Secondary bile acids effects in colon pathology. Experimental mice study

ABSTRACTPURPOSE:To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon.METHODS:The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically.RESULTS:No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA.CONCLUSION: Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Overexpression of cyclin D1 and cyclin E in 1,2-dimethylhydrazine dihydrochloride-induced rat colon carcinogenesis

Deregulation of G1 cyclins has been reported in several human and rodent tumors including colon cancer. To investigate the expression pattern of G1 cyclins in 1,2- dimethyl-hydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis, we studied the expression of cyclin D1 and cyclin E by quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry (IHC). The mRNA level of cyclin D1 was increased 1.2-fold in adenocarcinomas but not significantly in adenomas, when compared with normal rat colonic mucosa (p<0.05). The cyclin E mRNA level was increased 2.7-fold in adenomas and 3.3-fold in adenocarcinomas (p<0.05). The PCNA mRNA level was also increased 1.9-fold in adenomas and 1.8-fold in adenocarcinomas (p<0.05). Immunohistochemical staining revealed exclusive nuclear staining of the neoplastic cells for cyclin D1, cyclin E and PCNA. Cyclin D1 expression was detected in 56.3% of the adenomas and in 61.5% of the adenocarcinomas examined, whereas cyclin E expression was detected in 87.5% of the adenomas and in 92.3% of the adenocarcinomas. Overall, cyclin D1, cyclin E and PCNA expression was significantly increased at both the mRNA and protein levels in normal colonic mucosa, adenomas and adenocarcinomas, but there was no significant difference in the degree of expression of these genes in adenomas and adenocarcinomas. Our results indicate that the overexpression of cyclin D1 and cyclin E may play an important role during the multistage process of rat colon carcinogenesis, at a relatively early stage, and may disturb cell-cycle control in benign adenomas, and thereafter, participate in tumor progression.

Lung adenoma development and NK activity in mice treated with multiple carcinogens

A wide-spectrum initiation model was investigated in mice. Sequential treatments with diethylnitrosamine, urethane and N-methylnitrosourea, with or without a promoter, phenobarbital, resulted in tumor formation in the lungs in 85-90% of animals, but did not produce any tumorous lesions in other organs. The lung tumors were adenomas and the mean number of adenomas was 2.2-2.6 per mouse. Phenobarbital combination had no additive effect on lung tumor incidence and multiplicity. Splenic NK cell activity showed inconsistent increment in the carcinogen plus phenobarbital-treated group during the experiment (P less than 0.05).