Text

theses

Colorectal and prostate cancers are leading causes of morbidity and mortality in the United States and worldwide. While immense progress has been made in reducing incidence and death of these cancers in the past few decades, they remain major public health issues, highlighting the need for better understanding, prevention and intervention of these diseases. One major strategy to address these issues is research into more relevant animal cancer models and potent chemopreventive agents. The purpose of this dissertation research was to characterize a novel colon carcinogenesis model induced by the meat-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), with colitis from Dextran Sodium Sulfate (DSS) and determine the effects of different tocopherol forms of vitamin E on the colon carcinogenesis model as well as a PhIP-induced prostate carcinogenesis model. The rapid induction of PhIP/DSS-induced colon carcinogenesis in the CYP1A-humanized mice was determined to be caused by active Ctnnb1/β-catenin mutations in residual epithelial cells, which when promoted by colitis, developed into precancerous lesion, high-grade dysplasia, and finally adenocarcinoma. These features resembled human colitis-associated colon cancer. In the PhIP/DSS-induced colon carcinogenesis model, dietary supplementation with d-T and g-T, but not a-T, significantly attenuated colon tumor formation and inhibited oxidative and nitrosative stress as well as pro-inflammatory markers. Additional studies indicate the potent inhibitory effects of d-T and g-T was mainly due to protection against early cellular and DNA damage caused by the PhIP carcinogen. In the PhIP-induced prostate carcinogenesis model, dietary supplementation with g-TmT and d-T effectively reduced the formation and severity of mouse PIN lesions as well as p-Akt expression, whereas g-T and a-T were less effective. Further studies suggest the chemopreventive effects of the tocopherols involved the reduction in cellular oxidative and nitrosative stress and inhibition of the PI3K/Akt signaling pathway that regulate cell survival and proliferation. Together, the findings from this research demonstrate the relevance of PhIP dietary carcinogen-induced and DSS colitis-promoted colon carcinogenesis model and the superior cancer preventive activities of d-T and g-T compared to the classic a-T.

ETD_7630

Ph.D.

Includes bibliographical references

by Jayson Xiao-Chen Chen

doi:10.7282/T30004D4

ETD doctoral

The author owns the copyright to this work.