Esophageal adenocarcinoma (EAC) has the fastest rate of increase among all cancers in America, yet there is very little research on the mechanisms and prevention of its development. EAC primarily affects White males and has one of the poorest prognoses among all cancers. Barrett's esophagus (BE) is a pre-cancerous lesion associated with the development of EAC. BE is caused by chronic heartburn, which affects more than 19 million Americans every year. Pharmaceutical treatments to cure heartburn do not appear to largely affect EAC incidence. New intervention strategies are urgently needed to address this issue. Commonly available berries, such as blueberries (BB) and black raspberries (BRB), are natural chemopreventative agents that can be easily incorporated into the American diet and used for clinical intervention. Moreover, dietary BRBs are highly effective in preventing squamous cell carcinoma (SCC), another type of esophageal cancer, the incidence of which is declining. We have developed an animal model that mimics the clinical development of EAC. In this model, chronic esophageal reflux resembling heartburn is induced in rats using a surgical procedure. More than one-third of the rats develop EAC at the end of 6 months. We can effectively use this model to study the preventive efficacy of dietary berries. Two types of berries have been chosen, since they differ widely in their phytochemical profiles. Our objective is to study the efficacy of dietary berries to prevent the development of reflux-induced EAC and to understand the mechanisms by which they do so. To achieve this, we plan to provide BB and BRB via the diet to male rats at a dose of 2.5%, which is equivalent of consuming one-half cup of dried berries every day. We will surgically-induce chronic reflux. At the end of 6 months, the rats that were provided with berry diet will be compared with those that did not receive intervention to evaluate the incidence of tumors. To further understand the mechanisms by which berries may prevent esophageal tumorigenesis, we plan to use intermediary monthly time points during the development of EAC to study the biomarkers that are altered. The first set of biomarkers deal with oxidative stress and will determine whether berries can induce cellular antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, which ultimately protect the cells from oxidative damage. Lipid peroxidation and oxidative DNA damage will be used as markers of oxidative stress. The second set of biomarkers deal with inflammation associated with BE. Nuclear factor kappa B (NF?B), a transcription factor that controls the expression of several cancer-inducing genes, is found to be activated by inflammation in BE. We will evaluate whether berries can prevent this activation. Thus, by following a two-part approach, we will be able to determine whether berries prevent EAC progression and the mechanisms involved in this prevention.
Barrett's esophagus (BE) is a pre-cancerous lesion associated with the development of esophageal adenocarcinoma, the fastest growing cancer among Americans. We propose to use an animal model of BE to study the preventive effects of 2 types of dietary berries (blueberries and black raspberries) on EAC incidence.
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