Human recombinant erythropoietin does not promote cancer growth in presence of functional receptors expressed in cancer cells

Abstract

Human recombinant erythropoietin (hrEPO) therapy might be associated with tumor progression and death. This effect has been suggested to be secondary to rhEPO binding to its receptor (EPOR) expressed on cancer cells. However, there are several concerns about EPOR functionality when expressed on cancer cells. In this paper we have provided evidence that EPOR expressed in cancer cells could be implicated in proliferation events because a transfection of EPOR siRNA to EPOR-expressing bladder cancer cells resulted in a marked reduction in cell growth. However, these cell lines do not grow in the presence of hrEPO. Furthermore, bladder cancer patients that expressed EPOR in tumor samples had a reduced survival in absence of rhEPO treatment. Therefore, EPOR is implicated in bladder cancer growth but this effect appears to be independent from rhEPO supplementation. Reports which suggest that rhEPO promotes cancer growth due to the expression of EPOR in cancer cells must be observed with caution since in the presence of functional EPOR rhEPO does not promote growth.

EPO gene expression induces the proliferation, migration and invasion of bladder cancer cells through the p21WAF1-mediated ERK1/2/NF-κB/MMP-9 pathway

“…Published evidence has indicated that EPO may be involved in the differentiation of erythroid progenitor cells in vitro (12)(13)(14). However, previous studies have also shown that EPO did not stimulate the growth of tumor cell lines (20)(21)(22). In the present study, transfection of the EPO gene into bladder cancer 5637 cells resulted in increased thymidine uptake at the basal level.…”

“…Several studies have shown that the exogenous treatment of EPO and the overexpression of EPOR stimulate proliferation, migration and invasiveness in various cell types (15)(16)(17)(18)(19). On the other hand, other reports have not associated EPO with a proliferative effect on cancer cells (20)(21)(22). Although many studies have investigated the role of EPO in cancer cells, the precise molecular mechanisms underlying the cell-cycle regulation and signaling pathways that are linked with cell proliferation, migration and invasion of cancer cells remain unclear.…”

Erythropoietin Stimulates Tumor Growth via EphB4

“…However, EpoR expression on cancer cells has largely failed to explain the effects of rhEpo on tumor growth. For example, rhEpo can affect proliferative and survival responses in cancer cells without EpoR expression (Okazaki et al, 2008), while failing to induce proliferation in EpoR-positive tumor cells (Belda-Iniesta et al, 2007). Other explanations (e.g., EpoR variants) have also been inadequate in explaining the effects of rhEpo on tumor growth (Foley, 2008).…”

Erythropoietin receptor contributes to melanoma cell survival in vivo

“…We and others have previously shown that a variety of cancer cells, including carcinomas of ovary, breast, lung, thyroid, prostate, endometrium, cervix, head and neck (squamous), renal cell carcinoma, glioma, and melanoma, express EpoR mRNA transcripts and protein(Acs et al 2001; Acs et al 2004b; Arcasoy et al 2002; Arcasoy et al 2003; Arcasoy et al 2005; Jeong et al 2009; Lai et al 2005; Yates et al 2006). A number of studies suggested that Epo/EpoR may play a role in tumor progression (Acs et al 2004a; Hardee et al 2007; Kumar et al 2005; Mohyeldin et al 2005) whereas other reports contradicted these findings (Belda-Iniesta et al 2007; LaMontagne et al 2006) and thus, the role of Epo/EpoR during tumor progression is still controversial.…”