An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Christiane A. Opitz, Ulrike M. Litzenburger, Felix Sahm, Martina Ott, Isabel Tritschler, Saskia Trump, Theresa Schumacher, Leonie Jestaedt, Dieter Schrenk, Michael Weller, Manfred Jugold, Gilles J. Guillemin, Christine L. Miller, Christian Lutz, Bernhard Radlwimmer, Irina Lehmann, Andreas von Deimling, Wolfgang Wick and Michael Platten ()
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Christiane A. Opitz: Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
Ulrike M. Litzenburger: Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
Felix Sahm: Institute of Pathology, University Hospital of Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)
Martina Ott: Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
Isabel Tritschler: University Hospital Zurich
Saskia Trump: Helmholtz Center for Environmental Research
Theresa Schumacher: Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
Leonie Jestaedt: University Hospital of Heidelberg
Dieter Schrenk: Food Chemistry and Toxicology, University of Kaiserslautern
Michael Weller: University Hospital Zurich
Manfred Jugold: Small Animal Imaging Center, German Cancer Research Center (DKFZ)
Gilles J. Guillemin: School of Medical Sciences, University of New South Wales
Christine L. Miller: Johns Hopkins University
Christian Lutz: Heidelberg Pharma AG
Bernhard Radlwimmer: German Cancer Research Center (DKFZ)
Irina Lehmann: Helmholtz Center for Environmental Research
Andreas von Deimling: Institute of Pathology, University Hospital of Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)
Wolfgang Wick: Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
Michael Platten: Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg

Nature, 2011, vol. 478, issue 7368, 197-203

Abstract: Abstract Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO–AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.

Date: 2011
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DOI: 10.1038/nature10491

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