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Characterization of dextran sodium sulfate-induced inflammation and colonic tumorigenesis in Smad3(-/-) mice with dysregulated TGFβ.

Seamons A, Treuting PM, Brabb T, Maggio-Price L - PLoS ONE (2013)

Bottom Line: There are few mouse models that adequately mimic large bowel cancer in humans or the gastrointestinal inflammation which frequently precedes it.Smad3(-/-) mice are deficient in the transforming growth factor beta (TGFβ) signaling molecule, SMAD3, resulting in dysregulation of the cellular pathway most commonly affected in human colorectal cancer, and develop inflammation-associated colon cancer.Studies presented here in Smad3(-/-) mice detail disease induction with DSS, without the use of AOM, and show a) Smad3(-/-) mice develop a spectrum of lesions ranging from acute and chronic colitis, crypt herniation, repair, dysplasia, adenomatous polyps, disseminated peritoneal adenomucinosis, adenocarcinoma, mucinous adenocarcinoma (MAC) and squamous metaplasia; b) the colon lesions have variable galactin-3 (Mac2) staining c) increased DSS concentration and duration of exposure leads to increased severity of colonic lesions; d) heterozygosity of SMAD3 does not confer increased susceptibility to DSS-induced disease and e) disease is partially controlled by the presence of T and B cells as Smad3(-/-) Rag2(-/-) double knock out (DKO) mice develop a more severe disease phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
There are few mouse models that adequately mimic large bowel cancer in humans or the gastrointestinal inflammation which frequently precedes it. Dextran sodium sulphate (DSS)-induces colitis in many animal models and has been used in combination with the carcinogen azoxymethane (AOM) to induce cancer in mice. Smad3(-/-) mice are deficient in the transforming growth factor beta (TGFβ) signaling molecule, SMAD3, resulting in dysregulation of the cellular pathway most commonly affected in human colorectal cancer, and develop inflammation-associated colon cancer. Previous studies have shown a requirement for a bacterial trigger for the colitis and colon cancer phenotype in Smad3(-/-) mice. Studies presented here in Smad3(-/-) mice detail disease induction with DSS, without the use of AOM, and show a) Smad3(-/-) mice develop a spectrum of lesions ranging from acute and chronic colitis, crypt herniation, repair, dysplasia, adenomatous polyps, disseminated peritoneal adenomucinosis, adenocarcinoma, mucinous adenocarcinoma (MAC) and squamous metaplasia; b) the colon lesions have variable galactin-3 (Mac2) staining c) increased DSS concentration and duration of exposure leads to increased severity of colonic lesions; d) heterozygosity of SMAD3 does not confer increased susceptibility to DSS-induced disease and e) disease is partially controlled by the presence of T and B cells as Smad3(-/-) Rag2(-/-) double knock out (DKO) mice develop a more severe disease phenotype. DSS-induced disease in Smad3(-/-) mice may be a useful animal model to study not only inflammation-driven MAC but other human diseases such as colitis cystica profunda (CCP) and pseudomyxomatous peritonei (PMP).

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Histopathology scores of DSS-treated Smad3−/− and Smad3/Rag-DKO mice treated with different doses of DSS.Smad3+/−, Smad3−/− and Smad3/Rag-DKO (DKO) mice were treated with either a single DSS cycle or 9 cycles of DSS. Experimental endpoint was 17 weeks. A) IBD score, B) Invasion score, C) Summed dysplasia score and (D) Distribution score (as described in materials and methods) are shown for individuals in each treatment group. Negative control groups were all statistically different (significance not shown in figure) from their respective DSS-treated group except for untreated water vs. 1.5% DSS Smad3−/− in (B). *P≤0.05, **P≤0.01.
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pone-0079182-g002: Histopathology scores of DSS-treated Smad3−/− and Smad3/Rag-DKO mice treated with different doses of DSS.Smad3+/−, Smad3−/− and Smad3/Rag-DKO (DKO) mice were treated with either a single DSS cycle or 9 cycles of DSS. Experimental endpoint was 17 weeks. A) IBD score, B) Invasion score, C) Summed dysplasia score and (D) Distribution score (as described in materials and methods) are shown for individuals in each treatment group. Negative control groups were all statistically different (significance not shown in figure) from their respective DSS-treated group except for untreated water vs. 1.5% DSS Smad3−/− in (B). *P≤0.05, **P≤0.01.

Mentions: In order to investigate the role of T and B cells in inflammation and tumor development in this model, we compared DSS-induced disease in Smad3−/− and Smad3/Rag-DKO mice using two different DSS regimens (single cycle of 1.5% DSS for 7 days or 9 cycles of 1.5% DSS). A comparison of scores between Smad3−/− and Smad3/Rag-DKO mice are shown in Figure 2. Exposure to DSS cycles resulted in significantly higher IBD scores in both Smad3−/− and Smad3/Rag-DKO mice when compared to single DSS exposures (Figure 2A). IBD scores were not significantly different between DSS-treated Smad3−/− and Smad3/Rag-DKO mice (Figure 2a), although increased invasion scores, dysplasia scores and distribution of high grade dysplasia were seen in Smad3/Rag-DKO when compared to Smad3−/− (Figure 2A–D). Generally, repeated exposure to DSS (cycles) was associated with higher IBD scores (Figure 2A), invasion scores (Figure 2B), dysplasia scores (Figure 2C) and increased distribution of high grade dysplasia throughout the colon (Figure 2D).


Characterization of dextran sodium sulfate-induced inflammation and colonic tumorigenesis in Smad3(-/-) mice with dysregulated TGFβ.

Seamons A, Treuting PM, Brabb T, Maggio-Price L - PLoS ONE (2013)

Histopathology scores of DSS-treated Smad3−/− and Smad3/Rag-DKO mice treated with different doses of DSS.Smad3+/−, Smad3−/− and Smad3/Rag-DKO (DKO) mice were treated with either a single DSS cycle or 9 cycles of DSS. Experimental endpoint was 17 weeks. A) IBD score, B) Invasion score, C) Summed dysplasia score and (D) Distribution score (as described in materials and methods) are shown for individuals in each treatment group. Negative control groups were all statistically different (significance not shown in figure) from their respective DSS-treated group except for untreated water vs. 1.5% DSS Smad3−/− in (B). *P≤0.05, **P≤0.01.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3823566&req=5

pone-0079182-g002: Histopathology scores of DSS-treated Smad3−/− and Smad3/Rag-DKO mice treated with different doses of DSS.Smad3+/−, Smad3−/− and Smad3/Rag-DKO (DKO) mice were treated with either a single DSS cycle or 9 cycles of DSS. Experimental endpoint was 17 weeks. A) IBD score, B) Invasion score, C) Summed dysplasia score and (D) Distribution score (as described in materials and methods) are shown for individuals in each treatment group. Negative control groups were all statistically different (significance not shown in figure) from their respective DSS-treated group except for untreated water vs. 1.5% DSS Smad3−/− in (B). *P≤0.05, **P≤0.01.
Mentions: In order to investigate the role of T and B cells in inflammation and tumor development in this model, we compared DSS-induced disease in Smad3−/− and Smad3/Rag-DKO mice using two different DSS regimens (single cycle of 1.5% DSS for 7 days or 9 cycles of 1.5% DSS). A comparison of scores between Smad3−/− and Smad3/Rag-DKO mice are shown in Figure 2. Exposure to DSS cycles resulted in significantly higher IBD scores in both Smad3−/− and Smad3/Rag-DKO mice when compared to single DSS exposures (Figure 2A). IBD scores were not significantly different between DSS-treated Smad3−/− and Smad3/Rag-DKO mice (Figure 2a), although increased invasion scores, dysplasia scores and distribution of high grade dysplasia were seen in Smad3/Rag-DKO when compared to Smad3−/− (Figure 2A–D). Generally, repeated exposure to DSS (cycles) was associated with higher IBD scores (Figure 2A), invasion scores (Figure 2B), dysplasia scores (Figure 2C) and increased distribution of high grade dysplasia throughout the colon (Figure 2D).

Bottom Line: There are few mouse models that adequately mimic large bowel cancer in humans or the gastrointestinal inflammation which frequently precedes it.Smad3(-/-) mice are deficient in the transforming growth factor beta (TGFβ) signaling molecule, SMAD3, resulting in dysregulation of the cellular pathway most commonly affected in human colorectal cancer, and develop inflammation-associated colon cancer.Studies presented here in Smad3(-/-) mice detail disease induction with DSS, without the use of AOM, and show a) Smad3(-/-) mice develop a spectrum of lesions ranging from acute and chronic colitis, crypt herniation, repair, dysplasia, adenomatous polyps, disseminated peritoneal adenomucinosis, adenocarcinoma, mucinous adenocarcinoma (MAC) and squamous metaplasia; b) the colon lesions have variable galactin-3 (Mac2) staining c) increased DSS concentration and duration of exposure leads to increased severity of colonic lesions; d) heterozygosity of SMAD3 does not confer increased susceptibility to DSS-induced disease and e) disease is partially controlled by the presence of T and B cells as Smad3(-/-) Rag2(-/-) double knock out (DKO) mice develop a more severe disease phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
There are few mouse models that adequately mimic large bowel cancer in humans or the gastrointestinal inflammation which frequently precedes it. Dextran sodium sulphate (DSS)-induces colitis in many animal models and has been used in combination with the carcinogen azoxymethane (AOM) to induce cancer in mice. Smad3(-/-) mice are deficient in the transforming growth factor beta (TGFβ) signaling molecule, SMAD3, resulting in dysregulation of the cellular pathway most commonly affected in human colorectal cancer, and develop inflammation-associated colon cancer. Previous studies have shown a requirement for a bacterial trigger for the colitis and colon cancer phenotype in Smad3(-/-) mice. Studies presented here in Smad3(-/-) mice detail disease induction with DSS, without the use of AOM, and show a) Smad3(-/-) mice develop a spectrum of lesions ranging from acute and chronic colitis, crypt herniation, repair, dysplasia, adenomatous polyps, disseminated peritoneal adenomucinosis, adenocarcinoma, mucinous adenocarcinoma (MAC) and squamous metaplasia; b) the colon lesions have variable galactin-3 (Mac2) staining c) increased DSS concentration and duration of exposure leads to increased severity of colonic lesions; d) heterozygosity of SMAD3 does not confer increased susceptibility to DSS-induced disease and e) disease is partially controlled by the presence of T and B cells as Smad3(-/-) Rag2(-/-) double knock out (DKO) mice develop a more severe disease phenotype. DSS-induced disease in Smad3(-/-) mice may be a useful animal model to study not only inflammation-driven MAC but other human diseases such as colitis cystica profunda (CCP) and pseudomyxomatous peritonei (PMP).

Show MeSH
Related in: MedlinePlus