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Background and Aims: Epithelial cells affected by somatic mutations undergo transition from tumor-suppressive to carcinogenic Smad pathway during sporadic colorectal carcinogenesis, and the specific linker threonine phosphorylation of Smad2/3 in colon epithelial cells indicates stem-like cells. This study extends previous our observations (Cancer Res 2005; 65: 157–65, Cancer Res 2007; 67: 5090–6, Dig Dis Sci 2015; 60: 362–74) to a model of colitis-associated colorectal cancer. Methods: After Crl:CD-1 mice received an intraperitoneal administration of azoxymethane (AOM), the mice were given dextran sodium sulfate (DSS) for seven days. AOM/DSS-treated mice (AOM/DSS mice) were killed at 10 or 20 weeks. After macroscopic observations, a histopathological analysis was conducted. Immunohistochemical staining was performed using the avidin-biotin immunoperoxidase method (pSmad3C-Ser, pSmad3L-Ser, c-Myc) and immunofluorescent methods (Ki67, β-catenin, CDK4, cyclin D1, Sox9, pSmad2/3L-Thr). Results: Colons from AOM/DSS mice were shorter than those from control mice. The number of colon tumors at week 20 was higher than at week 10. Inflammation scores for AOM/DSS mice were greater than those for control mice. Immunostainingpositive cells {staining by Ki67, β-catenin (nuclear and cytoplasmic), cyclin D1, and Sox9} were diffusely distributed in colon tumors. The percentage of pSmad3L-Ser-positive cells in colon tumors was higher than in sites of colitis, and that in sites of colitis was higher than in control mice. pSmad2/3L-Thr-positive cells were sparsely detected around crypt bases in non-neoplastic colon epithelia and at the tops of tumors, and immunohistochemical co-localization of pSmad2/3L-Thr with Ki67 was not observed. Immunohistochemical co-localization of pSmad2/3L-Thr with β-catenin and CDK4 was observed. Conclusions: pSmad3L-Ser signaling is an early event in colitis-associated colorectal cancer, and pSmad2/3L-Thr immunostaining-positive cells might be cancer stem cells.

Carcinogenic and stem cell-like phenotypes of Smad2/3 linker phosphorylation in a mouse model of colitis-associated colorectal cancer