A novel model of small intestine cancer in hCYP1A-db/db mice and the inhibitory effect of delta-tocopherol on colorectal cancer in hCYP1A mice

In the digestive tract, cancer is common in colon and rectum but rare in small intestine. However, during the last 30 years, small intestine cancer has increased from 1% to 3% in the newly diagnosed digestive tract cancers for unknown reasons, whereas colorectal cancer has dropped by about 10%. In our experimental study, we used a humanized mouse model by replacing the mouse Cyp1a with human CYP1A to mimic human metabolism of the dietary carcinogen, 2-amino-1-methyl-6- phenylimidazo [4,5-b] pyridine (PhIP) to study PhIP-induced carcinogenesis. We bred hCYP1A mice with db/+ mice to investigate cancer promotion by obesity. Remarkably, we found that all PhIP-treated hCYP1A-db/db mice develop tumors in small intestine at the ages of Week 28-44. The tumor region of small intestine showed overexpression of COX-2 and nitrotyrosine. In contrast, we have not observed tumor in small intestine in PhIP-treated hCYP1A mice. This result strongly suggests the promotion of small intestine cancer by obesity. Our finding provides a model for further exploration of small intestine carcinogenesis and related preventive studies. Many chemoprevention studies of colorectal cancer have been done. However, the results of the inhibitory effect of α -tocopherol on carcinogenesis were inconsistent. Our recent studies showed δ-tocopherol has strong inhibitory effect on different type of cancer such as lung and prostate cancer. In my experiment, hCYP1A mice were fed AIN93M (control) diet or diet supplement with 0.3% δ-tocopherol. All mice were administrated 200 mg/kg PhIP by oral gavage and one week later, administered 1.5% DSS in drinking water for 4 days. All mice were sacrificed 8 week after PhIP administration. The results showed decreased tumor multiplicity, tumor volume, expression of COX-2 and 8-oxo-dG, and increased expression of cleaved caspase-3, in the 0.3% δ-tocopherol treated group. Our findings suggest that δ-tocopherol inhibits tumorigenesis by decreasing inflammation and increasing cell apoptosis in colorectal cancer in hCYP1A mice.M.S.Includes bibliographical referencesby Ying-Yi Ku