Universität zu Köln

Koliaraki, Vasiliki ORCID: 0000-0003-1694-6987, Chalkidi, Niki, Henriques, Ana, Tzaferis, Christos, Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Waisman, Ari, Muller, Werner ORCID: 0000-0002-1297-9725, Hackam, David J., Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Kollias, George (2019). Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis. Cell Reports, 26 (3). S. 536 - 550. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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Abstract

MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis of the Apc(min/+) model, which carries a mutation in the Apc gene. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces tumorigenesis in this model. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not interleukin-1 receptor (IL-1R), in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis in IMCs indicated that these effects could be mediated through downstream signals involving growth factors and inflammatory and extracellular matrix (ECM)-regulating genes, also found in human cancer-associated fibroblasts (CAFs). Our results provide direct evidence that during tumorigenesis, IMCs and CAFs are activated by innate TLR4/MyD88-mediated signals and promote carcinogenesis in the intestine.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Koliaraki, Vasiliki UNSPECIFIED orcid.org/0000-0003-1694-6987 UNSPECIFIED Chalkidi, Niki UNSPECIFIED UNSPECIFIED UNSPECIFIED Henriques, Ana UNSPECIFIED UNSPECIFIED UNSPECIFIED Tzaferis, Christos UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Waisman, Ari UNSPECIFIED UNSPECIFIED UNSPECIFIED Muller, Werner UNSPECIFIED orcid.org/0000-0002-1297-9725 UNSPECIFIED Hackam, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kollias, George UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-159229
DOI:	10.1016/j.celrep.2018.12.072
Journal or Publication Title:	Cell Reports
Volume:	26
Number:	3
Page Range:	S. 536 - 550
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2211-1247
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COLORECTAL-CANCER; CELLS; TOLL; ACTIVATION; BETA Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15922