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P029 Intestinal mesenchymal-specific IKK2 promotes initiation of colitis and colitis-associated cancer

V. Koliaraki*1, M. Pasparakis2, G. Kollias1, 3

1BSRC "Alexander Fleming", Vari, Greece, 2University of Cologne, Institute of Genetics, Cologne, Germany, 3University of Athens, Department of Physiology, Athens, Greece

Background

The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognised.1,2,3 However, both their role in the initiation of these processes and the molecular mechanisms underlying them, particularly in the intestine, remain elusive.

Methods

We generated mice with a deletion of IKK2 in intestinal mesenchymal cells (IMCs) and subjected them to chemically induced mouse models of colitis (DSS) and colorectal carcinogenesis (AOM/DSS, repeated AOM injections) or crossed them with the APC1638N/+ model of intestinal tumourigenesis. We collected intestinal tissue at different time points and evaluated tissue damage and inflammatory infiltration, measured tumour incidence, number, and size; assessed proliferation and apoptosis; and performed immunohistochemistry, Western blot analysis; and organ cultures. We also isolated IMCs and performed biochemical analysis.

Results

We show that IMC-specific deletion of IKK2 leads to amelioration of DSS colitis and protects against colitis-associated but not spontaneous intestinal tumourigenesis. We further demonstrate that in colitis-associated cancer, IMC-specific IKK2 is critically involved in the initiation stage of the disease, because, in its absence, mice develop reduced immune cell infiltration, epithelial cell proliferation, apoptosis, and dysplasia. Conditional knockout mice further show reduced pro-inflammatory cytokine and chemokine production, including IL-6, and reduced STAT3 activation at these early time points. In-vitro studies demonstrate that IKK2-deficient IMCs display defective innate immune signalling, as shown by decreased NF-κB activation and reduced expression of NF-κB-induced soluble mediators, which affect STAT3 activation in epithelial cells.

Conclusion

Collectively, our data show that deletion of IKK2 in IMCs has a protective role in intestinal inflammation and inflammation-driven carcinogenesis. Intestinal mesenchymal cells sense tissue damage and respond to produce pro-inflammatory and tissue-remodelling molecules. These secondary signals attract and activate inflammatory cells establishing a pro-inflammatory milieu in the microenvironment and further support neoplastic cell proliferation through downstream activation of the STAT3 signalling pathway thus promoting tumour development.

References

[1] Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumour microenvironment. Cancer Cell 2012;21(3):309–22.

[2] Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6(5)392–401.

[3] Powell DW, Pinchuk IV, Saada JI, et al. Mesenchymal cells of the intestinal lamina propria. Annu Rev Physiol 2011;73:213–37.