Richard M. Peek, Jr., MD

The gastrointestinal tract is a dynamic interactive barrier that normally segregates microbial populations from their cognate human hosts. An aberrant consequence of contact between microbes and gut epithelial cells is the development of mucosal inflammation, which, if allowed to become persistent, can initiate carcinogenic pathways. Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and Helicobacter pylori, a bacterial species that persistently colonizes the human stomach and induces chronic gastritis, is the strongest known risk factor for this malignancy. However, only a fraction of infected persons ever develop cancer, underscoring the importance of defining mechanisms that regulate the biological interactions of H. pylori with their hosts that promote neoplastic transformation. Adherence of H. pylori to gastric epithelial cells is critical for induction of inflammation and injury; therefore, the overarching theme for our research has been delineation of the molecular signaling events initiated by bacterial:epithelial cell contact that regulate phenotypes related to carcinogenesis. The most important known H. pylori strain-specific determinant associated with cancer is the cag pathogenicity island, and cag+ strains augment the risk for severe gastritis and gastric cancer. Using in vitro models of bacterial:gastric epithelial cell interactions, we have shown that cag island genes are required for pro-inflammatory cytokine release and induction of apoptosis, and that these events are mediated by activation of NF-kB and/or mitogen-activated protein kinases (MAPK). Recently, we have used global proteomics approaches to identify additional H. pylori products that are related to pathogenesis within the gastric niche. Extending these results into rodent models of H. pylori-induced inflammation and carcinogenesis (Mongolian gerbils and mice), we have shown that inactivation of such genes attenuates the development gastric injury and cancer. In human gastric tissue, however, gastric epithelial cell proliferation is significantly higher but apoptotic indices are lower among persons colonized with cag+ compared to cag- strains or uninfected persons leading us to postulate that reduced rates of cell loss, when accompanied by hyperproliferation, may heighten retention of mutagenized cells, which could predispose towards cancer. Therefore, we have also focused our investigations on host determinants that influence disease outcomes occurring within the context of H. pylori infection. One host effector that may influence carcinogenesis in response to H. pylori is MMP-7, a matrix metalloproteinase that enhances tumor formation in rodents, and is over-expressed in premalignant and malignant lesions within H. pylori-infected human mucosa. Although epithelial cells acutely exposed to matrilysin rapidly undergo apoptosis, constitutive expression of MMP-7 selects for cells with a reduced sensitivity to apoptosis. Our experiments have recently shown that MMP-7 is detected exclusively in human mucosa colonized by cag+ strains, and these same H. pylori strains selectively induce MMP-7 in vitro through cag-mediated activation of NF-kB and MAPK. Based upon these data, we hypothesize that strain-selective activation of NF-kB and/or MAPK by H. pylori cag+ strains regulates MMP-7 expression, which may contribute to the augmentation in carcinogenic risk associated with these strains by attenuating apoptosis within chronically colonized mucosa. We have also recently shown that carcinogenic strains of H. pylori can selectively activate B-catenin, and this is due to translocation of CagA into the host epithelial cell. Our current studies therefore, are not only allowing us to investigate discrete interactions that lead to H. pylori-induced neoplasias but also are providing mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.