title: 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.
authors.affiliation: Institute of Brain Research (Neuropathology), University of Tuebingen, Tuebingen, Germany. michel-guy-andr.mittelbronn@med.uni-tuebingen.de
authors.forename: M
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: D
authors.initials: D
authors.lastname: Capper
authors.forename: B
authors.initials: B
authors.lastname: Bunz
authors.forename: K
authors.initials: K
authors.lastname: Dietz
authors.forename: B
authors.initials: B
authors.lastname: Goeppert
authors.forename: R
authors.initials: R
authors.lastname: Ajaaj
authors.forename: G
authors.initials: G
authors.lastname: Tabatabai
authors.forename: F
authors.initials: F
authors.lastname: Stubenvoll
authors.forename: H
authors.initials: H
authors.lastname: Schlaszus
authors.forename: A S
authors.initials: AS
authors.lastname: Merseburger
authors.forename: R
authors.initials: R
authors.lastname: Becker
authors.forename: D
authors.initials: D
authors.lastname: Freudenstein
authors.forename: W
authors.initials: W
authors.lastname: Wick
authors.forename: M
authors.initials: M
authors.lastname: Weller
authors.forename: R
authors.initials: R
authors.lastname: Meyermann
authors.forename: P
authors.initials: P
authors.lastname: Simon
mesh_terms: D000367:Age Factors; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D005910:Glioma / Q000401:mortality* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D017467:Receptors, Erythropoietin / Q000096:biosynthesis*; D046888:Tissue Array Analysis
chemical_list: D017467:Receptors, Erythropoietin