The G-Protein―Coupled Receptor CLR Is Upregulated in an Autocrine Loop with Adrenomedullin in Clear Cell Renal Cell Carcinoma and Associated with Poor Prognosis

• Published in: Clinical cancer research Vol. 19; no. 20; pp. 5740 - 5748
• Main Authors: NIKITENKO, Leonid L, LEEK, Russell, HARRIS, Adrian L, FOX, Stephen B, HENDERSON, Stephen, PILLAY, Nischalan, TURLEY, Helen, GENERALI, Daniele, GUNNINGHAM, Sarah, MORRIN, Helen R, PELLAGATTI, Andrea, REES, Margaret C. P
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2013
• Subjects: Adrenomedullin - genetics; Adrenomedullin - metabolism; Aged; Autocrine Communication - genetics; Calcitonin Receptor-Like Protein - genetics; Calcitonin Receptor-Like Protein - metabolism; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Female; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prognosis; Tumor Burden
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-1712

The G-protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) and its ligand peptide adrenomedullin (encoded by ADM gene) are implicated in tumor angiogenesis in mouse models but poorly defined in human cancers. We therefore investigated the diagnostic/prognostic use for CLR in human tumor types that may rely on adrenomedullin signaling and in clear cell renal cell carcinoma (RCC), a highly vascular tumor, in particular.
In silico gene expression mRNA profiling microarray study (n = 168 tumors) and cancer profiling cDNA array hybridization (n = 241 pairs of patient-matched tumor/normal tissue samples) were carried out to analyze ADM mRNA expression in 13 tumor types. Immunohistochemistry on tissue microarrays containing patient-matched renal tumor/normal tissues (n = 87 pairs) was conducted to study CLR expression and its association with clinicopathologic parameters and disease outcome.
ADM expression was significantly upregulated only in RCC and endometrial adenocarcinoma compared with normal tissue counterparts (P < 0.01). CLR was localized in tumor cells and vessels in RCC and upregulated as compared with patient-matched normal control kidney (P < 0.001). Higher CLR expression was found in advanced stages (P < 0.05), correlated with high tumor grade (P < 0.01) and conferred shorter overall survival (P < 0.01).
In human tissues ADM expression is upregulated in cancer type-specific manner, implicating potential role for adrenomedullin signaling in particular in RCC, where CLR localization suggests autocrine/paracrine mode for adrenomedullin action within the tumor microenvironment. Our findings reveal previously unrecognized CLR upregulation in an autocrine loop with adrenomedullin in RCC with potential application for this GPCR as a target for future functional studies and drug development.