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.