| Chemical-induced hemangiosarcomas (HS), malignant tumors of endothelial cells (ECs), have become important in evaluating the potential human risk of several agents. Spontaneous HS frequently occur in mice, less in rats, and are rare in humans. Peroxisome proliferator activated receptor gamma (PPARgamma) agonists are non-genotoxic pharmaceuticals for the treatment of type II diabetes mellitus. Many produced HS in multiple tissues in mice, including liver and adipose tissue, but not rats in 2-year bioassays. Our research objective was to understand how PPARgamma agonists induce HS in mice, using the prototypical sarcomagenic troglitazone (TG) and non-sarcomagenic pioglitazone (P1O). Understanding the mechanism of PPARgamma agonist-induced tumorigenesis is critical to evaluate human risk. Since TG does not react with DNA, we hypothesized that increased EC proliferation was involved in TG-induced hemangiosarcomagenesis in mice. Increased EC proliferation can lead to increased DNA replications due to the increased cell number, resulting in the increased possibility of genetic errors. We showed that TG increased EC proliferation in liver and brown (BAT) and white (WAT) adipose tissue in mice at sarcomagenic doses. PIO increased EC proliferation in BAT only. TG directly increased DNA synthesis, inhibited apoptosis, and activated IGF signaling in mouse ECs in vitro . PIO increased DNA synthesis but did not inhibit apoptosis. These results indicate: (1) increased EC proliferation contributes to TG-induced hemangiosarcomagenesis in mice, at least in liver and WAT; (2) a direct proliferative effect of TG on mouse ECs in vitro may be involved in TG-increased EC proliferation in vivo; and (3) TG likely increases the total number of DNA replications greater than PIO since TG inhibits apoptosis. In addition to a direct proliferative effect, we demonstrated that TG-increased hypoxic conditions might be involved in TG-increased EC proliferation, but only in liver. Oxidative stress does not likely play a role. In human ECs, TG did not elevate proliferation or induce gene expression changes observed in TG-treated mouse ECs, indicating a species difference. Further investigation to determine the mechanism of TG-induced HS in mice and identify the biological similarities and species differences will contribute to understanding the possible human relevance of TG-induced HS in mice. |
