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Extremely weak tumor-promoting effect of troglitazone on splenic hemangiosarcomas in rasH2 mice induced by urethane
Meilan Jin1, Sayaka Matsumoto, Yasuaki Dewa
1Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. meilan@cc.tuat.ac.jp
Abstract:
To examine the tumor-promoting effect of troglitazone (TRG), a novel thiazolidinedione insulin-sensitizing agent, on splenic hemangiosarcomas in rasH2 mice, histopathological and molecular analyses were performed in the spleen of female rasH2 mice fed a diet containing 6,000 or 0 ppm TRG for 16 weeks after 1,000 or 0 mg/kg urethane (UR) initiation. Histopathologically, splenic hemangiosarcomas were observed in the UR-alone and UR + TRG groups, but there was no significant difference in the incidence of splenic hemangiosarcomas between the UR-alone and UR+TRG groups. There were increasing tendencies in the number of positive cells for anti-PCNA antibody and gene expression in the UR + TRG group, but such a change was not statistically significant as compared to that in the UR-alone group. The gene expressions of VEGF, VEGFR1, VEGFC, VEGFR2 and Tie2 related to angiogenesis; c-fos related to MAPK cascade activation; and cyclin D1 related to cell cycle in the UR-alone and UR + TRG groups were significantly higher than those in the untreated control group. However, only the Tie2 gene in the UR + TRG group was significantly increased as compared to that in the UR-alone group. These results suggest that the vascular tumor-promoting activity of TRG in rasH2 mice is extremely low in the present experimental condition and a part of the gene related to angiogenesis probably contributes to the promotion of splenic hemangiosarcomas in rasH2 mice given TRG.
Insights
Troglitazone (TRG) showed very low tumor-promoting activity on splenic hemangiosarcomas in rasH2 mice. Angiogenesis-related genes, particularly Tie2, were implicated in tumor promotion when TRG was administered.
Area of Science:
- Oncology
- Pharmacology
- Toxicology
Background:
- Troglitazone (TRG) is an insulin-sensitizing agent.
- RasH2 mice are genetically engineered to be susceptible to carcinogens.
- Splenic hemangiosarcomas are aggressive vascular tumors.
Purpose of the Study:
- To investigate the tumor-promoting effect of TRG on splenic hemangiosarcomas in rasH2 mice.
- To evaluate histopathological and molecular changes associated with TRG exposure.
- To assess the role of angiogenesis and cell cycle-related genes in TRG-induced tumor promotion.
Main Methods:
- Female rasH2 mice were administered urethane (UR) followed by diets containing TRG or a control diet.
- Histopathological analysis of splenic hemangiosarcomas was performed.
- Molecular analyses included PCNA expression and gene expression of angiogenesis (VEGF, VEGFR1, VEGFC, VEGFR2, Tie2), MAPK cascade (c-fos), and cell cycle (cyclin D1).
Main Results:
- No significant difference in splenic hemangiosarcoma incidence was observed between UR-alone and UR + TRG groups.
- A non-significant increasing tendency in PCNA-positive cells and gene expression was noted in the UR + TRG group.
- Gene expressions related to angiogenesis, MAPK, and cell cycle were elevated in UR-treated groups compared to controls, with a significant increase in Tie2 in the UR + TRG group.
Conclusions:
- TRG exhibits extremely low vascular tumor-promoting activity in rasH2 mice under the tested conditions.
- Angiogenesis-related genes, especially Tie2, may contribute to splenic hemangiosarcoma promotion in TRG-treated rasH2 mice.
- Further research is needed to fully elucidate the role of TRG in tumorigenesis.
