Associate Professor Graham Baldwin
Position: Associate Professor and NHMRC Senior Research Fellow
Affiliation: Surgery, Austin and Repatriation Medical Centre
Phone: +61 (3) 9496 5592
My particular interest over the last 20 years has been the role of gastrointestinal peptides, and gastrin in particular, as growth factors for the gut mucosa and in gastrointestinal cancer.
Gastrin was first defined as a hormonal stimulant of acid secretion from the stomach, but over the past fifteen years it has become increasingly apparent that progastrin-derived peptides act as autocrine growth factors in the normal and malignant colonic mucosa. As well as defining the components of the autocrine loop, we have demonstrated stimulation of cell proliferation by exogenous gastrins in vitro and in vivo. The functional importance of endogenous gastrin was confirmed by the observations that expression of antisense gastrin constructs in a colonic cell line inhibited cell proliferation. Our work with gastrin receptor antagonists also indicated that a novel class of receptors was involved.
As well as investigating the effects of progastrin-derived peptides on cell proliferation, we have been one of the first groups to demonstrate that gastrins can also modulate cell migration. Our recent research has clearly demonstrated that only non-amidated gastrins modulate the subcellular localization of adhesion proteins, and promote cell migration in wound healing assays. The significance of these observations is that reduction in adhesion is a necessary prerequisite to cell migration, and hence to the transition from adenoma to malignant carcinoma.
We recently made the exciting discovery that Ggly and progastrin bind 2 additional ferric ions with high affinity, and that ferric ion binding is essential for biological activity. This is the first demonstration of an essential role for metal ions in the biological action of any hormone. The clinical significance of this observation follows from the demonstration that bismuth ions, or metal chelating agents, reverse the growth promoting effects of non-amidated gastrins on colorectal carcinoma cell lines. Interestingly the actions of amidated gastrins are uneffected by bismuth ions or by chelating agents.