The role of gastrin and cholecystokinin in normal and neoplastic gastrointestinal growth.
Gastrin and cholecystokinin (CCK) act as growth factors for the gastric mucosa and the pancreas, respectively. CCK is also responsible, via the CCK-A receptor, for the pancreatic hyperplasia observed following the feeding of protease inhibitors or pancreaticobiliary diversion. Hypergastrinaemia does not increase the incidence of spontaneous gastrointestinal carcinoma, but does stimulate the proliferation of gastric enterochromaffin-like cells via the gastrin/CCK-B receptor, with a consequent increase in the incidence of gastric carcinoids. Whether gastrin influences mutagen-induced gastrointestinal carcinogenesis is still controversial, but CCK clearly enhances the induction by carcinogens of acinar tumours in the pancreas. While gastrin increases xenograft growth of 50% of gastrointestinal tumours tested, effects on the proliferation of gastrointestinal tumour cell lines in vitro have been more difficult to demonstrate, perhaps because many cell lines are already maximally stimulated by autocrine gastrin. Gastrin mRNA and progastrin, but not mature amidated gastrin, have been detected in all gastrointestinal cell lines tested. Although cell proliferation is inhibited by gastrin/CCK receptor antagonists, the spectrum of antagonist affinities is not consistent with binding to either CCK-A or gastrin/CCK-B receptors. Definition of the molecular structure of the receptor involved in the autocrine loop may lead to novel therapies for gastrointestinal cancer.
Baldwin
G S
GS
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Parkville, Victoria, Australia.
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002766:Cholecystokinin / Q000502:physiology*; D005753:Gastric Mucosa / Q000166:cytology*; D005755:Gastrins / Q000502:physiology*; D005770:Gastrointestinal Neoplasms / Q000473:pathology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000166:cytology*; D014407:Tumor Cells, Cultured
D005755:Gastrins; D006133:Growth Substances; D002766:Cholecystokinin