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 7

In vivo inhibition of HGF-driven c-Met activation blocks enhanced dysplasia in Tpl2D/D mice.

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In vivo inhibition of HGF-driven c-Met activation blocks enhanced dyspla...
(A) Diagram of PHA-665752 administration during the first 15 days of the AOM/DSS model. Tpl2D/D and wild-type littermate controls (5 mice per group) received 4 daily i.v. injections of PHA-665752 at a concentration of 25 mg/kg during the first DSS cycle of the CAC protocol. (B) Body weight changes were measured throughout the regime, and (C) colon length was measured at the end of the protocol. Data represent mean ± SEM from one of 2 experiments performed. *P < 0.05, **P < 0.01, Tpl2D/D mice that were injected with the inhibitor versus those that received control DMSO. n = 5. (D) Colon tissue slides were stained with H&E for the assessment of dysplasia index. Staining against BrdU and TUNEL-positive cells was used to determine the effect of the inhibitor in proliferation and apoptosis, respectively. Representative images from one of 2 experiments are shown. Scale bars: 50 μm. Arrows indicate TUNEL-positive cells (E) H&E-stained sections were scored for dysplasia. Data represent mean ± SEM from one of 2 experiments performed. n = 5. Quantification of BrdU-positive cells per crypt (F) and TUNEL-positive cells per field (G) in colon tissue from wild-type and Tpl2D/D mice with and without treatment with the c-Met inhibitor on day 15 after AOM injection. At least 20 random crypts and 10 random fields were used, respectively. Data represent mean ± SEM. n = 6; *P < 0.05, **P < 0.01.