Genomic variants in mouse model induced by azoxymethane and dextran sodium sulfate improperly mimic human colorectal cancer

Abstract

Mouse model induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) is generally accepted as an ideal object to study on the carcinogenesis mechanisms of human colorectal cancer (CRC). The genomic responses to the AOM/DSS treatment in mouse that possibly lead to elucidation of CRC pathological mechanism are still poorly understood. For the first time, we investigated the cancer genome landscape of AOM/DSS mouse model by exome sequencing, to testify its molecular faithfulness to human CRC. Of 14 neoplastic samples, 7575 somatic variants were identified, which resulted in 2507 mutant genes and exhibited a large diversity in both colorectal aberrant crypt foci (ACF) and tumors even those tissues that were gained from the similar morphology or same treatment period. Cross-species comparison of the somatic variants demonstrated the totally different patterns of variable sites, mutant genes and perturbed pathways between mouse and human CRC. We therefore come to a conclusion that the tumorigenesis at genomic level in AOM/DSS model may not be properly comparable with that in human CRC, and the molecular mechanism elicited from this animal model should be carefully evaluated.

Diffuse reflectance spectroscopy to monitor murine colorectal tumor progression and therapeutic response

“…Also, the model selected is chemically induced and presents different metabolic activity when compared to human tumors. 61 Finally, the selected metronomic dosage and schedule is also a limitation as changes in the frequency of the treatment or fraction of reduction of the dose can potentially correlate with different physiological values.…”

Switching to a Healthy Diet Prevents the Detrimental Effects of Western Diet in a Colitis-Associated Colorectal Cancer Model

“…This study has several limitations. Although the AOM/DSS model is largely used to understand human tumorigenesis, it needs to be considered that there are large differences in the pattern of mutant genes and perturbed pathways between human and mouse colorectal tumors [113]. In our study, we used only female BALB/c mice, in order to have a more homogeneous group; therefore, the findings might be different in male mice, or in other mouse strains.…”

From Colitis to Cancer: An Evolutionary Trajectory That Merges Maths and Biology

“…AOM-DSS mice remain the most utilized model, with mice exposed to the carcinogen azoxymethane (AOM), followed by repeated ingestion of dextran sulfate sodium (DSS) to induce inflammation. However, whole exome sequencing of these mouse cancers shows little overlap in terms of mutational landscape with human CRC, in particular the near absence of the most common IBD-CRC driver mutations such as TP53, APC, KRAS , and PIK3CA , no shared ( 132 ). Indeed, AOM-DSS mouse CRC are striking for the over-representation of C>T substitutions, which is more typical of DNA damage by alkylating agents like azoxymethane ( 132 ).…”

“…However, whole exome sequencing of these mouse cancers shows little overlap in terms of mutational landscape with human CRC, in particular the near absence of the most common IBD-CRC driver mutations such as TP53, APC, KRAS , and PIK3CA , no shared ( 132 ). Indeed, AOM-DSS mouse CRC are striking for the over-representation of C>T substitutions, which is more typical of DNA damage by alkylating agents like azoxymethane ( 132 ). Likewise, IL10 −/− mice develop colitis-associated cancers that do not demonstrate the chromosomal instability ( 133 ) that is typically encountered in most human IBD-CRCs ( 134 ); recent studies suggest the need for additional microbial and immunological stressors to improve IL10 −/− mouse model fidelity ( 61 ).…”