Different susceptibility to the development of hepatocellular carcinoma induced by diethylnitrosamine in female and male C3H mice

Abstract

Abstract Histopathological features of hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in mice displays strong similarities with those seen in humans, including the higher tumor prevalence in males than in females. Previous studies have demonstrated that continual production of the pro-inflammatory IL-6 by Kupffer cells is involved in the initiation and progression of DEN-induced HCC and that estrogen-mediated reduction of IL-6 secretion would decrease its incidence in females. However, the mechanisms by which different IL-6 concentrations affect tumor growth are not entirely understood. In this model, we demonstrated that the increased tumor growth observed in males accompanied significant liver damage and larger chronic inflammatory areas. Most tumors were placed into or close to senescent areas (detected by expression of β-galactosidase), and these areas were more extensive in DEN-treated males than in similarly-treated female mice. Further, different markers of systemic and regional immunosuppression (such as neutrophil-to-lymphocyte ratio, PD-1 expression in CD8 T cells, number of PD-L1 + myeloid-derived suppressor cells, etc.) were significantly higher in males than in females from the time the tumors started their exponential growth, suggesting that immunosuppressive mechanisms could contribute to the accelerated tumor growth observed in males. The relationship between chronic inflammation and immunosuppression has been previously documented. In contrast, little is known about the link between senescence and immunosuppression, raising the possibility that senescence may contribute to tumor growth by mechanisms other than immunological. Comparative studies between susceptible and resistant hosts to chemical carcinogenesis may help to unveil novel therapeutic strategies against cancer.