (signal transducer and activator of transcription 5). Stimulation of cytoplasmic signalling proteins such as STAT5, AKT, and ERK1/2 activates signalling cascades that can lead to cellular differentiation, anti-apoptotic effects, and cellular proliferation.