Single-dose DSS-induced inflammation enhances colorectal tumorigenesis in APC and KRAS mutant mice.

Colorectal cancer (CRC) arises through interactions between driver mutations, such as in APC and KRAS, and the tumor microenvironment (TME), including inflammatory factors. While chronic inflammation is a known risk factor, the role of transient mild inflammation in tumorigenesis remains unclear. This study assessed the impact of mild inflammation on CRC development using genetically modified KRAS mutant (mut), APC mut, and APC; KRAS double mut mouse models. Mice received tamoxifen at six weeks and were evaluated with or without a 5-day administration of 1.5% dextran sulfate sodium (DSS). Mice were sacrificed at 20 weeks, and tumor number, size, location, histology, immunofluorescence, and RNA sequencing were analyzed. Tumors were absent in APC and KRAS mut mice not treated with DSS, while APC; KRAS mut mice developed small proximal colon tumors. DSS-treated KRAS mut mice remained tumor-free, but APC and APC; KRAS mut mice developed multiple tumors throughout the colon. In APC; KRAS mut mice, DSS significantly increased tumor number and size in the proximal colon. Although DSS did not alter immune infiltration in proximal tumors, regulatory T cells and M2 macrophages were elevated in APC; KRAS compared to APC mutants, suggesting immunosuppressive TME. These findings indicate that transient inflammation promotes CRC development in APC mutant mice.