Abstract

Background: Activation of the gastrin-cholecystokinin_B (CCK_B) receptor stimulates cell proliferation and increases production of ligands for the epidermal growth factor receptor (EGF-R).

Aims: To determine the role of gastrin-CCK_B activation in stimulation of cell proliferation via paracrine activation of EGF-R.

Methods: AGS cells were transfected with the gastrin-CCK_B receptor (AGS-G_R cells) or with green fluorescent protein (AGS-GFP cells). Proliferation was determined by [³H] thymidine incorporation, flow cytometry, and cell counting.

Results: Gastrin inhibited proliferation of AGS-G_R cells by delaying entry into S phase. However, when AGS-G_R cells were cocultured with AGS-GFP cells, gastrin stimulated proliferation of the latter. Immunoneutralisation and pharmacological studies using metalloproteinase and kinase inhibitors indicated that the proliferative response was mediated by paracrine stimulation of EGF-R and activation of the mitogen activated protein kinase pathway through release of heparin binding EGF.

Conclusions: Gastrin can directly inhibit, and indirectly stimulate, proliferation of gastric AGS cells.