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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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Progressive postnatal loss of epithelial integrity of matriptase-ablated colon precedes malignant transformationHistological appearance of St14+ (a–e) and littermate St14− (a′-e′) colons at postnatal day 0 (a,a′), 5 (b,b′), 10 (c,c′), 15 (d,d′), and 20 (e,e′). No histological differences can be observed between normal and matriptase-ablated colon at days 0 and 5 (compare a and a′, b and b′). At day 10, St14− colons show sporadic foci of detaching and apoptotic cells (arrowheads in c′). This phenotype is significantly stronger at days 15 and 20 with extensive anoikis (arrowheads in d′), apoptotic cells (arrows in d′, e′), ulcerations (arrowhead in e′) and inflammatory cell infiltrates (star in e′). Scale bar = 100 μm.
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Figure 6: Progressive postnatal loss of epithelial integrity of matriptase-ablated colon precedes malignant transformationHistological appearance of St14+ (a–e) and littermate St14− (a′-e′) colons at postnatal day 0 (a,a′), 5 (b,b′), 10 (c,c′), 15 (d,d′), and 20 (e,e′). No histological differences can be observed between normal and matriptase-ablated colon at days 0 and 5 (compare a and a′, b and b′). At day 10, St14− colons show sporadic foci of detaching and apoptotic cells (arrowheads in c′). This phenotype is significantly stronger at days 15 and 20 with extensive anoikis (arrowheads in d′), apoptotic cells (arrows in d′, e′), ulcerations (arrowhead in e′) and inflammatory cell infiltrates (star in e′). Scale bar = 100 μm.

Mentions: St14-ablated colonic tissue was histologically unremarkable when examined at birth and at postnatal day five (compare Figures 6a and a′, b and b′). The first observable pathological manifestation (day 10) was the detachment and apoptosis (anoikis) of distal crypt cells (compare Figure 6c and c′). This was followed by the failure of colonic epithelial cells to undergo proper terminal differentiation, as evidenced by cessation of mucin formation (data not shown). Thereafter, St14− colons entered a progressively hyperplastic inflammatory and ulcerative state that eventually resulted in the gross distortion of colonic tissue architecture (compare Figure 6d and d′, and 6e and e′). BrdU incorporating cells initially were confined to the bottom of the crypts, but later were present also in distal segments of the crypts (data not shown). Inflammatory infiltrates were evident at day 15. Inflammation at first was mild, but rapidly became severe, with inflammatory cells eventually constituting the dominant cell population of the mucosa and submucosa. Polyps were not observed in any of the examined colons prior to malignant transformation, indicating that St14 ablation-associated adenocarcinomas, like inflammatory bowel disease-associated colorectal cancers arise from flat lesions within hyperproliferative and inflamed mucosa.


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)

Progressive postnatal loss of epithelial integrity of matriptase-ablated colon precedes malignant transformationHistological appearance of St14+ (a–e) and littermate St14− (a′-e′) colons at postnatal day 0 (a,a′), 5 (b,b′), 10 (c,c′), 15 (d,d′), and 20 (e,e′). No histological differences can be observed between normal and matriptase-ablated colon at days 0 and 5 (compare a and a′, b and b′). At day 10, St14− colons show sporadic foci of detaching and apoptotic cells (arrowheads in c′). This phenotype is significantly stronger at days 15 and 20 with extensive anoikis (arrowheads in d′), apoptotic cells (arrows in d′, e′), ulcerations (arrowhead in e′) and inflammatory cell infiltrates (star in e′). Scale bar = 100 μm.
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Related In: Results  -  Collection

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Figure 6: Progressive postnatal loss of epithelial integrity of matriptase-ablated colon precedes malignant transformationHistological appearance of St14+ (a–e) and littermate St14− (a′-e′) colons at postnatal day 0 (a,a′), 5 (b,b′), 10 (c,c′), 15 (d,d′), and 20 (e,e′). No histological differences can be observed between normal and matriptase-ablated colon at days 0 and 5 (compare a and a′, b and b′). At day 10, St14− colons show sporadic foci of detaching and apoptotic cells (arrowheads in c′). This phenotype is significantly stronger at days 15 and 20 with extensive anoikis (arrowheads in d′), apoptotic cells (arrows in d′, e′), ulcerations (arrowhead in e′) and inflammatory cell infiltrates (star in e′). Scale bar = 100 μm.
Mentions: St14-ablated colonic tissue was histologically unremarkable when examined at birth and at postnatal day five (compare Figures 6a and a′, b and b′). The first observable pathological manifestation (day 10) was the detachment and apoptosis (anoikis) of distal crypt cells (compare Figure 6c and c′). This was followed by the failure of colonic epithelial cells to undergo proper terminal differentiation, as evidenced by cessation of mucin formation (data not shown). Thereafter, St14− colons entered a progressively hyperplastic inflammatory and ulcerative state that eventually resulted in the gross distortion of colonic tissue architecture (compare Figure 6d and d′, and 6e and e′). BrdU incorporating cells initially were confined to the bottom of the crypts, but later were present also in distal segments of the crypts (data not shown). Inflammatory infiltrates were evident at day 15. Inflammation at first was mild, but rapidly became severe, with inflammatory cells eventually constituting the dominant cell population of the mucosa and submucosa. Polyps were not observed in any of the examined colons prior to malignant transformation, indicating that St14 ablation-associated adenocarcinomas, like inflammatory bowel disease-associated colorectal cancers arise from flat lesions within hyperproliferative and inflamed mucosa.

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