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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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Characteristics of acute typhlocolitis induced by DSS.(A) Smad3−/−1.5% DSS. Cecum (Ce) and colon (PC, proximal; MC, mid; DC, distal; A, anus). The cecum is contracted with darkly discolored contents. The colon lacks formed fecal pellets. The mid and distal colon are thickened and turgid. (B) Smad3+/−3% DSS. Subgross hematoxylin and eosin-stained section of DSS-exposed colon. The cecum has been removed. The mid and distal colon the luminal (L) contents are fluid with no formed fecal pellets. The submucosa (arrow) is markedly expanded by edema. (C) Smad3+/−3% DSS. Mid colon at the junction of erosive mucosal loss and effacement by inflammatory cells adjacent to intact mucosa (M). Note the muscularis mucosae (arrowheads) and the expansion of the submucosa (*) with inflammatory cells. Tunica muscularis as indicted (TM). (D) Smad3+/−3% DSS. Exudate adherent to ulcerated mucosa contains degenerate inflammatory cells, erythrocytes, fibrin and proteinaceous fluid with hazy coccoid bacterial colonies (arrow). (E) Smad3−/−3%DSS. Chronic-active proliferative and ulcerative colitis. The mucosa adjacent to an ulcer is proliferative with irregular and angular glands with loss of goblet cells, and increased mitotic figures. (F) Smad3−/−1.5% DSS. Glands adjacent to areas of active inflammation are classified as indefinite for dysplasia due to active inflammatory milieu. Dilated crypt filled with filamentous bacteria with a portion escaping into the adjacent lamina propria/submucosa (arrow).
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pone-0079182-g003: Characteristics of acute typhlocolitis induced by DSS.(A) Smad3−/−1.5% DSS. Cecum (Ce) and colon (PC, proximal; MC, mid; DC, distal; A, anus). The cecum is contracted with darkly discolored contents. The colon lacks formed fecal pellets. The mid and distal colon are thickened and turgid. (B) Smad3+/−3% DSS. Subgross hematoxylin and eosin-stained section of DSS-exposed colon. The cecum has been removed. The mid and distal colon the luminal (L) contents are fluid with no formed fecal pellets. The submucosa (arrow) is markedly expanded by edema. (C) Smad3+/−3% DSS. Mid colon at the junction of erosive mucosal loss and effacement by inflammatory cells adjacent to intact mucosa (M). Note the muscularis mucosae (arrowheads) and the expansion of the submucosa (*) with inflammatory cells. Tunica muscularis as indicted (TM). (D) Smad3+/−3% DSS. Exudate adherent to ulcerated mucosa contains degenerate inflammatory cells, erythrocytes, fibrin and proteinaceous fluid with hazy coccoid bacterial colonies (arrow). (E) Smad3−/−3%DSS. Chronic-active proliferative and ulcerative colitis. The mucosa adjacent to an ulcer is proliferative with irregular and angular glands with loss of goblet cells, and increased mitotic figures. (F) Smad3−/−1.5% DSS. Glands adjacent to areas of active inflammation are classified as indefinite for dysplasia due to active inflammatory milieu. Dilated crypt filled with filamentous bacteria with a portion escaping into the adjacent lamina propria/submucosa (arrow).

Mentions: Acute changes induced by DSS in the Smad3−/− and Smad3+/− mice are consistent with those previously reported in other DSS models [19], [25], [26]. Acute colitis grossly presented with turgid and thickened colons often with contracted ceca and devoid of formed fecal pellets (Figure 3A). Histologically acute lesions included erosive to necroulcerative typhlocolitis with variable intralumenal hemorrhages, fibrin and cellular debris (Figure 3 B–D). In the subacute phase, epithelial proliferation was present and often associated with active areas of ulceration (Figure 3E–F). Over time, the mice developed chronic typhlocolitis with secondary lesions such as intussusceptions, obstruction and serosal masses, however, this was rarely seen in Smad3+/− animals (Figure 4 A–C). Chronic lesions included mucosal proliferation, dense intramucosal inflammatory infiltrates, epithelial dysplasia, and distal colon squamous metaplasia (Figure 4 D–I).


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)

Characteristics of acute typhlocolitis induced by DSS.(A) Smad3−/−1.5% DSS. Cecum (Ce) and colon (PC, proximal; MC, mid; DC, distal; A, anus). The cecum is contracted with darkly discolored contents. The colon lacks formed fecal pellets. The mid and distal colon are thickened and turgid. (B) Smad3+/−3% DSS. Subgross hematoxylin and eosin-stained section of DSS-exposed colon. The cecum has been removed. The mid and distal colon the luminal (L) contents are fluid with no formed fecal pellets. The submucosa (arrow) is markedly expanded by edema. (C) Smad3+/−3% DSS. Mid colon at the junction of erosive mucosal loss and effacement by inflammatory cells adjacent to intact mucosa (M). Note the muscularis mucosae (arrowheads) and the expansion of the submucosa (*) with inflammatory cells. Tunica muscularis as indicted (TM). (D) Smad3+/−3% DSS. Exudate adherent to ulcerated mucosa contains degenerate inflammatory cells, erythrocytes, fibrin and proteinaceous fluid with hazy coccoid bacterial colonies (arrow). (E) Smad3−/−3%DSS. Chronic-active proliferative and ulcerative colitis. The mucosa adjacent to an ulcer is proliferative with irregular and angular glands with loss of goblet cells, and increased mitotic figures. (F) Smad3−/−1.5% DSS. Glands adjacent to areas of active inflammation are classified as indefinite for dysplasia due to active inflammatory milieu. Dilated crypt filled with filamentous bacteria with a portion escaping into the adjacent lamina propria/submucosa (arrow).
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Related In: Results  -  Collection

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pone-0079182-g003: Characteristics of acute typhlocolitis induced by DSS.(A) Smad3−/−1.5% DSS. Cecum (Ce) and colon (PC, proximal; MC, mid; DC, distal; A, anus). The cecum is contracted with darkly discolored contents. The colon lacks formed fecal pellets. The mid and distal colon are thickened and turgid. (B) Smad3+/−3% DSS. Subgross hematoxylin and eosin-stained section of DSS-exposed colon. The cecum has been removed. The mid and distal colon the luminal (L) contents are fluid with no formed fecal pellets. The submucosa (arrow) is markedly expanded by edema. (C) Smad3+/−3% DSS. Mid colon at the junction of erosive mucosal loss and effacement by inflammatory cells adjacent to intact mucosa (M). Note the muscularis mucosae (arrowheads) and the expansion of the submucosa (*) with inflammatory cells. Tunica muscularis as indicted (TM). (D) Smad3+/−3% DSS. Exudate adherent to ulcerated mucosa contains degenerate inflammatory cells, erythrocytes, fibrin and proteinaceous fluid with hazy coccoid bacterial colonies (arrow). (E) Smad3−/−3%DSS. Chronic-active proliferative and ulcerative colitis. The mucosa adjacent to an ulcer is proliferative with irregular and angular glands with loss of goblet cells, and increased mitotic figures. (F) Smad3−/−1.5% DSS. Glands adjacent to areas of active inflammation are classified as indefinite for dysplasia due to active inflammatory milieu. Dilated crypt filled with filamentous bacteria with a portion escaping into the adjacent lamina propria/submucosa (arrow).
Mentions: Acute changes induced by DSS in the Smad3−/− and Smad3+/− mice are consistent with those previously reported in other DSS models [19], [25], [26]. Acute colitis grossly presented with turgid and thickened colons often with contracted ceca and devoid of formed fecal pellets (Figure 3A). Histologically acute lesions included erosive to necroulcerative typhlocolitis with variable intralumenal hemorrhages, fibrin and cellular debris (Figure 3 B–D). In the subacute phase, epithelial proliferation was present and often associated with active areas of ulceration (Figure 3E–F). Over time, the mice developed chronic typhlocolitis with secondary lesions such as intussusceptions, obstruction and serosal masses, however, this was rarely seen in Smad3+/− animals (Figure 4 A–C). Chronic lesions included mucosal proliferation, dense intramucosal inflammatory infiltrates, epithelial dysplasia, and distal colon squamous metaplasia (Figure 4 D–I).

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