De novo erythropoietin receptor (EPO‐R) expression in human neoplastic glial cells decreases with grade of malignancy but is favourably associated with patient survival

Abstract

The erythropoietin receptor (EPO-R) is mainly known as a regulator of erythropoiesis. However, recent studies revealed that the EPO-R is not exclusively expressed in haematopoietic tissues but also in various cancer cell types and normal tissue such as the central nervous system (CNS). EPO-R is up-regulated under hypoxia and is able to counteract the deleterious effects of hypoxia on tumour growth, metastasis and treatment resistance. Therefore, the EPO-EPO-R signalling pathway is considered as a possible target for tumour treatment. Here, we investigated brain tumour samples obtained from patients between 1993 and 2003 to study EPO-R expression in vivo. Tissue samples included 194 gliomas of different WHO grades, additionally 25 infiltration zone samples and 31 relapses of WHO grade IV glioblastomas as well as 23 normal CNS tissue specimens to address the in vivo situation. Immunohistochemistry of the tissue microarray samples revealed significantly higher levels of EPO-R expression in neoplastic glial cells compared with glial cells derived from normal brain. EPO-R expression showed a highly significant decrease from low- to high-grade gliomas. Age-stratified Kaplan-Meier analysis revealed longer survival for patients exhibiting high EPO-R status in high-grade gliomas. Our results show a grade-dependent EPO-R down-regulation and might contribute to the understanding of high-grade glioma resistance to radio- and chemotherapy as both were shown to be improved by a well functioning EPO-EPO-R pathway in previous studies. Further studies are needed to investigate to what extent the decreased mortality in age-stratified patient groups with high EPO-R levels reflects a direct beneficial role of EPO-R expression.

CD133 expression is associated with small round blue cell tumour morphology in human central nervous system neoplasms

“…Immunohistochemistry was performed as described previously 30 . Briefly, samples were placed in 4% formalin (pH 7.4) after surgery, and routinely embedded in paraffin.…”

Comparative analysis of annexin-1 in neuroepithelial tumors shows altered expression with the grade of malignancy but is not associated with survival

“…In 80 astrocytomas we were able to compare annexin-1 expression scores in the tumor center with diffuse infiltration border as defined previously. 21 The mean annexin-1 expression levels in the tumor center (3.6; 95% CI: 3.2-4.1) were higher, compared with the infiltration zone (mean: 1.9; 95% CI: 0.7-3.2; P ¼ 0.0146). There was no significant survival difference in annexin-1-positive and annexin-1-negative tumors ( Figure 5), although there was a trend for worse survival in annexin-1-negative glioblastomas.…”

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.…”