Gastric cancer ranks high among the leading causes of cancer-related deaths worldwide, with 989,600 new cases and 738,000 deaths each year. The majority of human stomach tumors are associated with chronic infection with the bacterial pathogen Helicobacter pylori. It is therefore critical to understand mechanisms that regulate and facilitate malignant progression to efficiently identify potential targets for preventative therapies. In the USA, death rates from gastric cancer follow ethnic divisions with the highest mortality rates among African Americans, followed by Asian/Pacific Islanders, Native Americans, Hispanics, and Caucasians. 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. Furthermore, it is well established that inappropriate activation of Wnt/?-catenin signaling has an important function in gastric cancer development. The central objective of our proposed project is to identify accelerating factors by investigating the interaction of MyD88 signaling and a known gastric oncogenic pathway, Wnt/?-catenin and to elucidate the biological significance of these interactions in cancer progression. We recently showed using a Helicobacter-induced mouse model of gastric cancer that a key immune signal transduction adaptor protein, myeloid differentiation primary response gene 88 (MyD88), regulates Helicobacter-induced gastric cancer progression. However, the mediators of this cancer progression are unknown. We hypothesize that MyD88 deficiency leads to increased Wnt/?-catenin signaling in response to Helicobacter infection, which promotes gastric cancer development. It is known that Wnt/?-catenin signaling regulates gastrointestinal epithelial cell proliferation. However, the extent to which interactions between MyD88 and Wnt/?-catenin signaling pathways impact H. pylori-associated gastric carcinogenesis is unknown and has not been investigated. Our overall hypothesis is that the dramatic -/- acceleration in progression to gastric cancer found in Myd88 mice is due to interactions with oncogenic pathways, such as Wnt/?-catenin. Herein using a novel ex vivo gastric organoid culture system and a well- established Helicobacter-induced model of gastric cancer we will pursue the following specific aims:
Specific aim 1 : Investigate the effect of MyD88 on Wnt/?-catenin activity in H. pylori-induced epithelial cell proliferation using a gastric organoid culture system;
Specific aim 2 : Examine the function of Wnt/?- catenin signaling during acute inflammatory response and chronic inflammation in the absence and presence of MyD88 in a gastric cancer mouse model. First, this work first seeks to show that deficiency in MyD88 results in increased Wnt/?-catenin signaling. Second, this work will inform for the first time on the crosstalk between the MyD88 and Wnt/?-catenin signaling pathways and its significance in initiation and progression of gastric cancer.
Gastric cancer, which is caused by H. pylori infection is one of the most common and lethal type of cancer. However, the mechanisms underlying disease progression are still unclear. We will investigate the interaction between innate immune response and an oncogenic pathway to identify factors that promote gastric cancer.
