PATHOPHYSIOLOGY OF THE FUNDIC ENTEROCHROMAFFIN-LIKE (ECL) CELL AND GASTRIC CARCINOID-TUMORS

The genesis of human gastric carcinoma is ill understood but is invari ably related to achlorhydria. Gastrin secretion is negatively regulate d by luminal acid and hypergastrinaemia is thus associated with low ac id states which may be natural (atrophic gastritis) or owing to acid i nhibitory 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 gastr in levels, ECL cell hyperplasia and even neoplasia have been noted. Th e relationship between low acid, hypergastrinaemia, ECL cell hyperplas ia, and neoplasia may be of relevance since ECL cells secrete and TGF alpha which are both recognised We studied the rodent mastomys, which spontaneously develop gastric carcinoid tumours, which can be generate d in 4 months under conditions of drug-induced acid inhibition and inh ibited by octreotide administration. A pure (90-95%) cell preparation was used to evaluate ECL cell physiology and trophic regulation. A gas trin/CCKB receptor responsible for histamine secretion and DNA synthes is was identified, cloned and sequenced. Octreotide lowers plasma gast rin levels, decreases ECL cell neoplasia and, in vitro, inhibits ECL c ell DNA synthesis. H-1 receptor antagonists inhibited DNA synthesis in vitro and ECL neoplasia in vivo without altering gastrin levels. Hype rgastrinaemia increased TGF alpha/EGF receptor and TGF alpha productio n and TGF alpha massively stimulated ECL cell DNA synthesis. Since ECL cells produce both histamine and TGF alpha and regulate parietal cell s which produce TGF alpha, it is possible that achlorhydria-generated ECL cell dysfunction may play an initiative role in the pathobiology o f gastric adenocarcinoma. The long-term clinical consequences of drug- induced sustained acid inhibition are worthy of further consideration.