title: Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia.
abstract: Signalling by erythropoietin (EPO) is increasingly recognised as a relevant mechanism in tumour biology, potentially leading to enhanced proliferation, angiogenesis and therapy resistance. Paraneoplastic polycythemia by cancerous overproduction of EPO is a rare event, but most frequently seen in patients with renal cell carcinoma (RCC). The majority of clear cell RCC displays a strong activation of the transcription factor regulating EPO, the Hypoxia-inducible Factor (HIF). Therefore, it is unclear why only a small minority of patients develop polycythemia. We studied 70 RCC for EPO gene and HIFalpha isoform expression. 34% of all RCC showed expression of EPO mRNA in RNase protection assays, which were almost exclusively of the clear cell type. Only 1 patient presented with polycythemia. In situ hybridisation revealed that expression of EPO was in the tumour cells. Expression of EPO mRNA was always associated with activation of HIF, which could involve HIF-1alpha and/or HIF-2alpha. The frequency of EPO gene expression in RCC is therefore much higher than the prevalence of polycythemia. Furthermore, activation of HIF appears necessary for EPO gene expression in RCC, but is clearly not the only determinant. Further to the reported expression of EPO receptors in tumour tissues, the finding of widespread expression of EPO in RCC supports the recent notion of an involvement of this system in paracrine or autocrine effects of tumour cells.
authors.affiliation: Interdisciplinary Centre for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremburg, Erlangen, Germany. mwiesene@molmed.uni-erlangen.de
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wiesener
authors.forename: Philine
authors.initials: P
authors.lastname: Münchenhagen
authors.forename: Markus
authors.initials: M
authors.lastname: Gläser
authors.forename: Bettina A
authors.initials: BA
authors.lastname: Sobottka
authors.forename: Karl X
authors.initials: KX
authors.lastname: Knaup
authors.forename: Katrin
authors.initials: K
authors.lastname: Jozefowski
authors.forename: Jan Steffen
authors.initials: JS
authors.lastname: Jürgensen
authors.forename: Jan
authors.initials: J
authors.lastname: Roigas
authors.forename: Christina
authors.initials: C
authors.lastname: Warnecke
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000150:complications / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000150:complications / Q000378:metabolism*; D045744:Cell Line, Tumor; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005858:Germany / Q000453:epidemiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015151:Immunoblotting; D017403:In Situ Hybridization; D007680:Kidney Neoplasms / Q000150:complications / Q000378:metabolism*; D010257:Paraneoplastic Syndromes / Q000453:epidemiology* / Q000209:etiology; D011086:Polycythemia / Q000453:epidemiology* / Q000209:etiology / Q000378:metabolism; D015995:Prevalence; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D012260:Ribonucleases; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human