Modlin I M, Lawton G P, Miu K, Kidd M, Luque E A, Sandor A, Tang L H
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
Ann R Coll Surg Engl. 1996 Mar;78(2):133-8.
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.
人类胃癌的发病机制尚不清楚，但总是与胃酸缺乏有关。胃泌素的分泌受腔内酸的负调节，因此高胃泌素血症与低酸状态相关，低酸状态可能是自然的（萎缩性胃炎）或由于酸抑制治疗。除了其酸分泌活性外，胃泌素还通过刺激胃底肠嗜铬样（ECL）细胞分泌组胺对黏膜具有营养作用。在胃泌素水平升高的情况下，已观察到ECL细胞增生甚至肿瘤形成。低酸、高胃泌素血症、ECL细胞增生和肿瘤形成之间的关系可能具有相关性，因为ECL细胞分泌组胺和TGFα，这两种物质都是公认的有丝分裂原。我们研究了啮齿动物非洲沼鼠，它会自发发生胃类癌肿瘤，在药物诱导的酸抑制条件下4个月内即可发生，且可通过给予奥曲肽来抑制。使用纯的（90-95%）细胞制剂来评估ECL细胞生理学和营养调节。鉴定、克隆并测序了负责组胺分泌和DNA合成的胃泌素/CCKB受体。奥曲肽可降低血浆胃泌素水平，减少ECL细胞肿瘤形成，并且在体外可抑制ECL细胞DNA合成。H1受体拮抗剂在体外抑制DNA合成，在体内抑制ECL肿瘤形成，而不改变胃泌素水平。高胃泌素血症增加TGFα/EGF受体和TGFα的产生，并且TGFα大量刺激ECL细胞DNA合成。由于ECL细胞既产生组胺又产生TGFα，并调节产生TGFα的壁细胞，因此胃酸缺乏导致的ECL细胞功能障碍可能在胃腺癌的病理生物学中起主动作用。药物诱导的持续酸抑制的长期临床后果值得进一步考虑。
