title: Adrenomedullin production is increased in colorectal adenocarcinomas; its relation to matrix metalloproteinase-9.
abstract: Adrenomedullin (AM) is highly expressed in various cancer cell lines, suggesting a possible association with cancer growth. In the present study, we examined the expression and/or concentration of AM, its related peptide, adrenomedullin2/intermedin (AM2/IMD) and their receptors in human colorectal cancer and the surrounding normal tissue. In addition, we assessed the correlation between the expression of AM and AM2/IMD with that of vascular endothelial growth factor (VEGF)-A and matrix metalloproteinase (MMP)-9. Using a specific immunoradiometric assay, we found that AM concentrations were 2-11-fold higher in colorectal cancer tissues than in the surrounding normal tissues. Moreover, real-time quantitative RT-PCR showed that the expression levels of preproAM (+548%), preproAM2/IMD (+2674%), calcitonin receptor-like receptor (CLR) (+518%), receptor activity modifying protein (RAMP)2 (+281%), RAMP3 (+178%), VEGF-A (+277%) and MMP-9 (+864%) mRNAs were significantly higher in cancer tissues than in the surrounding normal tissues, and there was a positive correlation between the gene expressions of MMP-9 and preproAM (r=0.352; p=0.005), but not with preproAM2/IMD (r=0.041, p=0.406). Both AM and AM2/IMD immunoreactivity were detected mainly within cancer cells, whereas MMP-9 immunoreactivity was mostly seen in the surrounding stroma. These findings suggest that AM produced in colorectal tumors acts in concert with MMP-9 in the stroma to contribute to the pathogenesis of colorectal cancer.
authors.affiliation: Department of Internal Medicine, Division of Circulation and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hikosaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tsuruda
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nagata
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuwasako
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Shinri
authors.initials: S
authors.lastname: Hoshiko
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Inatsu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Chijiiwa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C484330:ADM2 protein, human; D058286:Calcitonin Receptor-Like Protein; D036361:Peptide Hormones; D011498:Protein Precursors; C545503:RAMP2 protein, human; C545504:RAMP3 protein, human; D012333:RNA, Messenger; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C112034:preproadrenomedullin; D020780:Matrix Metalloproteinase 9