Epithelial organisation depends on interactions between epithelial and sub-epithelial cells including myofibroblasts, and control of these interactions is likely to be important in responses to injury, infection, inflammation, and the progression to cancer. In the gastric epithelium exposure to Helicobacter pylori is associated in some patients with increased plasma gastrin, increased acid secretion and a progression to peptic ulcer. In other subjects, infection of the gastric corpus leads to a progression to gastric cancer via the premalignant condition of chronic atrophic gastritis. The latter is characterized by loss of gastric glands and acid-secreting parietal cells, hyperproliferation, inflammation and fibrosis consistent with disruption of epithelial — mesenchymal signaling. The mechanisms by which H.pylori disrupts tissue organization are not well understood. Recent work suggests epithelial responses to H.pylori include increased expression of genes associated with control of extracellular matrix (Varro et al., 2004). For example, we and others have shown that MMP-7 is increased in gastric epithelial cells in response to H.pylori infection. Using an MMP-7-promoter/luciferase reporter construct in gastric epithelial AGS cells we showed that H.pylori strains with the cag pathogenicity island stimulated expression by a mechanism involving NF?B and the Rho family small GTPase RhoA (Wroblewski et al, 2003). We have now examined the hypothesis that MMP-7 plays a role in epithelial mesenchymal signaling. Using human primary gastric glands and gastric myofibroblasts we found that epithelial cells released MMP-7 which stimulated myofibroblast migration. Recombinant MMP-7 stimulated by both [3H] thymidine incorporation into myofibroblasts and increased migration in Boyden chamber assays. These responses were significantly reduced by specific inhibitors of MMP-3 and -8 but not MMP-2/9 suggesting selective activation of protease cascades by MMP-7. The capacity of MMP-7 to increase secretion of MMP-3 and -8 was confirmed using Western blot and fluorogenic substrate analysis. In addition, MMP-7 increased phosphorylation of p42/44 (max at 10min) and Akt (Ser473, max at 2h) in gastric myofibroblasts and inhibitors of MEK (UO126), PI3K (LY294002) and Akt significantly reduced myofibroblast migration and proliferation. The data suggest that H.pylori increases epithelial MMP-7 which in turn acts as a signalling molecule to increase myofibroblast migration and proliferation. We suggest this pathway plays a role in tissue responses to injury and infection. It may also contribute to stromal formation in epithelial tumours.