title: An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.
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.
authors: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, 69120 Heidelberg, Germany.
authors: Christiane A
authors: CA
authors: Opitz
authors: Ulrike M
authors: UM
authors: Litzenburger
authors: Felix
authors: F
authors: Sahm
authors: Martina
authors: M
authors: Ott
authors: Isabel
authors: I
authors: Tritschler
authors: Saskia
authors: S
authors: Trump
authors: Theresa
authors: T
authors: Schumacher
authors: Leonie
authors: L
authors: Jestaedt
authors: Dieter
authors: D
authors: Schrenk
authors: Michael
authors: M
authors: Weller
authors: Manfred
authors: M
authors: Jugold
authors: Gilles J
authors: GJ
authors: Guillemin
authors: Christine L
authors: CL
authors: Miller
authors: Christian
authors: C
authors: Lutz
authors: Bernhard
authors: B
authors: Radlwimmer
authors: Irina
authors: I
authors: Lehmann
authors: Andreas
authors: A
authors: von Deimling
authors: Wolfgang
authors: W
authors: Wick
authors: Michael
authors: M
authors: Platten
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007737:Kynurenine / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019899:Paracrine Communication; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D007737:Kynurenine; D014364:Tryptophan; D014366:Tryptophan Oxygenase