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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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Related in: MedlinePlus

Model for matriptase ablation-induced colon carcinogenesisLoss of matriptase from intestinal epithelium compromises epithelial barrier function thereby causing exposure of the commensal microbiota to resident immune cells. This triggers a repair response that includes activation of local inflammatory circuits and colonic stem cell activation. This response is perpetual, rather than transient, due to the intrinsic inability of matriptase-ablated to form a functional barrier. Persistent hyperproliferation of colonic stem cells within a DNA damaging chronic inflammatory microenvironment causes the formation of adenocarcinoma.
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Figure 9: Model for matriptase ablation-induced colon carcinogenesisLoss of matriptase from intestinal epithelium compromises epithelial barrier function thereby causing exposure of the commensal microbiota to resident immune cells. This triggers a repair response that includes activation of local inflammatory circuits and colonic stem cell activation. This response is perpetual, rather than transient, due to the intrinsic inability of matriptase-ablated to form a functional barrier. Persistent hyperproliferation of colonic stem cells within a DNA damaging chronic inflammatory microenvironment causes the formation of adenocarcinoma.

Mentions: Taken together, the data are compatible with a principal role of the commensal microbiota in pre-neoplastic progression. A mechanistic model for matriptase ablation-induced colon cancer based on the above findings is shown in Figure 9. We propose that the intrinsic defect in barrier function associated with the failure to form functional tight junctions (Buzza et al., 2010, List et al., 2009) causes increased exposure of the immune system to the commensal microbiota. This exposure elicits vigorous inflammatory and repair responses that involve epithelial stem cell activation and are continuous, rather than transient, due to the inherent failure of matriptase-ablated colonic epithelial cells to establish a functional barrier. The sustained hyperproliferation of epithelial stem cells within a genotoxic chronic inflammatory microenvironment in turn induces the progressive genomic instability and subsequent rapid malignant conversion.


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)

Model for matriptase ablation-induced colon carcinogenesisLoss of matriptase from intestinal epithelium compromises epithelial barrier function thereby causing exposure of the commensal microbiota to resident immune cells. This triggers a repair response that includes activation of local inflammatory circuits and colonic stem cell activation. This response is perpetual, rather than transient, due to the intrinsic inability of matriptase-ablated to form a functional barrier. Persistent hyperproliferation of colonic stem cells within a DNA damaging chronic inflammatory microenvironment causes the formation of adenocarcinoma.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3299858&req=5

Figure 9: Model for matriptase ablation-induced colon carcinogenesisLoss of matriptase from intestinal epithelium compromises epithelial barrier function thereby causing exposure of the commensal microbiota to resident immune cells. This triggers a repair response that includes activation of local inflammatory circuits and colonic stem cell activation. This response is perpetual, rather than transient, due to the intrinsic inability of matriptase-ablated to form a functional barrier. Persistent hyperproliferation of colonic stem cells within a DNA damaging chronic inflammatory microenvironment causes the formation of adenocarcinoma.
Mentions: Taken together, the data are compatible with a principal role of the commensal microbiota in pre-neoplastic progression. A mechanistic model for matriptase ablation-induced colon cancer based on the above findings is shown in Figure 9. We propose that the intrinsic defect in barrier function associated with the failure to form functional tight junctions (Buzza et al., 2010, List et al., 2009) causes increased exposure of the immune system to the commensal microbiota. This exposure elicits vigorous inflammatory and repair responses that involve epithelial stem cell activation and are continuous, rather than transient, due to the inherent failure of matriptase-ablated colonic epithelial cells to establish a functional barrier. The sustained hyperproliferation of epithelial stem cells within a genotoxic chronic inflammatory microenvironment in turn induces the progressive genomic instability and subsequent rapid malignant conversion.

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