用于结直肠癌预防和治疗动物疗效试验的加速型Pirc大鼠模型

PURPOSE: The Pirc rat (F344/NTac-Apc am1137 ) model has played a critical role in advancing our understanding of colorectal cancer (CRC) pathogenesis and in evaluating preventive/therapeutic strategies. The objective of this study was to establish an inflammation-driven accelerated model of colon polyp growth in Pirc rats. This model replicates chronic epithelial barrier disruption and low-grade gut inflammation, thereby reflecting real-world scenarios of lifestyle and environmental factors combined with genetic predisposition towards CRC development. METHODS: Dextran sodium sulfate/DSS (in drinking water) and/or high-fat diet/HFD (60 kcal% as fat) treatment was given to Pirc rats, whereas control rats received a regular rodent diet with no DSS. Two cycles (5 days ON, 9 days OFF, and 3 days ON) of DSS treatment (1-2% w/v) were administered starting at 6.5 weeks of age to accelerate colon polyp development without causing colitis. The effects of HFD treatment alone (6.5-16.5 weeks) and in combination with 2%DSS treatment were established. 2%DSS+HFD-treated rats received Celecoxib (70 mg/Kg/day, p.o. from 10.5-16.5 weeks) to confirm the response of the model to the anti-inflammatory agent. The colon polyp burden was determined after euthanizing rats at Week 16.5. RESULTS: No colitis was observed in animals during 1% or 2%DSS treatment, whereas consumption of HFD caused constipation. Minor body weight loss (<5%) was observed during DSS treatment. Administration of 2%DSS but not 1%DSS or HFD alone increased the polyp burden (n=2/group). However, the addition of HFD to 2%DSS treatment dramatically increased colon polyp number (9.7-fold, p<0.001 ) and volume (12.7-fold , p<0.01 ) in treated female rats (n=10) as compared to control rats (n=10), with larger size (>6 mm in diameter) polyps observed in the treated group only. In male rats, 2% DSS alone (n=4) or in combination with HFD (n=7) led to higher polyp numbers (2.6-2.8-fold), volumes (1.8-3.5-fold), and larger size compared to control (n=7). Celecoxib treatment reduced the polyp growth in male and female rats treated with 2%DSS+HFD (n=7), though statistical significance was not achieved. CONCLUSION: We successfully established an accelerated polyp development Pirc rat model, providing a better platform for high-throughput screening of pharmacological and dietary interventions for CRC chemoprevention in FAP and other high-risk populations, with greater translational potential. A single anti-inflammatory agent was ineffective at preventing aggressive polyp growth in this model, suggesting that combination therapies targeting multiple targets may be required. The mechanism of action underlying CRC development in this model is being investigated to identify new pharmacological targets and combinations. ACKNOWLEDGEMENTS: This research was funded by CPRIT RP240401. Rashim Singh is supported by the NCATS under award number K12TR004522.