Abstract B28: Exploring the host immune response to understand the existence of Helicobacter-induced gastric cancer disparity.

Abstract

Abstract Gastric cancer is the second most common cause of death from cancer worldwide, with approximately 800,000 deaths each year. The majority of human stomach tumors are associated with chronic infection with the bacterial pathogen Helicobacter pylori. In the U.S. gastric cancer incidences and mortality rates are higher among minority groups (African Americans, Asian/Pacific Islanders, Alaskan Natives, Hispanic-Latino) than whites. Accordingly, colonization rates of H. pylori are also higher in these groups with 75% for Alaska Natives, 62% for Mexican Americans, and 53% for non-Hispanic blacks compared to 26% for non-Hispanic whites, making H. pylori infection a disease that disproportionately afflicts minorities. The cause of this disparity is unknown. There is now considerable amount of confirmatory evidence that the host response to H. pylori is crucial in determining susceptibility to gastric cancer. Our objective was to study the role of the host innate immune response in Helicobacter disease progression to understand the existence of gastric cancer disparity. Specifically, we investigated the role of a key signaling molecule, myeloid differentiation primary response gene 88 (MyD88) in Helicobacter-induced gastric cancer. MyD88 is an adaptor protein that plays a central role in the innate and adaptive immune response. It is involved in inflammatory pathways of interleukin (IL) -1/IL-18 and Toll-like receptor signaling and is considered to be responsible for the chronic inflammation attributed to Helicobacter infection. Induction of chronic inflammation during infection with H. pylori is widely accepted to be the trigger for gastric carcinogenesis. We used a well-characterized animal model of gastric carcinogenesis that involves infection of C57BL/6 mice with H. felis, which is a close relative of the human pathogen H. pylori. Wild type (WT) and mice deficient in MyD88 (Myd88-/-) in the C57BL/6 background were infected with H. felis for 25 or 47 weeks and mouse stomachs processed for histology, immunohistochemistry, gene expression analysis, and apoptosis. Myd88-/- mice had a higher apoptotic index and progressed rapidly to neoplasia than WT mice. Microarray data showed differential gene expression between Helicobacter infected WT and Myd88-/- mice. At 25 weeks, Myd88-/- mice showed evidence of dysplasia, which was absent in WT mice. By 47 weeks, Myd88-/- mice had developed severe dysplasia, which is considered gastric cancer in situ while WT mice only showed early evidence of dysplasia. MyD88 deficiency therefore resulted in rapid progression to gastric dysplasia. In conclusion, our data show that in the absence of MyD88, infection with Helicobacter resulted in accelerated development of gastric cancer. These data suggest that the host immune response is a critical determinant of Helicobacter disease progression. Knowledge on the status of the immune responses during Helicobacter infection is the first step in understanding mechanisms of Helicobacter-induced carcinogenesis, which may lead to a better understanding of the existence of gastric cancer disparity. Citation Format: Kelly S. Doran, Ellese M. Carmona, Anirban Banerjee, Arnika Sharma, Marygorret Obonyo. Exploring the host immune response to understand the existence of Helicobacter-induced gastric cancer disparity. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B28.