title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
authors: Authors' Affiliations: Cancer Research UK Viral Oncology Group and Sarcoma Biology Group, UCL Cancer Institute, University College London, London; Keble College, Linacre College, Nuffield Department of Clinical Laboratory Sciences; Cancer Research UK Oncology Laboratory, Weatherall Institute of Molecular Medicine; Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Scientific Centre of the Family Health and Human Reproduction Problems, Siberian Branch of Russian Academy of Medical Sciences, Irkutsk, Russia; Unità di Patologia Mammaria Senologia e Breast, Unit Centro di Medicina Molecolare, Istituti Ospitalieri di Cremona, Cremona, Italy; Department of Pathology, Cancer Society Tissue Bank, University of Otago, Christchurch, New Zealand; Department of Pathology, University of Melbourne, Parkville; and Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: Leonid L
authors: LL
authors: Nikitenko
authors: Russell
authors: R
authors: Leek
authors: Stephen
authors: S
authors: Henderson
authors: Nischalan
authors: N
authors: Pillay
authors: Helen
authors: H
authors: Turley
authors: Daniele
authors: D
authors: Generali
authors: Sarah
authors: S
authors: Gunningham
authors: Helen R
authors: HR
authors: Morrin
authors: Andrea
authors: A
authors: Pellagatti
authors: Margaret C P
authors: MC
authors: Rees
authors: Adrian L
authors: AL
authors: Harris
authors: Stephen B
authors: SB
authors: Fox
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D019898:Autocrine Communication / Q000235:genetics; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D047368:Tumor Burden
chemical_list: D058286:Calcitonin Receptor-Like Protein; D053607:Adrenomedullin
references: BMJ. 1996 May 4;312(7039):1146-8
references: 8620134
references: Biochem Biophys Res Commun. 1993 Apr 30;192(2):553-60
references: 8387282
references: Radiobiol Radiother (Berl). 1987;28(6):845-6
references: 3444887
references: Bioinformatics. 2004 Feb 12;20(3):307-15
references: 14960456
references: Nat Rev Cancer. 2002 Jan;2(1):38-47
references: 11902584
references: Br J Cancer. 2006 Jan 16;94(1):1-7
references: 16251875
references: Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):667s-670s
references: 17255291
references: Am J Surg Pathol. 1982 Oct;6(7):655-63
references: 7180965
references: Endocr Rev. 2000 Apr;21(2):138-67
references: 10782362
references: Cardiovasc Res. 2008 Dec 1;80(3):339-45
references: 18708640
references: Nat Genet. 2004 Jul;36(7):687-93
references: 15220918
references: Clin Sci (Lond). 2006 Jul;111(1):61-70
references: 16515534
references: Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50
references: 12209124
references: Nature. 2010 Sep 30;467(7315):543-9
references: 20882008
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: Nat Rev Drug Discov. 2011 Jan;10(1):47-60
references: 21193867
references: BJU Int. 2007 May;99(5 Pt B):1296-300
references: 17441927
references: J Cell Sci. 2006 Mar 1;119(Pt 5):910-22
references: 16495482
references: Int J Urol. 2002 Jun;9(6):285-95
references: 12110091
references: Nature. 1998 May 28;393(6683):333-9
references: 9620797
references: Curr Opin Oncol. 1999 May;11(3):213-7
references: 10328597
references: Clin Cancer Res. 2006 Oct 1;12(19):5648-58
references: 17020966
references: Nat Rev Cancer. 2007 Feb;7(2):79-94
references: 17251915
references: Genome Biol. 2005;6(9):R76
references: 16168083
references: J Biol Chem. 2001 Aug 3;276(31):29575-81
references: 11387328
references: Nat Rev Cancer. 2008 Apr;8(4):309-16
references: 18337733
references: Trends Mol Med. 2011 Mar;17(3):126-39
references: 21183406
references: J Cell Sci. 2003 Dec 15;116(Pt 24):4867-9
references: 14625380
references: Pharmacol Rev. 2002 Jun;54(2):233-46
references: 12037140
references: Expert Opin Investig Drugs. 2005 Oct;14(10):1251-8
references: 16185167
references: Cancer Med. 2013 Apr;2(2):196-207
references: 23634287
references: Blood. 2012 Jul 12;120(2):477-88
references: 22668851
references: Br J Cancer. 1999 Feb;79(5-6):991-5
references: 10070902
references: Nucleic Acids Res. 2001 May 1;29(9):e45
references: 11328886
references: FASEB J. 2009 Oct;23(10):3424-35
references: 19546305
references: Int J Cancer. 2009 Nov 15;125(10):2307-15
references: 19610056
references: BJU Int. 2010 Jun;105(12):1663-6
references: 19930178
references: Regul Pept. 2003 Apr 15;112(1-3):175-83
references: 12667640
references: Cancer Res. 2005 Oct 1;65(19):8690-7
references: 16204037
references: Mol Hum Reprod. 2001 Jul;7(7):655-64
references: 11420389
references: J Invest Dermatol. 2013 Jul;133(7):1768-76
references: 23364478
references: Br J Cancer. 2009 Jan 27;100(2):405-11
references: 19165203
references: Trends Pharmacol Sci. 2011 Oct;32(10):591-600
references: 21722971
references: J Clin Invest. 2008 Jan;118(1):40-50
references: 18097475
references: Nat Rev Clin Oncol. 2009 Jun;6(6):327-38
references: 19483739
references: Am J Pathol. 2010 Apr;176(4):2019-28
references: 20167860
references: Endocrinology. 2011 Jul;152(7):2845-56
references: 21558311