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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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Mucinous neoplasia and high grade dysplasia induced by DSS.(A) Smad3/Rag-DKO DSS cycles. A cecal-colic multicystic mass (arrow) is present adjacent to the pancreas (asterisk). (B) Smad3/Rag-DKO 1.5%DSS. Multiple serosal masses are indicated on the mid to distal colon. (C) Smad−/− DSS cycles. A large multicystic mesenteric mass. (D) Smad−/− DSS cycles. Expansile mass in (A). Pancreas (asterisk) and mesenteric lymph node (upper right). Box region presented in (G). (E) Herniated proliferative mucosa (H) with compression the tunica muscularis (TM) with preservation of the submucosa (arrowhead). At left are invasive angular glands, dissecting mucin in the TM with focal penetration of the serosa (S) and intraperitoneal mucus (asterisk). (F) Smad−/− DSS cycles. Mesenteric implant of mucinous cysts (asterisk) with mucin-producing epithelial lined glands (arrowheads). Note abscess (A) and mesenteric lymph node (ML). (G) Boxed region in (D). Note dissecting lakes of mucin and isolated epithelium and epithelial rafts within the cysts. (H) Higher magnification of asterisked region in (F). (I) Smad3+/−3%DSS. Within mesenteric cysts are free large round cells (arrowhead) and clumps of basophilic cells (arrow) and rare signet rings (inset, Smad3−/− DSS cycles) (J) Foci of high grade dysplasia with in a hyperplastic polyp.
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pone-0079182-g005: Mucinous neoplasia and high grade dysplasia induced by DSS.(A) Smad3/Rag-DKO DSS cycles. A cecal-colic multicystic mass (arrow) is present adjacent to the pancreas (asterisk). (B) Smad3/Rag-DKO 1.5%DSS. Multiple serosal masses are indicated on the mid to distal colon. (C) Smad−/− DSS cycles. A large multicystic mesenteric mass. (D) Smad−/− DSS cycles. Expansile mass in (A). Pancreas (asterisk) and mesenteric lymph node (upper right). Box region presented in (G). (E) Herniated proliferative mucosa (H) with compression the tunica muscularis (TM) with preservation of the submucosa (arrowhead). At left are invasive angular glands, dissecting mucin in the TM with focal penetration of the serosa (S) and intraperitoneal mucus (asterisk). (F) Smad−/− DSS cycles. Mesenteric implant of mucinous cysts (asterisk) with mucin-producing epithelial lined glands (arrowheads). Note abscess (A) and mesenteric lymph node (ML). (G) Boxed region in (D). Note dissecting lakes of mucin and isolated epithelium and epithelial rafts within the cysts. (H) Higher magnification of asterisked region in (F). (I) Smad3+/−3%DSS. Within mesenteric cysts are free large round cells (arrowhead) and clumps of basophilic cells (arrow) and rare signet rings (inset, Smad3−/− DSS cycles) (J) Foci of high grade dysplasia with in a hyperplastic polyp.

Mentions: Neoplastic lesions noted in these studies are similar to those we previously reported with H. bilis infection [16], [17]. While neoplasia induced by H. bilis infection are primarily located in the proximal cecocolic junction [16], the preferred niche for Helicobacter, DSS-induced tumors occurred in multiple locations, including the proximal, mid and distal colon (Figure 5 A–C). Grossly, the larger masses were characterized as either multilocular straw-colored gelatinous masses with a grape cluster-like appearance (Figure 5A) or unilocular cream-colored and firm masses (Figure 5B and C) protruding into the serosa and expanding the attached mesentery. Histologically, opaque masses were often inflamed with numerous macrophages and variable neutrophils, whereas clear cysts were characterized as mucin-filled cysts lined by normal to mildly dysplastic epithelium and no associated inflammation. Most well-developed neoplasias were MAC (Figure 5 A–I); rarely, solid adenocarcinomas were also noted (Figure 5 J). The characteristic mucinous adenocarcinomas were composed of multiple mucin-filled cysts, lined by neoplastic epithelial cells and within mesenteric cysts were numerous large round cells with abundant foamy cytoplasm. Cysts were present within and penetrating the colonic muscular tunics and serosa. Often there was marked expansion into and compression of the mesentery and peritoneal structures including lymph nodes and occasionally the pancreas (Figure 5D). Free and dissecting mucus, mucin pools with isolated floating cells and a desmoplastic response were frequent (Figure 5 G and H). The epithelium lining the peritoneal cysts varied from well-differentiated to mildly dysplastic colonic epithelium with abundant mucus-producing cells and rare signet rings (Figure 5 G–I). Infrequently, free peritoneal mucous or epithelial lined mucus-filled cysts were noted in an individual animal with no evidence of a primary focus in the tissues examined histologically.


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)

Mucinous neoplasia and high grade dysplasia induced by DSS.(A) Smad3/Rag-DKO DSS cycles. A cecal-colic multicystic mass (arrow) is present adjacent to the pancreas (asterisk). (B) Smad3/Rag-DKO 1.5%DSS. Multiple serosal masses are indicated on the mid to distal colon. (C) Smad−/− DSS cycles. A large multicystic mesenteric mass. (D) Smad−/− DSS cycles. Expansile mass in (A). Pancreas (asterisk) and mesenteric lymph node (upper right). Box region presented in (G). (E) Herniated proliferative mucosa (H) with compression the tunica muscularis (TM) with preservation of the submucosa (arrowhead). At left are invasive angular glands, dissecting mucin in the TM with focal penetration of the serosa (S) and intraperitoneal mucus (asterisk). (F) Smad−/− DSS cycles. Mesenteric implant of mucinous cysts (asterisk) with mucin-producing epithelial lined glands (arrowheads). Note abscess (A) and mesenteric lymph node (ML). (G) Boxed region in (D). Note dissecting lakes of mucin and isolated epithelium and epithelial rafts within the cysts. (H) Higher magnification of asterisked region in (F). (I) Smad3+/−3%DSS. Within mesenteric cysts are free large round cells (arrowhead) and clumps of basophilic cells (arrow) and rare signet rings (inset, Smad3−/− DSS cycles) (J) Foci of high grade dysplasia with in a hyperplastic polyp.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0079182-g005: Mucinous neoplasia and high grade dysplasia induced by DSS.(A) Smad3/Rag-DKO DSS cycles. A cecal-colic multicystic mass (arrow) is present adjacent to the pancreas (asterisk). (B) Smad3/Rag-DKO 1.5%DSS. Multiple serosal masses are indicated on the mid to distal colon. (C) Smad−/− DSS cycles. A large multicystic mesenteric mass. (D) Smad−/− DSS cycles. Expansile mass in (A). Pancreas (asterisk) and mesenteric lymph node (upper right). Box region presented in (G). (E) Herniated proliferative mucosa (H) with compression the tunica muscularis (TM) with preservation of the submucosa (arrowhead). At left are invasive angular glands, dissecting mucin in the TM with focal penetration of the serosa (S) and intraperitoneal mucus (asterisk). (F) Smad−/− DSS cycles. Mesenteric implant of mucinous cysts (asterisk) with mucin-producing epithelial lined glands (arrowheads). Note abscess (A) and mesenteric lymph node (ML). (G) Boxed region in (D). Note dissecting lakes of mucin and isolated epithelium and epithelial rafts within the cysts. (H) Higher magnification of asterisked region in (F). (I) Smad3+/−3%DSS. Within mesenteric cysts are free large round cells (arrowhead) and clumps of basophilic cells (arrow) and rare signet rings (inset, Smad3−/− DSS cycles) (J) Foci of high grade dysplasia with in a hyperplastic polyp.
Mentions: Neoplastic lesions noted in these studies are similar to those we previously reported with H. bilis infection [16], [17]. While neoplasia induced by H. bilis infection are primarily located in the proximal cecocolic junction [16], the preferred niche for Helicobacter, DSS-induced tumors occurred in multiple locations, including the proximal, mid and distal colon (Figure 5 A–C). Grossly, the larger masses were characterized as either multilocular straw-colored gelatinous masses with a grape cluster-like appearance (Figure 5A) or unilocular cream-colored and firm masses (Figure 5B and C) protruding into the serosa and expanding the attached mesentery. Histologically, opaque masses were often inflamed with numerous macrophages and variable neutrophils, whereas clear cysts were characterized as mucin-filled cysts lined by normal to mildly dysplastic epithelium and no associated inflammation. Most well-developed neoplasias were MAC (Figure 5 A–I); rarely, solid adenocarcinomas were also noted (Figure 5 J). The characteristic mucinous adenocarcinomas were composed of multiple mucin-filled cysts, lined by neoplastic epithelial cells and within mesenteric cysts were numerous large round cells with abundant foamy cytoplasm. Cysts were present within and penetrating the colonic muscular tunics and serosa. Often there was marked expansion into and compression of the mesentery and peritoneal structures including lymph nodes and occasionally the pancreas (Figure 5D). Free and dissecting mucus, mucin pools with isolated floating cells and a desmoplastic response were frequent (Figure 5 G and H). The epithelium lining the peritoneal cysts varied from well-differentiated to mildly dysplastic colonic epithelium with abundant mucus-producing cells and rare signet rings (Figure 5 G–I). Infrequently, free peritoneal mucous or epithelial lined mucus-filled cysts were noted in an individual animal with no evidence of a primary focus in the tissues examined histologically.

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