Expression of erythropoietin and its receptor in neuroblastomas

Abstract

BACKGROUND. Children with high‐risk neuroblastomas (NB) potentially may benefit from treatment with recombinant human erythropoietin (Epo). Epo is a stimulator of erythropoiesis, acting through its receptor (EpoR). The objective of the current study was to evaluate expression levels of Epo and EpoR in NB and in normal tissues and their effects on the proliferation of tumor cells. METHODS. A tissue microarray study was performed with 101 primary tumors, 39 paired metastases, 56 paired control tissues, and 6 human NB cell lines. Immunohistochemical staining was performed using antibodies against Epo and EpoR. Immunostaining intensity was evaluated by using a semiquantitative score based on the percentage of positive cells. An in vitro analysis of cell proliferation and cell cycle in the presence of recombinant Epo was performed in the 6 cell lines. RESULTS. The expression of EpoR was found to be significantly higher in tumors than in paired control tissues (P < .0001) compared with the expression of Epo (P = .06), and the expression of EpoR was significantly higher in lymph node metastases than in paired primary tumors (P = .02) compared with Epo (P = .99). Survival analysis demonstrated that the patients who had tumors with the highest expression of EpoR had a significantly better overall survival (P = .03). In the in vitro study, recombinant Epo did not modify proliferation and cell cycle in the cell lines regardless of the EpoR expression level. CONCLUSIONS. Epo and EpoR were expressed in NB but did not modify tumor cell proliferation. The results of the current study suggested that Epo may be used safely for supportive care in children with NB. Cancer 2007. © 2007 American Cancer Society.

Erythropoietin protects neuroblastoma cells against etoposide and vincristine by activating ERK and AKT pathways but has no effect in kidney cells

“…In contrast, it has been shown that the addition of Epo to SH-SY5Y and Kelly cells has no effect on cell proliferation [24]. Likewise, incubation of six neuroblastoma-derived cell lines with different concentrations of Epo did not increase cell numbers [27]. However, it is worth noting that the expression of EpoR was absent in three of the aforementioned cell lines, it was low in two of them, and only moderate in one cell line [27].…”

“…Likewise, incubation of six neuroblastoma-derived cell lines with different concentrations of Epo did not increase cell numbers [27]. However, it is worth noting that the expression of EpoR was absent in three of the aforementioned cell lines, it was low in two of them, and only moderate in one cell line [27]. Furthermore, a prior report showed that Epo stimulated proliferation in only one of four EpoR-expressing glioblastoma cell lines [10].…”

“…The expression of EpoR has been documented in various neuroblastoma-derived cell lines [2]. Besides, immunohistochemical analysis of neuroblastoma samples has demonstrated that EpoR is expressed in neuroblastic cells [2], and that EpoR expression is significantly higher in lymph node metastasis compared with primary tumours [27]. Interestingly, although ectopic production of Epo by a neuroblastoma tumour was conclusively demonstrated in a 2-year-old patient [38], Epo expression in cell lines has not been proved significant [27].…”

“…In addition, there is evidence showing that administration of Epo to tumour cells expressing EpoR induces cell proliferation [19] and tumour cell survival [2]. Since the expression of EpoR has been documented in neuroblastoma tumours and cell lines [2,27] a careful assessment of the potential impact of exogenous Epo would be valuable. Here, we explored the effect of Epo on the proliferation of the neuroblastoma-derived MSN cell line, and the human embryonic kidney HEK 293 cells.…”

Erythropoietin Augments Survival of Glioma Cells After Radiation and Temozolomide

“…Conversely, G28 cells, with their high-level expression of EPOR, showed a reduced clonogenic survival after EPO plus irradiation and TMZ. Along the same lines, recent clinical studies found significantly better overall survival in neuroblastoma (44) and GBM patients (45) who had tumors with the highest expression of EPOR. Therefore quantification of EPOR mRNA expression will neither allow any kind of prediction of an EPO effect on tumor survival nor help to make a decision regarding EPO treatment in a particular GBM patient.…”