Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment

Claudia M. Wunderlich, P. Justus Ackermann, Anna Lena Ostermann, Petra Adams-Quack, Merly C. Vogt, My-Ly Tran, Alexei Nikolajev, Ari Waisman, Christoph Garbers, Sebastian Theurich, Jan Mauer, Nadine Hövelmeyer and F. Thomas Wunderlich ()
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Claudia M. Wunderlich: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne
P. Justus Ackermann: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne
Anna Lena Ostermann: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne
Petra Adams-Quack: University Hospital Mainz
Merly C. Vogt: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne
My-Ly Tran: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne
Alexei Nikolajev: University Hospital Mainz
Ari Waisman: University Hospital Mainz
Christoph Garbers: Kiel University, Medical Faculty
Sebastian Theurich: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne
Jan Mauer: Cornell University
Nadine Hövelmeyer: University Hospital Mainz
F. Thomas Wunderlich: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Colorectal cancer (CRC) is one of the most lethal cancers worldwide in which the vast majority of cases exhibit little genetic risk but are associated with a sedentary lifestyle and obesity. Although the mechanisms underlying CRC and colitis-associated colorectal cancer (CAC) remain unclear, we hypothesised that obesity-induced inflammation predisposes to CAC development. Here, we show that diet-induced obesity accelerates chemically-induced CAC in mice via increased inflammation and immune cell recruitment. Obesity-induced interleukin-6 (IL-6) shifts macrophage polarisation towards tumour-promoting macrophages that produce the chemokine CC-chemokine-ligand-20 (CCL-20) in the CAC microenvironment. CCL-20 promotes CAC progression by recruiting CC-chemokine-receptor-6 (CCR-6)-expressing B cells and γδ T cells via chemotaxis. Compromised cell recruitment as well as inhibition of B and γδ T cells protects against CAC progression. Collectively, our data reveal a function for IL-6 in the CAC microenvironment via lymphocyte recruitment through the CCL-20/CCR-6 axis, thereby implicating a potential therapeutic intervention for human patients.

Date: 2018
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DOI: 10.1038/s41467-018-03773-0

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