Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice
Katerina Vlantis, Andy Wullaert, Yoshiteru Sasaki, Marc Schmidt-Supprian, Klaus Rajewsky, Tania Roskams, Manolis Pasparakis
Katerina Vlantis, Andy Wullaert, Yoshiteru Sasaki, Marc Schmidt-Supprian, Klaus Rajewsky, Tania Roskams, Manolis Pasparakis
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Research Article

Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice

Abstract

Many cancers display increased NF-κB activity, and NF-κB inhibition is known to diminish tumor development in multiple mouse models, supporting an important role of NF-κB in carcinogenesis. NF-κB activation in premalignant or cancer cells is believed to promote tumor development mainly by protecting these cells from apoptosis. However, it remains unclear to what extent NF-κB activation exhibits additional protumorigenic functions in premalignant cells that could be sufficient to induce spontaneous tumor development. Here we show that expression of constitutively active IκB kinase 2 (IKK2ca) in mouse intestinal epithelial cells (IECs) induced spontaneous tumors in aged mice and also strongly enhanced chemical- and Apc mutation–mediated carcinogenesis. IECs expressing IKK2ca displayed altered Wnt signaling and increased proliferation and elevated expression of genes encoding intestinal stem cell–associated factors including Ascl2, Olfm4, DLK1, and Bmi-1, indicating that increased IKK2/NF-κB activation synergized with Wnt signaling to drive intestinal tumorigenesis. Moreover, IECs expressing IKK2ca produced cytokines and chemokines that induced the recruitment of myeloid cells and activated stromal fibroblasts to become myofibroblasts, thus creating a tumor-promoting microenvironment. Taken together, our results show that constitutively increased activation of IKK2/NF-κB signaling in the intestinal epithelium is sufficient to induce the full spectrum of cell-intrinsic and stromal alterations required for intestinal tumorigenesis.

Authors

Katerina Vlantis, Andy Wullaert, Yoshiteru Sasaki, Marc Schmidt-Supprian, Klaus Rajewsky, Tania Roskams, Manolis Pasparakis

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Figure 1

IKK2ca expression in IECs induces NF-κB activation and mild intestinal inflammation.

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IKK2ca expression in IECs induces NF-κB activation and mild intestinal i...
(A) Immunoblot reveals increased IKK2 expression and reduced levels of IκBα in SI IECs from IKK2caIEChom mice compared with IKK2casFL littermates. (B) Immunofluorescent staining with anti-FLAG antibodies shows IEC-specific expression of FLAG-IKK2ca in IKK2caIEChom colon sections. Background staining in the lumen of the IKK2casFL colon results from incomplete removal of luminal contents. (C) EMSA reveals increased NF-κB DNA-binding activity in nuclear extracts from IKK2caIEChom SI and colonic IECs. (D) Representative endoscopic images of colons from 8-week-old IKK2casFL and IKK2caIEChom mice. (E) Quantification of MEICS showing no significant colonic inflammation in 7- to 9-week-old IKK2caIEChom (n = 10) mice compared with IKK2casFL (n = 5) littermates. Data are presented as mean ± SD. (F) H&E-stained sections show crypt elongation and increased immune cell infiltration in the SI and colon of IKK2caIEChom compared with IKK2casFL mice. Note the lack of Paneth cells in ileal crypts in IKK2caIEChom mice (indicated by white arrows in inset). The black arrow indicates a mislocalized Paneth cell. Scale bars: 50 μm.