An emerging concept over the last decade is that most gastrointestinal malignancies actually arise from chronic inflammation. In keeping with this concept I have made a major component of my research program how the dysregulation of mucosal immune responses can lead to neoplastic transformation.

Exploding knowledge about Helicobacter pylori in the 1990's and the elegance of this area of investigation as a perfect model to study mucosal immunology caused me to study this area for the last 10 years. My work has focused on host response to the infection. These studies have involved the innate immune response and the identification of ways that this response is ineffective. In this context we have also elucidated several important mechanisms whereby the epithelial responses may also be inappropriate, leading to risk for cancer development. My laboratory seeks to unravel novel mechanisms for inflammation and cellular damage, which in the case of H. pylori infection leads to increased cancer risk. One such pathway that we have reported is that H. pylori specifically induces the enzyme spermine oxidase (SMO), originally known as polyamine oxidase 1, which selectively utilizes the polyamine spermine as substrate. Our studies showed that the generation of H2O2 by SMO results in mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, and apoptosis. Our work has also shown that spermine itself contributes to the inadequacy of the host response, by blocking iNOS translation and hence NO production that is needed for the killing of H. pylori. We have specifically reported that upregulation of SMO is a major source of oxidative stress in gastric epithelial cells that leads to both apoptosis and DNA damage. Our funded studies are focused on the role of SMO in inflammatory responses and the mechanisms of ODC and SMO gene promoter activation. We are now moving further into the direction of the role of SMO in cancer, since we will be working with carcinogenic strains of H. pylori developed at Vanderbilt and a mouse model of gastric cancer, hypergastrinemic INS-GAS mice.

My lab will also be investigating the role of SMO in colon cancer derived from inflammatory bowel disease and in esophageal cancer derived from Barrett's esophagus. We also have substantial experience working with COX-2 in inflammation-associated carcinogenesis in the case of Barrett's esophagus and H. pylori infection.