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Open Full Page Published OnlineFirst August 22, 2013; DOI: 10.1158/1078-0432.CCR-13-1712 Clinical Cancer Imaging, Diagnosis, Prognosis Research 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 Leonid L. Nikitenko1,3,4,8, Russell Leek5, Stephen Henderson1, Nischalan Pillay2, Helen Turley5, Daniele Generali6,9, Sarah Gunningham10, Helen R. Morrin11, Andrea Pellagatti5, Margaret C.P. Rees7, Adrian L. Harris6, and Stephen B. Fox12,13 Abstract Purpose: 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. Experimental Design: In silico gene expression mRNA profiling microarray study (n ¼ 168 tumors) and cancer profiling cDNA array hybridization (n ¼ 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 ¼ 87 pairs) was conducted to study CLR expression and its association with clinicopathologic parameters and disease outcome. Results: 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). Conclusions: 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. Clin Cancer Res; 19(20); 5740–8. Ó2013 AACR. 1 Authors' Affiliations: Cancer Research UK Viral Oncology Group and Introduction 2Sarcoma Biology Group, UCL Cancer Institute, University College Lon- don, London; 3Keble College, 4Linacre College, 5Nuffield Department of Adrenomedullin (encoded by an ADM gene) is a multi- Clinical Laboratory Sciences; 6Cancer Research UK Oncology Laboratory, Weatherall Institute of Molecular Medicine; 7Nuffield Department of Obstet- functional peptide involved in cellular proliferation, rics and Gynaecology, John Radcliffe Hospital, University of Oxford, survival, and angiogenesis (1, 2). Whilst the role of adre- 8 Oxford, United Kingdom; Scientific Centre of the Family Health and nomedullin in tumor biology has been established from Human Reproduction Problems, Siberian Branch of Russian Academy of in vitro Medical Sciences, Irkutsk, Russia; 9Unita di Patologia Mammaria Senolo- studies using and mouse models and although gia e Breast, Unit Centro di Medicina Molecolare, Istituti Ospitalieri di ADM gene expression is known to be upregulated by 10 11 Cremona, Cremona, Italy; Department of Pathology, Cancer Society hypoxia (a typical feature of solid tumors; refs. 3–5), there Tissue Bank, University of Otago, Christchurch, New Zealand; 12Depart- ment of Pathology, University of Melbourne, Parkville; and 13Department of is a general lack of information about the expression of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia adrenomedullin receptors in human cancers and its cor- Note: Supplementary data for this article are available at Clinical Cancer relation with the disease outcome in particular (reviewed Research Online (http://clincancerres.aacrjournals.org/). in ref. 4). In vitro R. Leek and S. Henderson contributed equally to this work. , adrenomedullin mediates its activities through binding to G-protein–coupled receptor (GPCR) calcitonin- Corresponding Author: Leonid L. Nikitenko, Cancer Research UK Viral CALCRL Oncology Group, UCL Cancer Institute, 72 Huntley Street, London WC1E like receptor (CLR, encoded by the gene; refs. 6, 7). 6BT, United Kingdom. Phone: 44-207-679-6857; Fax: 44-207-679-6817; The GPCRs are the largest family of cell surface molecules E-mail: [email protected] involved in signal transduction and they control key phys- doi: 10.1158/1078-0432.CCR-13-1712 iologic functions, including regulation of blood pressure, Ó2013 American Association for Cancer Research. immune system activity, and inflammation. These receptors 5740 Clin Cancer Res; 19(20) October 15, 2013 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst August 22, 2013; DOI: 10.1158/1078-0432.CCR-13-1712 GPCR CLR Expression Predicts RCC Patient Survival Materials and Methods Translational Relevance Please see details of the following methods in the Sup- Renal cancer is often resistant to conventional system- plementary Data: antibody, cell culture, SDS–PAGE and ic treatments or current targeted therapies. This study immunoblotting, cancer profiling microarray hybridization reveals that G-protein–coupled receptor (GPCR) calcito- and Northern blotting, RNA isolation, cDNA synthesis, and nin receptor-like receptor (CLR) expression in renal cell quantitative real-time PCR (qRT-PCR). carcinoma (RCC) is associated with poor outcome for patients’ survival. These findings suggest application of GeneChip human genome array analysis CLR as a molecular target for therapeutic agents/drug Public Affymetrix GeneChip HG-U133plus2 arrays data development, while avoiding adverse effects on normal for 11 carcinoma types (n ¼ 168 samples) were obtained tissues. from the Expression Project for Oncology expO (http:// www.intgen.org/) via the National Center for Biotechno- logy Information (NCBI) Gene Expression Omnibus (GEO) repository (http://www.ncbi.nlm.nih.gov/projects/ are involved in some of the most prevalent human diseases, geo; accession GSE2109). Raw data were preprocessed and as reflected by the fact that GPCRs directly or indirectly normalized using Bioconductor software for R (13), and the represent the targets of 50% to 60% of all current ther- robust-multiarray algorithm (rma) as previously described apeutic agents (8–10). For example, the analgesic drugs (14–16). codeine and morphine target opioid receptors in the The cancer profiling microarray hybridization and nervous system and the GPCR antagonist zibotentan Northern blotting (ZD4054) targets the endothelin A receptor in solid The Cancer Profiling Microarray 7841 (cDNA microar- tumors(9,11).Recently,someGPCRs,suchaschemo- ray), consisting of normalized paired cDNA samples (n ¼ kine and prostaglandin receptors, have emerged as crucial 241) generated from the total RNA of 13 organs (breast, players in tumor growth and metastasis, suggesting their uterus, colon, stomach, ovary, lung, kidney, rectum, thy- importance in initiation and progression of cancer in roid, prostate, cervix, small intestine, and pancreas) was humans (4, 11, 12). obtained from Clontech (http://www.clontech.com). Each In the present study, we tested the hypothesis that cDNA pair consisted of carcinoma and corresponding GPCR CLR may be important in tumor biology in man organ-matched normal tissue samples obtained from the and could play a role in some human cancers. Our aims same patient, represented the entire mRNA message were to determine those tumor types that may rely on expressed in given tissues, and was used to provide com- adrenomedullin, examine the pattern and level of expres- prehensive ADM gene–disease correlation data. sion of adrenomedullin receptor CLR in a prototypical ADM cDNA was cloned into TOPO vector (Promega) and example, and conduct a clinicopathologic analysis to ubiquitin cDNA probe was from BD Biosciences. Inserts were assess its diagnostic and/or prognostic use. We therefore excised with restriction enzymes and labeled with 32P-dCTP in silico carried out a large-scale gene expression (mRNA using the Megaprime DNA Labeling Kit (GE Healthcare). profiling) microarray study coupled with cancer profiling The specificity of the probes was confirmed by Northern cDNA array hybridization and identified tumors that had blotting, which was conducted as previously described (17). ADM upregulated expression compared with patient- Cancer profiling microarray was consequentially hybridized matched normal tissue counterparts. Our data showed with each individual probe according to the manufacturer’s ADM that expression was significantly upregulated only instructions. The microarray was exposed to Hyperfilm in clear cell renal cell carcinoma (RCC) and endometrial (GE Healthcare) and subsequently to Phosphoscreen. The P < adenocarcinoma ( 0.01) but not in other tumor types, hybridization signals were further analyzed using Image- suggesting that in human tissues/organs it is upregulated Quant software. Ratio of ADM:Ubiquitin was calculated to in cancer type–specific manner. We then focused on RCC determine the relative mRNA expression levels and jittered as potentially an adrenomedullin signaling–driven
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