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Suppression of Tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis.

Kosa P, Szabo R, Molinolo AA, Bugge TH - Oncogene (2011)

Bottom Line: Colitis-associated colorectal cancers are an etiologically distinct subgroup of colon cancers that occur in individuals suffering from inflammatory bowel disease and arise as a consequence of persistent exposure of hyperproliferative epithelial stem cells to an inflammatory microenvironment.Matriptase is a membrane-anchored serine protease encoded by Suppression of Tumorigenicity-14 (ST14) that strengthens the intestinal epithelial barrier by promoting tight junction formation.This study demonstrates that inflammation-associated colon carcinogenesis can be initiated and promoted solely by an intrinsic intestinal permeability barrier perturbation, establishes St14 as a critical tumor-suppressor gene in the mouse gastrointestinal tract and adds matriptase to the expanding list of pericellular proteases with tumor-suppressive functions.

View Article: PubMed Central - PubMed

Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
Colitis-associated colorectal cancers are an etiologically distinct subgroup of colon cancers that occur in individuals suffering from inflammatory bowel disease and arise as a consequence of persistent exposure of hyperproliferative epithelial stem cells to an inflammatory microenvironment. An intrinsic defect in the intestinal epithelial barrier has been proposed to be one of several factors that contribute to the inappropriate immune response to the commensal microbiota that underlies inflammatory bowel disease. Matriptase is a membrane-anchored serine protease encoded by Suppression of Tumorigenicity-14 (ST14) that strengthens the intestinal epithelial barrier by promoting tight junction formation. Here, we show that intestinal epithelial-specific ablation of St14 in mice causes formation of colon adenocarcinoma with very early onset and high penetrance. Neoplastic progression is preceded by a chronic inflammation of the colon that resembles human inflammatory bowel disease and is promoted by the commensal microbiota. This study demonstrates that inflammation-associated colon carcinogenesis can be initiated and promoted solely by an intrinsic intestinal permeability barrier perturbation, establishes St14 as a critical tumor-suppressor gene in the mouse gastrointestinal tract and adds matriptase to the expanding list of pericellular proteases with tumor-suppressive functions.

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Rapid and spontaneous malignant transformation of St14-ablated colonic epithelium(a) Representative example of adenocarcinoma in the large intestine of an eight week old St14− mouse. Tumor cells invading the muscularis externa (star) are shown with arrows. (b) The epithelial origin of the tumor cells invading the muscularis externa (star) is demonstrated by immunohistochemical staining for keratin (examples with arrows). (c) Combined immunohistochemical staining for keratin in red (examples with arrows) and the lymphatic vessel marker LYVE-1 in brown (examples with arrowheads) shows invasion of malignant cells into lymphatic vessels of a seven week old St14− mouse. Scale bar for a, b, and c = 100 μm. (d) Enumeration of colonic lesions in four to 18 week old St14+ (left) and littermate St14− mice (right), showing adenocarcinoma with lymphatic invasion in 6, adenocarcinoma without lymphatic invasion in 2, and regenerative atypia in the remaining 16 St14− mice. See Table 1 for additional details.
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Figure 2: Rapid and spontaneous malignant transformation of St14-ablated colonic epithelium(a) Representative example of adenocarcinoma in the large intestine of an eight week old St14− mouse. Tumor cells invading the muscularis externa (star) are shown with arrows. (b) The epithelial origin of the tumor cells invading the muscularis externa (star) is demonstrated by immunohistochemical staining for keratin (examples with arrows). (c) Combined immunohistochemical staining for keratin in red (examples with arrows) and the lymphatic vessel marker LYVE-1 in brown (examples with arrowheads) shows invasion of malignant cells into lymphatic vessels of a seven week old St14− mouse. Scale bar for a, b, and c = 100 μm. (d) Enumeration of colonic lesions in four to 18 week old St14+ (left) and littermate St14− mice (right), showing adenocarcinoma with lymphatic invasion in 6, adenocarcinoma without lymphatic invasion in 2, and regenerative atypia in the remaining 16 St14− mice. See Table 1 for additional details.

Mentions: Unexpectedly, histological analysis of moribund St14− mice revealed the presence of invasive adenocarcinoma of the colon in 8 of 24 (33%) of St14− mice examined at four to 18 weeks of age (Table 1, Figure 2a, b, and d) and dysplastic colonic epithelium (regenerative atypia) in the remaining 16 mice (Table 1 and Figure 2d). Remarkably, in light of the fact that these mice were not carcinogen treated or exposed to other insults to the intestinal tract, adenocarcinoma could be found in mice less than five weeks of age (Table 1). All adenocarcinomas had progressed to invade the muscularis mucosae underlying the colonic epithelium and the subadjacent muscularis externa (Figure 2a and b). Furthermore, in six of eight (75%) adenocarcinomas examined, the tumor cells had infiltrated the lymphatic vasculature, as revealed by combined immunohistochemical staining with pan-keratin antibodies and antibodies against the lymphatic endothelial marker, LYVE-1 (Table 1 and Figure 2c and d). The tumors displayed many hallmarks of human colitis-associated colon cancer, including activation of β-catenin (Figure 3a and a′), dysorganized basement membrane deposition (Figure 3b and b′), fibrosis (Figure 3c and c′), severe dysplasia with abundant atypical mitosis (Figure 3d), epithelial hyperproliferation (Figure 4a and a′), loss of terminal differentiation (Figure 4b and b′), and chronic inflammatory cell infiltrates (Figure 4c and c′, d and d′). Importantly, the small intestine was histologically unremarkable in all mice examined (data not shown), although St14 was efficiently ablated also from this tissue (Supplementary Figure 1d and e). Taken together, these data show that St14 is a critical tissue-specific tumor suppressor gene in the mouse intestine that suppresses the formation of early, invasive adenocarcinomas of the colon.


Suppression of Tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis.

Kosa P, Szabo R, Molinolo AA, Bugge TH - Oncogene (2011)

Rapid and spontaneous malignant transformation of St14-ablated colonic epithelium(a) Representative example of adenocarcinoma in the large intestine of an eight week old St14− mouse. Tumor cells invading the muscularis externa (star) are shown with arrows. (b) The epithelial origin of the tumor cells invading the muscularis externa (star) is demonstrated by immunohistochemical staining for keratin (examples with arrows). (c) Combined immunohistochemical staining for keratin in red (examples with arrows) and the lymphatic vessel marker LYVE-1 in brown (examples with arrowheads) shows invasion of malignant cells into lymphatic vessels of a seven week old St14− mouse. Scale bar for a, b, and c = 100 μm. (d) Enumeration of colonic lesions in four to 18 week old St14+ (left) and littermate St14− mice (right), showing adenocarcinoma with lymphatic invasion in 6, adenocarcinoma without lymphatic invasion in 2, and regenerative atypia in the remaining 16 St14− mice. See Table 1 for additional details.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3299858&req=5

Figure 2: Rapid and spontaneous malignant transformation of St14-ablated colonic epithelium(a) Representative example of adenocarcinoma in the large intestine of an eight week old St14− mouse. Tumor cells invading the muscularis externa (star) are shown with arrows. (b) The epithelial origin of the tumor cells invading the muscularis externa (star) is demonstrated by immunohistochemical staining for keratin (examples with arrows). (c) Combined immunohistochemical staining for keratin in red (examples with arrows) and the lymphatic vessel marker LYVE-1 in brown (examples with arrowheads) shows invasion of malignant cells into lymphatic vessels of a seven week old St14− mouse. Scale bar for a, b, and c = 100 μm. (d) Enumeration of colonic lesions in four to 18 week old St14+ (left) and littermate St14− mice (right), showing adenocarcinoma with lymphatic invasion in 6, adenocarcinoma without lymphatic invasion in 2, and regenerative atypia in the remaining 16 St14− mice. See Table 1 for additional details.
Mentions: Unexpectedly, histological analysis of moribund St14− mice revealed the presence of invasive adenocarcinoma of the colon in 8 of 24 (33%) of St14− mice examined at four to 18 weeks of age (Table 1, Figure 2a, b, and d) and dysplastic colonic epithelium (regenerative atypia) in the remaining 16 mice (Table 1 and Figure 2d). Remarkably, in light of the fact that these mice were not carcinogen treated or exposed to other insults to the intestinal tract, adenocarcinoma could be found in mice less than five weeks of age (Table 1). All adenocarcinomas had progressed to invade the muscularis mucosae underlying the colonic epithelium and the subadjacent muscularis externa (Figure 2a and b). Furthermore, in six of eight (75%) adenocarcinomas examined, the tumor cells had infiltrated the lymphatic vasculature, as revealed by combined immunohistochemical staining with pan-keratin antibodies and antibodies against the lymphatic endothelial marker, LYVE-1 (Table 1 and Figure 2c and d). The tumors displayed many hallmarks of human colitis-associated colon cancer, including activation of β-catenin (Figure 3a and a′), dysorganized basement membrane deposition (Figure 3b and b′), fibrosis (Figure 3c and c′), severe dysplasia with abundant atypical mitosis (Figure 3d), epithelial hyperproliferation (Figure 4a and a′), loss of terminal differentiation (Figure 4b and b′), and chronic inflammatory cell infiltrates (Figure 4c and c′, d and d′). Importantly, the small intestine was histologically unremarkable in all mice examined (data not shown), although St14 was efficiently ablated also from this tissue (Supplementary Figure 1d and e). Taken together, these data show that St14 is a critical tissue-specific tumor suppressor gene in the mouse intestine that suppresses the formation of early, invasive adenocarcinomas of the colon.

Bottom Line: Colitis-associated colorectal cancers are an etiologically distinct subgroup of colon cancers that occur in individuals suffering from inflammatory bowel disease and arise as a consequence of persistent exposure of hyperproliferative epithelial stem cells to an inflammatory microenvironment.Matriptase is a membrane-anchored serine protease encoded by Suppression of Tumorigenicity-14 (ST14) that strengthens the intestinal epithelial barrier by promoting tight junction formation.This study demonstrates that inflammation-associated colon carcinogenesis can be initiated and promoted solely by an intrinsic intestinal permeability barrier perturbation, establishes St14 as a critical tumor-suppressor gene in the mouse gastrointestinal tract and adds matriptase to the expanding list of pericellular proteases with tumor-suppressive functions.

View Article: PubMed Central - PubMed

Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
Colitis-associated colorectal cancers are an etiologically distinct subgroup of colon cancers that occur in individuals suffering from inflammatory bowel disease and arise as a consequence of persistent exposure of hyperproliferative epithelial stem cells to an inflammatory microenvironment. An intrinsic defect in the intestinal epithelial barrier has been proposed to be one of several factors that contribute to the inappropriate immune response to the commensal microbiota that underlies inflammatory bowel disease. Matriptase is a membrane-anchored serine protease encoded by Suppression of Tumorigenicity-14 (ST14) that strengthens the intestinal epithelial barrier by promoting tight junction formation. Here, we show that intestinal epithelial-specific ablation of St14 in mice causes formation of colon adenocarcinoma with very early onset and high penetrance. Neoplastic progression is preceded by a chronic inflammation of the colon that resembles human inflammatory bowel disease and is promoted by the commensal microbiota. This study demonstrates that inflammation-associated colon carcinogenesis can be initiated and promoted solely by an intrinsic intestinal permeability barrier perturbation, establishes St14 as a critical tumor-suppressor gene in the mouse gastrointestinal tract and adds matriptase to the expanding list of pericellular proteases with tumor-suppressive functions.

Show MeSH
Related in: MedlinePlus