Importance of gastrin in the pathogenesis and treatment of gastric tumors

Table 1 Phenotype of mice with transgenic alterations in members of the gastrin family of peptides

Transgenic strain	Transgenic abnormality	Gastric phenotype	Susceptibility to gastric carcinoma	Other relevant phenotype
hGAS[4]	Human gastrin minigene expressed in liver-resulting in elevated serum levels of human progastrin	No known gastric phenotype	Not altered	Increased colonic mucosal proliferation[4113] and susceptibility to azoxymethane-induced colon cancer[114]
MTI/G-Gly[5]	Human gastrin gene with two stop codons after glycine-72, spliced with MTI promoter. Transgenic animals have elevated serum levels of glycine extended gastrin	No known gastric phenotype	Not altered	Increased colonic mucosal proliferation[5]
INS-GAS[34]	Human gastrin minigene spliced with insulin promoter expressed in pancreatic islets-resulting in elevated serum levels of amidated gastrin	Initial gastric mucosal hypertrophy and excess gastric acid secretion. By 5 mo, gastric atrophy and hypochlorhydria. Increased gastric proliferation and increased susceptibility to apoptosis	Increased (spontaneous tumors at 20 mo and H Felis-induced tumors at 6 mo)	Increased colonic mucosalproliferation in proximal and distal colon but not rectum initially observed in 1-year-old animals[4], but no difference in apoptotic or mitotic rates seen in 10-12-wk-old mice[113] and no increase in AOM-induced cancers[114]
INS-GAS/ MTI/G-Gly[37]	MTI/G-Gly mice crossed with INS-Gas mice to result in a “double” transgenic mouse that expresses both increased amidated and glycine extended forms of gastrin	Hyperchlorhydric at birth but unlike INS-GAS, no mucosal atrophy at older ages. Reduced apoptosis compared to INS-GAS with similar levels of proliferation. Overall rates of malignant progression comparable to INS-GAS	Increased
GAS-KO[38]	Gastrin knockout mice generated by targeted gene disruption	Achlorhydric with reduced parietal cell numbers (gastric atrophy), clustering of ECL cells at gland bases and increased TFF2-positive cells (spasmolytic polypeptide expressing metaplasia)	Increased	Increased susceptibility to azoxymethane-induced colon carcinogenesis[115] (despite normal untreated proliferation indices[113])
CCK-B-null[49]	Gastrin receptor knockout mice generated by targeted gene disruption	Marked gastric atrophy and achlorhydria. Morphologically abnormal ECL cells with loss of normal secretory vesicles and replacement with dense core granules and microvesicles	Not reported	Increased sensitivity to dopamine[116] and altered behaviour in response to alcohol[117118] and other stimuli[119120]

Table 2 Causes of hypergastrinemia in humans

Acidic gastric pH	Elevated gastric pH
Gastrinoma	Chronic atrophic gastritis
Antral predominant H pylori infection	Autoimmune
Pyloric obstruction	H pylori infection
Renal failure	Acid-suppressing medication
Retained gastric antrum following Billroth II gastrectomy	Vagotomy

Table 3 Types of gastric neuroendocrine tumor

Type	Associated diseases	Proportion of gastric NETs	Typical endoscopic findings	Plasma gastrin	Gastric juice pH	Prognosis
I	Chronic autoimmune atrophic gastritis	80%	Multiple < 1 cm polyps	High	~7	Good
II	ZES and MEN1	5%	Multiple < 1 cm polyps	High	< 2	Variable
III	None	15%	Single 2-5 cm polyp	Unchanged	1-2	Poor