title: Adrenomedullin is induced by hypoxia and enhances pancreatic cancer cell invasion.
abstract: Adrenomedullin (ADM) is synthesized by different types of cells and acts by binding calcitonin receptor-like receptor (CRLR) and members of the receptor activity-modifying protein (RAMP) family. In this study, the expression and functional role of ADM and its signaling components were investigated in pancreatic adenocarcinoma (PDAC). By QRT-PCR, median mRNA levels of ADM and CRLR were 1.5- and 2.4-fold higher, respectively, in PDAC tissues compared to normal pancreatic tissues. By immunohistochemistry, ADM, CRLR, RAMP1 and RAMP2, but not RAMP3, were expressed in pancreatic cancer cells. ADM serum levels were significantly increased in PDAC patients compared to healthy controls and chronic pancreatitis (CP) patients, with an area under the ROC curve of 0.83 and 0.98, respectively. At a cut-off level of 30.6 ng/ml, the specificity of ADM to differentiate PDAC from controls and CP patients was 85.5 and 83.6%, with a sensitivity of 80 and 100%. All 5 evaluated pancreatic cancer cells lines expressed ADM, CRLR, RAMP1 and RAMP2, whereas RAMP3 was expressed in only 1/5 pancreatic cancer cell lines. ADM was strongly induced by hypoxia and significantly increased invasiveness in 3/5 human pancreatic cancer cells. Blocking of CRLR decreased invasiveness in 4/5 human pancreatic cancer cells. In addition, rADM slightly up-regulated vascular endothelial growth factor secretion in 3/5 cell lines. In conclusion, ADM is induced by hypoxia and over-expressed in PDAC and might therefore serve as a potential tumor marker. Furthermore, ADM increases invasiveness of some pancreatic cancer cells and might influence angiogenesis, suggesting that blocking this pathway might have a therapeutic potential.
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Shereen
authors.initials: S
authors.lastname: Keleg
authors.forename: Hany
authors.initials: H
authors.lastname: Kayed
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
mesh_terms: D000293:Adolescent; D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058286:Calcitonin Receptor-Like Protein; D015687:Cell Hypoxia; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000235:genetics; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C545502:RAMP1 protein, human; C545503:RAMP2 protein, human; C545504:RAMP3 protein, human; D012333:RNA, Messenger; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D053607:Adrenomedullin