Pathophysiology of the fundic enterochromaffin-like (ECL) cell and gastric carcinoid tumours.
The genesis of human gastric carcinoma is ill understood but is invariably related to achlorhydria. Gastrin secretion is negatively regulated by luminal acid and hypergastrinaemia is thus associated with low acid states which may be natural (atrophic gastritis) or owing to acid inhibitory therapy. Apart from its acid secretory activity, gastrin is trophic to the mucosa, via stimulation of the fundic enterochromaffin-like (ECL) cells to secrete histamine. In conditions of elevated gastrin levels, ECL cell hyperplasia and even neoplasia have been noted. The relationship between low acid, hypergastrinaemia, ECL cell hyperplasia, and neoplasia may be of relevance since ECL cells secrete histamine and TGF alpha which are both recognised mitogens. We studied the rodent mastomys, which spontaneously develop gastric carcinoid tumours, which can be generated in 4 months under conditions of drug-induced acid inhibition and inhibited by octreotide administration. A pure (90-95%) cell preparation was used to evaluate ECL cell physiology and trophic regulation. A gastrin/CCKB receptor responsible for histamine secretion and DNA synthesis was identified, cloned and sequenced. Octreotide lowers plasma gastrin levels, decreases ECL cell neoplasia and, in vitro, inhibits ECL cell DNA synthesis. H1 receptor antagonists inhibited DNA synthesis in vitro and ECL neoplasia in vivo without altering gastrin levels. Hypergastrinaemia increased TGF alpha/EGF receptor and TGF alpha production and TGF alpha massively stimulated ECL cell DNA synthesis. Since ECL cells produce both histamine and TGF alpha and regulate parietal cells which produce TGF alpha, it is possible that achlorhydria-generated ECL cell dysfunction may play an initiative role in the pathobiology of gastric adenocarcinoma. The long-term clinical consequences of drug-induced sustained acid inhibition are worthy of further consideration.
Modlin
I M
IM
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
Lawton
G P
GP
Miu
K
K
Kidd
M
M
Luque
E A
EA
Sandor
A
A
Tang
L H
LH
D000818:Animals; D001483:Base Sequence; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000648:ultrastructure; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004759:Enterochromaffin Cells / Q000378:metabolism* / Q000648:ultrastructure; D005755:Gastrins / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000648:ultrastructure; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D005755:Gastrins; D011949:Receptors, Cholecystokinin; D016211:Transforming Growth Factor alpha; D004247:DNA