On the other hand, 11 of 14 rats in the retired breeder group fed CDE had these tumors. The reason for the low number of such tumors in the younger rats is not clear, but could be due to sampling error or the fact that rats receiving CDE die at an earlier age than the controls or retired breeders fed CDE and thus could be dying before the interstitial cell tumors develop. Other check details cancers found in single

rats (Supporting Information Table 2, Supporting Fig. 2B-F) included leukemia, lung adenocarcinomas, renal cell carcinoma, mucinous carcinomatosis of the peritoneum, transitional cell carcinoma of the bladder, and an osteogenic sarcoma. These tumors are also found characteristically in aged Fischer 344 rats25 and did not show any clear association with CDE feeding.

For example, we found two leukemias in the control groups and one in the experimental. The incidence of leukemia here was lower than what has been reported in the literature, but we found that a number of both control and experimental rats showed extramedullary hematopoiesis in the liver; that condition could have been reported as leukemia in other studies. Localization of EpCAM, HNF6, and C-Met were done to determine expression in oval cells, cholangiofibrosis (CF), and CAA (Supporting Information Table 3, Supporting Fig. 5). EpCAM was present in normal ducts, oval cells, epithelial cells in CF, and CAA, but not in normal or reactive hepatocytes, MG-132 in vitro thus showing consistency of expression in biliary cell types. HNF6 was present in oval cells and CF, but unexpectedly not in CAA. C-Met was expressed weakly in normal hepatocytes, but was highly expressed in focal hepatocytes (notably in mitotic hepatocytes) selleck inhibitor in CDE-fed rats, as well as in oval cells, CF, and CAA. The cellular response of rats to a hepatocarcinogenic regimen is age-dependent. When fed five cycles of CDE diet beginning at age 3 weeks, seven of eight rats developed CCA, preceded by florid oval cell proliferation.

In rats fed the CDE diet beginning at 8 weeks of age, the oval cell response was much lower and a CCA developed in only 1 of 15 rats. When rats were fed the diet beginning at 1 year of age, there was minimal oval cell proliferation and no bile duct carcinomas were seen. This result supports the concept that cancers arise from tissue-determined stem cells, and that the number or potential, or both characteristics, of tissue stem cells to respond to carcinogens declines with aging. Unexpectedly, our cyclic CDE-fed rats did not develop either HBs, as predicted by our working hypothesis, or HCCs. In the literature, oval cell proliferation has generally been considered to be a precursor for development of HCC (for an extensive review, see Sell16).