Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor.
OBJECTIVE
Factors associated with the development and malignant progression of Barrett's esophagus are poorly understood. Gastrin is a mitogen capable of inducing growth in normal and malignant gastrointestinal mucosa. It is unknown whether gastrin can influence cellular events in the esophagus in Barrett's.


METHODS
Reverse-transcription polymerase chain reaction (RT-PCR) and northern analysis for the cholecystokinin (CCK(2)) receptor were performed on normal, inflamed, metaplastic, and malignant esophageal mucosa. Real-time PCR quantified expression of the receptor. [(125)I]-G17-autoradiography localized the CCK(2) receptor in mucosal sections. [(3)H]-thymidine and bromodeoxyuridine (BrdU) incorporation determined proliferation in response to G17 in biopsy specimens incubated ex vivo. Proliferation and signaling studies were performed on OE33(E) cells transfected with the CCK(2) receptor.


RESULTS
RT-PCR identified receptor expression in 3 of 9 controls, 5 of 7 patients with esophagitis, 10 of 10 patients with Barrett's metaplasia, and 7 of 12 esophageal adenocarcinomas. Real-time PCR quantified expression in 10 patients with Barrett's showing a level of expression 2 orders of magnitude higher than in 12 control patients. [(125)I]-G17 bound to epithelia within glandular regions of Barrett's mucosa. Ten nmol/L G17 induced a 2-fold (n = 7, P = 0.0257, t test) increase in [(3)H]-thymidine incorporation in mucosal biopsy specimens, abolished by the addition of the CCK(2) receptor antagonist L-740, 093. One nmol/L G17 induced a 1.94- +/- 0.13-fold (n = 6, t test, P = 0.001) increase in [(3)H]-thymidine incorporation in OE33(E)(GR) cells, abolished by L-740, 093.


CONCLUSIONS
Gastrin induces proliferation via the CCK(2) receptor in Barrett's mucosa. This may have implications for the management of patients with Barrett's esophagus in whom gastrin is elevated by acid-suppression therapy.
Haigh
Chris R
CR
Department of Medicine and Physiological Laboratory, University of Liverpool, Liverpool, England. c.haigh@liv.ac.uk
Attwood
Stephen E A
SE
Thompson
David G
DG
Jankowski
Janusz A
JA
Kirton
Chris M
CM
Pritchard
D Mark
DM
Varro
Andrea
A
Dimaline
Rod
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001345:Autoradiography; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology*; D001667:Binding, Competitive; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003199:Computer Systems; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D005755:Gastrins / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008679:Metaplasia; D008875:Middle Aged; D011863:Radioimmunoassay; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D005755:Gastrins; D007457:Iodine Radioisotopes; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C013550:gastrin 17; D013936:Thymidine