Identification of gastrin as a growth peptide in human pancreatic cancer

Abstract

The present study reports the first evidence that the gastrointestinal peptide gastrin stimulates the growth of several human pancreatic cancer cells in culture and in tumors transplanted to nude mice. Gastrin promoted growth of all cell lines tested at a dose comparable to the binding affinity, providing evidence for a physiologically relevant receptor. The stimulatory effects of gastrin were blocked by the CCK-B/gastrin receptor antagonist L-365,260 and not by the CCK-A receptor antagonist L-364,718. Growth of PANC-1 cells in culture were inhibited by L-365,260, suggesting that gastrin is tonically produced by PANC-1 cells for regulation of growth. Athymic nude mice bearing PANC-1 xenografts were treated for 24 days subcutaneously with either 1% bovine serum albumin (diluent), pentagastrin (1 mg/kg), or L-365,260 (1 mg/kg) twice daily. Tumors from the pentagastrin-treated mice were found to weigh more and have greater protein and DNA content than controls, whereas these values were all decreased in tumors of L-365,260-treated mice. Receptor binding capacity changed in tumors of animals treated with the peptide or antagonist, suggesting a regulatory process. Gastrin immunoreactivity was detected in a transplanted PANC-1 human tumor. These results identify gastrin as a potent trophic peptide that actively stimulates growth of human pancreatic cancer and does so through a CCK-B/gastrin-like receptor.

Constitutively active CCK2 receptor splice variant increases Src-dependent HIF-1α expression and tumor growth

“…Constitutive CCK 2i4sv R activity increases HEK293 tumor growth As gastrin and its biosynthetic precursor, non-amidated glycine-extended gastrin, both have the ability to stimulate the growth of GI cancers in rodents and humans (McGregor et al, 1982;Sirinek et al, 1985;Winsett et al, 1986;Smith and Solomon, 1988;Watson et al, 1989;Smith et al, 1995;Smith et al, 1998;Harris et al, 2004), we assessed whether the increased tumor growth rate associated with CCK 2i4sv R expression was due to receptor activation by endogenous gastrin. Mice were injected with cells stably transfected with CCK 2i4sv R or CCK 2 R. After 2 days, they were randomly separated into four groups for each receptor variant, and treated either with saline, the CCK 2 R selective antagonist (CR2945), the CCK 2 R agonist (pentagastrin), or a combination of CR2945 and pentagastrin.…”

Epidermal Growth Factor Potentiates Cholecystokinin/Gastrin Receptor-mediated Ca2+ Release by Activation of Mitogen-activated Protein Kinases

“…Administration of G17 stimulates the growth of human colon cancer cells in culture (34,35) and human tumors xenografted into nude mice (35). Additionally, G17 and its related peptide CCK stimulate the growth of stomach (36,37) and pancreatic cancers (38). EGF receptors and their ligands are also overexpressed and regulate the growth of the same cancers (39,40), suggesting the possibility for cross-talk between EGFR-and CCK 2 R-regulated pathways in these cancers.…”

Metastatic Pancreatic Cancer: Emerging Strategies in Chemotherapy and Palliative Care

“…Of interest, gastrin has been identified as a growth peptide in human pancreatic cancer, and coexpression of gastrin and its receptor in human pancreatic adenocarcinomas has been demonstrated [166,167]. G17DT is an antigastrin immunogen consisting of a nine-amino-acid fragment of the amino terminal of human gastrin-17 conjugated with diphtheria toxoid and formulated as a water-in-oil emulsion suitable for intramuscular injection.…”