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Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice
Katerina Vlantis, … , Tania Roskams, Manolis Pasparakis
Katerina Vlantis, … , Tania Roskams, Manolis Pasparakis
Published June 23, 2011
Citation Information: J Clin Invest. 2011;121(7):2781-2793. https://doi.org/10.1172/JCI45349.
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Research Article

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

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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 6

IKK2caIEChom mice spontaneously develop intestinal tumors.

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IKK2caIEChom mice spontaneously develop intestinal tumors.
   
(A) Aged ...
(A) Aged (≥48 week old) IKK2caIEChom mice showed endoscopically detectable colon inflammation, reflected by a heightened MEICS. (B) Representative endoscopic pictures of 1-year-old IKK2caIEChom mice, showing the presence of tumors exhibiting pronounced vascularization in the distal colon. IKK2casFL littermates did not show colon inflammation or tumors. (C) Histological analysis of colon cross sections showed the presence of tumors in 10 out of 17 animals examined, characterized by thickening of the mucosa, epithelial hyperplasia, aberrantly formed crypts, and inflammation. (D) Immunostaining for Ki67 showed strongly increased proliferation of epithelial cells in dysplastic and hyperplastic lesions in the colon and SI from IKK2caIEChom mice. Immunostaining for Sox9 also revealed strongly increased Sox9 expression in epithelial cells in colonic and SI tumors. IKK2casFL littermates showed normal Ki67 and Sox9 staining in the colon and SI. Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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