Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis
Vasiliki Koliaraki, … , Manolis Roulis, George Kollias
Vasiliki Koliaraki, … , Manolis Roulis, George Kollias
Published October 15, 2012
Citation Information: J Clin Invest. 2012;122(11):4231-4242. https://doi.org/10.1172/JCI63917.
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Research Article Oncology

Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis

Abstract

The tumor microenvironment plays a significant role in colitis-associated cancer (CAC). Intestinal myofibroblasts (IMFs) are cells in the intestinal lamina propria secreting factors that are known to modulate carcinogenesis; however, the physiological role of IMFs and signaling pathways influencing CAC have remained unknown. Tumor progression locus 2 (Tpl2) is a MAPK that regulates inflammatory and oncogenic pathways. In this study we addressed the role of Tpl2 in CAC using complete and tissue-specific ablation of Tpl2 in mutant mice. Tpl2-deficient mice did not exhibit significant differences in inflammatory burdens following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration compared with wild-type mice; however, the mutant mice developed significantly increased numbers and sizes of tumors, associated with enhanced epithelial proliferation and decreased apoptosis. Cell-specific ablation of Tpl2 in IMFs, but not in intestinal epithelial or myeloid cells, conferred a similar susceptibility to adenocarcinoma formation. Tpl2-deficient IMFs upregulated HGF production and became less sensitive to the negative regulation of HGF by TGF-β3. In vivo inhibition of HGF-mediated c-Met activation blocked early, enhanced colon dysplasia in Tpl2-deficient mice, indicating that Tpl2 normally suppresses the HGF/c-Met pathway. These findings establish a mesenchyme-specific role for Tpl2 in the regulation of HGF production and suppression of epithelial tumorigenesis.

Authors

Vasiliki Koliaraki, Manolis Roulis, George Kollias

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Figure 1

Tpl2D/D mice display increased tumorigenesis upon AOM/DSS administration.

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Tpl2D/D mice display increased tumorigenesis upon AOM/DSS administratio...
Western blot of Tpl2 expression on days 0 and 15 of the AOM/DSS regime (A) and densitometric analysis (B) of both isoforms of Tpl2 protein (52 kDa and 58 kDa) relative to β-actin. Data represent mean ± SEM. n = 5; **P < 0.01. Tpl2D/D mice and wild-type littermate controls were subjected to the AOM/DSS model of colitis-associated colon carcinogenesis. Body weight changes (C) and survival rates (D) were monitored during the course of the experimental procedure. (E) Disease index was measured on day 13 after initial AOM injection. Colon length (F), number of tumors per mouse (G), and size of tumors (H) measured at the end of the experimental protocol. The data correspond to one representative experiment of three (n = 6), except in the case of survival curves and size distribution graphs, which are cumulative from 3 experiments. Data represent mean ± SEM. *P < 0.05, **P < 0.01. (I) Representative images of formalin-fixed and H&E-stained colon sections at the end of the experimental protocol (day 60). Scale bars: 200 μm. (J) Representative images of formalin-fixed and H&E-stained colon sections early (day 15) during the experimental protocol. Scale bars: 50 μm. (K) Dysplasia incidence was measured at an early time point, 5 days after the end of the first DSS cycle. The data shown correspond to the average of 4 experiments performed (n = 6). Data represent mean ± SEM. **P < 0.01.