Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence.
The role of hyper-gastrinaemia in the incidence of colonic cancer remains to be clarified. The aim of this study was to determine whether cholecystokinin-2 (CCK-2) receptor expression predicts the sensitivity of human colonic adenomas to the proliferative effects of serum hyper-gastrinaemia. Gene expression of the classical (74 kDa) CCK-2 receptor in human colonic adenoma specimens and cell lines, was quantified by real-time PCR. Western blotting, using a CCK-2 receptor antiserum, confirmed protein expression. A transformed human colonic adenoma was grown in SCID mice, with hyper-gastrinaemia induced by proton pump inhibitors. CCK-2 receptor blockade was achieved by using neutralising antiserum. Both human colonic adenoma cell lines and biopsies expressed CCK-2 receptor mRNA at levels comparable with CCK-2 receptor transfected fibroblasts and oxyntic mucosa. Western blotting confirmed immunoreactive CCK-2 receptor bands localised to 45, 74 and 82.5 kDa. Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively). The effect of hypergastrinaemia on tumour growth was reversed by use of antiserum directed against the CCK-2 receptor. Hyper-gastrinaemia may promote proliferation of human colonic adenomas that express CCK-2 receptor isoforms.
Watson
S A
SA
Academic Unit of Cancer Studies, University of Nottingham, Nottingham, NG7 2UH, UK. sue.watson@nottingham.ac.uk
Morris
T M
TM
McWilliams
D F
DF
Harris
J
J
Evans
S
S
Smith
A
A
Clarke
P A
PA
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003199:Computer Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D005755:Gastrins / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012636:Secretory Rate / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
D004791:Enzyme Inhibitors; D005755:Gastrins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D009853:Omeprazole