The role of gastrin and cholecystokinin in normal and neoplastic gastrointestinal growth

Abstract

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 enterochmmafh-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 affimities is not consistent with binding to either CCK-A or gastrin/CCK-B receptors. Defintion of the molecular structure of the receptor involved in the autocrine loop may lead to novel therapies for gastrointestinal cancer.

Autocrine and paracrine signaling through neuropeptide receptors in human cancer

“…The potential role of gastrin and CCK as autocrine or paracrine factors in gastrointestinal cancers is controversial (reviewed in Baldwin, 1995, Baldwin andShulke, 1998). While the evidence indicates that most gastrointestinal carcinomas express and synthesize progastrin, con¯icting reports on the degree of gastrin amidation which is required for binding to the de®ned CCK-B receptor in cancer specimens and cell lines prevent a clear assignment of gastrin as an autocrine factor in gastrointestinal cancer.…”

Expression of the cholecystokinin 2-receptor in normal human thyroid gland and medullary thyroid carcinoma

“…Stimulation of CCK 2 R leads to acid secretion as well as cell proliferation within the gastric mucosa (1). In addition, gastrin has been shown to induce growth of a variety of normal as well as malignant gastrointestinal cell types in vitro (2). Furthermore, in several tumor systems an autocrine loop has been proposed between gastrin, secreted by tumor cells, and CCK 2 R, expressed on tumor cells (3 -6).…”

“…In recent years, CCK 2 Rs have been detected in various extraintestinal cell types and tumors (7,8). Based on the well-established proliferative effects of gastrin, CCK 2 Rs might be important promoters of growth in these extraintestinal organs and tumors and therefore might serve as interesting diagnostic and therapeutic targets.…”

Use of interfering RNA to investigate the role of endogenous gastrin in the survival of gastrointestinal cancer cells

“…Amidated gastrin, glygastrin and progastrin promote growth of a range of cell lines in vitro and in vivo (Watson et al, 1989;Seva et al, 1994;Baldwin, 1995b;Stepan et al, 1999;Baldwin et al, 2001) and upregulate expression of a range of anti-apoptotic proteins, including Akt and bcl-2 (Konturek et al, 2003;Harris et al, 2004a;Ramamoorthy et al, 2004). Gly-gastrin promotes invasion of human colon cancer cells by upregulating expression of matrix metalloproteinases (Baba et al, 2004), by increasing the rate of metastasis formation in vivo (Kermorgant and Lehy, 2001) and by promoting blood vessel formation through the stimulation of endothelial cells (Clarke et al, 2006).…”