Accumulating evidence in literature suggests that amidated and non-amidated
gastrins (
gastrin precursors) may play an important role in the proliferation and
carcinogenesis of gastrointestinal and
pancreatic cancers, especially in the presence of
DNA damaging agents and/or infectious agents. Amidated
gastrins appear to have a protective role, while progastrins exert growth promoting effects in
cancers. Several receptor subtypes and signal transduction pathways mediate the
biological effects of the
gastrin peptides.
Progastrin and
gastrins also exert anti-apoptotic effects, which may additionally contribute to the growth and co-carcinogenic effects of these
peptides on GI mucosal cells in vivo. Amidated
gastrins additionally play an important role in the migration of GI epithelial cells, and in glandular morphogenesis, while progastrins may play an important role in invasion and
metastasis. Therefore, targeting progastrins,
gastrins, and their cognate receptors may provide a therapeutic tool for treating GI and
pancreatic cancers. Targeting CCK2-receptors has, so far, not provided optimal beneficial effects. However, targeting
gastrins via a
vaccine approach has provided some encouraging results for treating GI and
pancreatic cancers. It is expected that targeting precursor
gastrins (progastrins and gly-
gastrins), exclusively rather than amidated
gastrins, may be more effective for treating GI
cancers. Since GI
cancers at advanced stages are largely responsive to autocrine and intracrine progastrins, down-regulation of intracellular progastrins will likely be more effective at this stage.