A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis

Lin Deng, Jin Feng Zhou, Rani S. Sellers, Jiu Feng Li, Andrew V. Nguyen, Yubao Wang, Amos Orlofsky, Qiang Liu, David A. Hume, Jeffrey W. Pollard, Leonard Augenlicht, Elaine Lin

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Inflammatory bowel disease (IBD) is a high-risk condition for human colorectal cancer. However, our mechanistic understanding of the link between inflammation and tumorigenesis in the colon is limited. Here we established a novel mouse model of colitisassociated cancer by genetically inactivating signal transducer and activator of transcription 3 (Stat3) in macrophages, with partial deletion in other myeloid and lymphoid cells. Inflammation developed in the colon of mutant mice spontaneously, and tumor lesions, including invasive carcinoma, arose in the inflamed region of the intestine with a frequency similar to that observed in human IBD patients. The development of both inflammation and tumors in the mutant mice required the presence of microflora. Indeed, inflammation was associated with disruption of colonic homeostasis, fulminant epithelial/tumor cell proliferation, and activation of the mammalian target of rapamycin (mTOR)-Stat3 pathway in epithelial and tumor cells. The activation of this pathway was essential for both the excess proliferation of epithelial/tumor cells and the disruption of colonic homeostasis in the mutant mice. Notably, a similar abnormal up-regulation of mTOR-Stat3 signaling was consistently observed in the colonic epithelial cells of human IBD patients with active disease. These studies demonstrate a novel mouse model of IBD-colorectal cancer progression in which disrupted immune regulation, mTOR-Stat3 signaling, and epithelial hyperproliferation are integrated and simultaneously linked to the development of malignancy.

Original languageEnglish (US)
Pages (from-to)952-967
Number of pages16
JournalAmerican Journal of Pathology
Volume176
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

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Sirolimus
Inflammatory Bowel Diseases
Carcinogenesis
Epithelium
STAT3 Transcription Factor
Inflammation
Epithelial Cells
Neoplasms
Colorectal Neoplasms
Colon
Homeostasis
Myeloid Cells
Intestines
Up-Regulation
Macrophages
Cell Proliferation
Lymphocytes
Carcinoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. / Deng, Lin; Zhou, Jin Feng; Sellers, Rani S.; Li, Jiu Feng; Nguyen, Andrew V.; Wang, Yubao; Orlofsky, Amos; Liu, Qiang; Hume, David A.; Pollard, Jeffrey W.; Augenlicht, Leonard; Lin, Elaine.

In: American Journal of Pathology, Vol. 176, No. 2, 02.2010, p. 952-967.

Research output: Contribution to journalArticle

Deng, L, Zhou, JF, Sellers, RS, Li, JF, Nguyen, AV, Wang, Y, Orlofsky, A, Liu, Q, Hume, DA, Pollard, JW, Augenlicht, L & Lin, E 2010, 'A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis', American Journal of Pathology, vol. 176, no. 2, pp. 952-967. https://doi.org/10.2353/ajpath.2010.090622
Deng, Lin ; Zhou, Jin Feng ; Sellers, Rani S. ; Li, Jiu Feng ; Nguyen, Andrew V. ; Wang, Yubao ; Orlofsky, Amos ; Liu, Qiang ; Hume, David A. ; Pollard, Jeffrey W. ; Augenlicht, Leonard ; Lin, Elaine. / A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. In: American Journal of Pathology. 2010 ; Vol. 176, No. 2. pp. 952-967.
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