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“Brake pedal” for cancer growth

19.12.2016

Kiel scientist from the Cluster of Excellence “Inflammation at Interfaces” helps to identify the function of an unknown immunoreceptor in colorectal cancer

Intestinal epithelial cells, i.e. the cells of the inner lining of the gut, protect us against potentially harmful pathogens and other external danger signals. NOD-like receptors (NLRs) are an important part of this first line of defense localized inside the epithelial cells. They recognise bacterial structures and trigger an immune response. Disturbance of this recognition by the receptors contributes to the development of inflammatory diseases. Philip Rosenstiel from the Cluster of Excellence “Inflammation at Interfaces” thus has has a long standing interest in this “alarm system” of intestinal epithelial cells. In a recent publication in cooperation with an American working group, he was involved in assigning an unexpected function to NLRC3, a previously poorly characterized NLR family member, and found: “The NLRC3 receptor controls the regeneration and proliferation of cells like a kind of brake pedal. If it is missing, there is more inflammation and cancer growth”. This is facilitated via a metabolic signalling pathway (mTOR kinase/PI3 Kinase). The results have now been published in advance online in the renowned research journal Nature.

The group led by Professor Philip Rosenstiel from the Institute of Clinical Molecular Biology at Kiel University’s Faculty of Medicine, focuses on understanding intestinal barrier integrity and its role for immune balance in the gut. In the study now published in Nature it is shown that mice with a genetic defect in the NOD-like receptor NLRC3 are prone to intestinal inflammation and subsequent development of carcinoma. “We find an uncontrolled proliferation of cells leading to increased tumour numbers and size,” explains Philip Rosenstiel. This is related to a metabolic signalling pathway, which is normally blocked when an active receptor is present. “The mTOR pathway primarily regulates nutrient-dependent cell division and cell growth. This activity is inhibited by the presence of NLRC3.”
Whether the receptor needs an endogenous or exogenous signal triggering this inhibiting effect still remains to be determined. Due to the proximity of the receptor to the gut microbiota, it seems likely that it might respond to physiological signals emanating from the commensal bacteria. “We hypothesize that the receptor recognises something happening within this complex ecosystem. We are currently investigating, which metabolic products of the bacteria may act on the receptor and under which conditions the NLRC3 receptor is able to block the proliferation signal.”

Original publication:
Karki R et al.: NLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer. Nature 2016, published online December 12, 2016. doi:10.1038/nature20597

Philip Rosenstiel, Cluster of Excellence "Inflammation at Interfaces", Professor of Molecular Medicine at Kiel University and Director of the Institute of Clinical Molecular Biology, Faculty of Medicine at Kiel University and the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel. Photo: Dr. Tebke Böschen/ Kiel University

Contact:
Prof. Dr. Philip Rosenstiel
The Institute of Clinical Molecular Biology
Tel.: +49 (0)431 500 15111


Cluster of Excellence "Inflammation at Interfaces"
Scientific Office, Head: Dr. habil. Susanne Holstein
Press and Communications, Sonja Petermann, Text: Kerstin Nees
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The Cluster of Excellence "Inflammation at Interfaces" has been funded since 2007 by the Excellence Initiative of the German Government and the federal states with a total budget of 68 million Euros. It is currently in its second phase of funding. Around 300 cluster members are spread across the four locations: Kiel (Kiel University, University Medical Center Schleswig-Holstein (UKSH)), Lübeck (University of Lübeck, UKSH), Plön (Max Planck Institute for Evolutionary Biology) and Borstel (Research Center Borstel (FZB) – Center for Medicine and Biosciences) and are researching an innovative, systematic approach to the phenomenon of inflammation, which can affect all barrier organs such as the intestines, lungs and skin.

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