The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice (human)

Gastric cancer continues to be one of the most common cancers, with the third highest cancer-related mortality in the world. After infection with Helicobacter pylori, a cascade of inflammatory events that can lead to gastric cancer is triggered. This inflammatory response to the infection is characterized by the infiltration of mononuclear and polymorphonuclear cells into the infected mucosa. The transition of these cells from the circulation to the tissues is mediated through the interaction of receptors on the immune cells and their ligands in the endothelial compartment. CD44 is the receptor for hyaluronan, but it also interacts with osteopontin and collagen, among other molecules. Previous reports have shown that CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied a subset of subjects from a cohort of individuals with various degrees of gastric inflammation to determine gene expression changes associated with disease progression over a period of six years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed over time (from multifocal atrophic gastritis to intestinal metaplasia or from intestinal metaplasia to dysplasia) along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive Helicobacter pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. Thus, we present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses. A cohort of individuals having at least Multifocal Atrophic Gastritis (MAG) was follwed for 6 six years to study the evolution of the gastric lesions over time. The gene CD44 was found to be significantly different between the baseline and follow-up samples of individuals with progression to more advanced gastric lesion. Mouse models of H. pylori infection in wild type and CD44-/- mice showed that the KO mice had reduced levels of gastric itestinal metaplasia than their wild type counterparts after infection. The lesions were associated with differential immune responses and infiltration of GR1 positive cells