Arnesen Henriette, Müller Mette Helen Bjørge, Aleksandersen Mona, Østby Gunn Charlotte, Carlsen Harald, Paulsen Jan Erik, Boysen Preben
Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences (NMBU), Oslo, Norway.
Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), Ås, Norway.
Lab Anim Res. 2021 Jul 27;37(1):19. doi: 10.1186/s42826-021-00096-y.
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide and thus mouse models of CRC are of significant value to study the pathogenesis. The Azoxymethane/Dextran sulfate sodium (AOM/DSS) model is a widely used, robust initiation-promotion model for chemical induction of colitis-associated CRC in rodents. However, the dosage of chemicals, treatment regimens and outcome measures vary greatly among studies employing this model. Thus, the aim of this study was to examine an AOM/DSS model involving a reduced (1%) dose of DSS for induction of carcinogenesis in A/J and C57BL/6J (B6) mice.
We show that colonic preneoplastic lesions can be reliably detected in A/J and B6 mice by use of a AOM/DSS model involving a single injection of 10 mg/kg AOM followed by three 7-day cycles of a low-dose (1%) DSS administration. Supporting existing evidence of A/J mice exhibiting higher susceptibility to AOM than B6 mice, our AOM/DSS-treated A/J mice developed the highest number of large colonic lesions. Clinical symptoms in both strains subjected to the AOM/DSS treatment did not persist in-between treatment cycles, demonstrating that the animals tolerated the treatment well.
Our findings suggest that a reduced dose of DSS in the AOM/DSS model can be considered in future studies of early phase colorectal carcinogenesis in the A/J and B6 mouse strains using preneoplastic lesions as an outcome measure, and that such regimen may reduce the risk of early trial terminations to accommodate human endpoints. Overall, our data emphasize the importance of devoting attention towards choice of protocol, outcome measures and mouse strain in studies of CRC in mice according to the study purpose.
结直肠癌（CRC）是全球最常被诊断出的癌症之一，因此CRC小鼠模型对于研究发病机制具有重要价值。氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）模型是一种广泛使用的、强大的启动-促进模型，用于在啮齿动物中化学诱导结肠炎相关的CRC。然而，在使用该模型的研究中，化学物质的剂量、治疗方案和结果测量差异很大。因此，本研究的目的是研究一种AOM/DSS模型，该模型使用降低剂量（1%）的DSS来诱导A/J和C57BL/6J（B6）小鼠发生癌变。
我们发现，通过使用AOM/DSS模型，即单次注射10mg/kg AOM，随后进行三个7天周期的低剂量（1%）DSS给药，可以在A/J和B6小鼠中可靠地检测到结肠肿瘤前病变。支持现有证据表明A/J小鼠对AOM的易感性高于B6小鼠，我们用AOM/DSS处理的A/J小鼠出现的大结肠病变数量最多。接受AOM/DSS治疗的两个品系小鼠的临床症状在治疗周期之间没有持续出现，这表明动物对治疗耐受性良好。
我们的研究结果表明，在未来使用肿瘤前病变作为结果测量指标的A/J和B6小鼠品系早期结直肠癌发生研究中，可以考虑在AOM/DSS模型中降低DSS剂量，并且这种方案可能会降低为适应人类终点而提前终止试验的风险。总体而言，我们的数据强调了在小鼠CRC研究中，根据研究目的关注方案选择、结果测量指标和小鼠品系的重要性。
