Characterization of Dextran Sodium Sulfate-Induced Inflammation and Colonic Tumorigenesis in Smad3−/− Mice with Dysregulated TGFβ

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).

Thiadiazolidinone-8 Ameliorates Inflammation Associated with Experimental Colitis in Mice

“…The intestine samples were fixed in 10% phosphate-buffered formalin, processed routinely for paraffin embedding, sectioned at 5 µm, and stained with hematoxylin and eosin. Sections of distal colon were evaluated based on adapted criteria of Corazza et al [14] and Seamons et al [15]. The histopathological score of lesions was partially scored (0-4 increasing severity) with some parameters, namely, (1) presence of tissue loss/necrosis, (2) severity of mucosal epithelial lesion, (3) inflammation, (4) extent 1 - the percentage of intestine affected in any manner, and (5) extent 2 - the percentage of intestine affected by the most severe lesion.…”

Anti‐Inflammatory Effect of Erythropoietin in the TNBS‐induced Colitis

“…The intestine samples were fixed in 10% phosphate‐buffered formalin, processed routinely for paraffin embedding, sectioned at 5 μm and stained with haematoxylin and eosin. Longitudinal sections of distal colon were evaluated based on adapted criteria of Corazza (1999) and Seamons (2013) and colleagues . The histopathological score of lesions were partially scored (0–4 increasing severity) with some parameters, namely: (1) presence of tissue loss/necrosis, (2) severity of mucosal epithelial lesion, (3) inflammation, (4) extent 1 – the percentage of intestine affected in any manner and (5) extent 2 – the percentage of intestine affected by the most severe lesion.…”

Genetic Suppression of Inflammation Blocks the Tumor-Promoting Effects of TGF-β in Gastric Tissue

“…Therefore, increased cell proliferation as measured by two markers, correlated with the degree of inflammation. The potential complexity of the contribution of inflammation to tumor production is further highlighted in a recent paper (27) that reported that tumor production in Smad3 −/− mice was enhanced in Smad3 −/− ;Rag2 −/− mice (27). …”