Tissue expression and plasma levels of adrenomedullin in renal cancer patients.
The peptide AM (adrenomedullin) is stimulated by hypoxia through HIF-1 (hypoxia-inducible factor-1). The majority of human CC-RCCs (clear cell renal cell carcinomas) display mutations in the tumour suppressor protein von Hippel-Lindau, which leads to constitutively elevated HIF-1. We hypothesized that AM is increased in CC-RCC tumours and that AM is a plasma biomarker for CC-RCC. Tumours and non-malignant kidney tissue were obtained from patients that underwent unilateral nephrectomy. Blood samples were drawn at the day of surgery, 3-6 days after surgery and 4-5 weeks after surgery. AM mRNA and peptide expression in tissue and AM plasma concentration were determined. HIF-1alpha was localized in tissue by immunohistochemistry. AM mRNA was elevated in CC-RCC compared with adjacent renal cortex (6-fold, n=18; P<0.02). There was no difference in AM mRNA between cortex and non-CC-RCC tissue (n=7). AM peptide concentration was elevated in CC-RCC tissue compared with adjacent cortex (4-fold, n=6; P<0.02), whereas there was no difference between cortex and non-CC-RCC tissue (n=5). HIF-1alpha immunoreactivity was detected in the majority of cell nuclei in 76% of CC-RCC, consistent with constitutive stabilization. In non-CC-RCC, HIF-1alpha staining was focal. Before surgery there was no difference in plasma AM concentration between tumour types. Nephrectomy increased plasma AM significantly after 3-6 days and a similar pre-surgery level was observed after 4-5 weeks in both groups of tumour patients. We conclude that elevated tissue AM is a distinguishing feature of CC-RCC compared with other kidney tumours. Plasma AM is not suited as a tumour marker for this disease.
Michelsen
Jens
J
Department of Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense, Denmark.
Thiesson
Helle
H
Walter
Steen
S
Ottosen
Peter D
PD
Skøtt
Ole
O
Jensen
Boye L
BL
D018262:Adenocarcinoma, Clear Cell / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D053607:Adrenomedullin; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D003937:Diagnosis, Differential; D005260:Female; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D009392:Nephrectomy; D010455:Peptides / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011184:Postoperative Period; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011863:Radioimmunoassay / Q000379:methods; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D010455:Peptides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D053607:Adrenomedullin