An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor (original) (raw)

Nature volume 478, pages 197–203 (2011)Cite this article

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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.

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Gene Expression Omnibus

Data deposits

Microarray data were deposited in the Gene Expression Omnibus repository (GEO) at http://www.ncbi.nlm.nih.gov/geo/ under accession number GSE25272.

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Acknowledgements

We thank K. Rauschenbach, J. Reiert, S. Koch and A. Mlitzko for technical assistance, P.-N. Pfenning for help with the invasion assays, J. Blaes for help generating genetically modified cells, T. V. Lanz and I. Oezen for help with animal experiments, C. Esser for providing _Ahr_−/− mice, M. Schwarz for providing the human DRE–luciferase construct, D. Lemke for generating GICs, K. Ochs for providing human umbilical-vein endothelial cell cDNA, A. Hertenstein for generation of CD4+ and CD8+ T cells, M. Betts and R. B. Russel for modelling of the binding of Kyn to the AHR, R. Koch for performing quantitative reverse transcriptase polymerase chain reaction analyses, R. Tudoran for generation of GL261 cells overexpressing murine TDO, M. Deponte for help with the radioligand binding assay, D. Schemmer for collecting and banking serum samples, W. Roth for providing tissue specimens, M. Remke for suggestions regarding data analysis, and G. Hämmerling, B. Arnold and M. Feuerer for discussions. This work was supported by grants from the Helmholtz Association (VH-NG-306) to M.P., the German Research Foundation to M.P. and W.W. (Deutsche Forschungsgemeinschaft SFB 938 TP K), the Hertie Foundation to W.W. and the Helmholtz Alliance on Systems Biology to S.T. and I.L. T.S. is supported by a DKFZ PhD Program stipend. C.A.O. is supported by a Heidelberg University Medical Faculty Postdoctoral Fellowship.

Author information

Author notes

  1. Christiane A. Opitz and Ulrike M. Litzenburger: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg, 69120 Heidelberg, Germany
    Christiane A. Opitz, Ulrike M. Litzenburger, Martina Ott, Theresa Schumacher, Wolfgang Wick & Michael Platten
  2. Experimental Neuroimmunology Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
    Christiane A. Opitz, Ulrike M. Litzenburger, Martina Ott, Theresa Schumacher & Michael Platten
  3. Department of Neuropathology, Institute of Pathology, University Hospital of Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
    Felix Sahm & Andreas von Deimling
  4. Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland
    Isabel Tritschler & Michael Weller
  5. Department for Environmental Immunology, Helmholtz Center for Environmental Research, 04318 Leipzig, Germany
    Saskia Trump & Irina Lehmann
  6. Department of Neuroradiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany
    Leonie Jestaedt
  7. Food Chemistry and Toxicology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
    Dieter Schrenk
  8. Small Animal Imaging Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
    Manfred Jugold
  9. Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, 2052 Australia
    Gilles J. Guillemin
  10. Department of Pediatrics, Johns Hopkins University, Baltimore, 21287, MD, USA
    Christine L. Miller
  11. Heidelberg Pharma AG, 68526 Ladenburg, Germany
    Christian Lutz
  12. Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
    Bernhard Radlwimmer
  13. Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
    Wolfgang Wick

Authors

  1. Christiane A. Opitz
  2. Ulrike M. Litzenburger
  3. Felix Sahm
  4. Martina Ott
  5. Isabel Tritschler
  6. Saskia Trump
  7. Theresa Schumacher
  8. Leonie Jestaedt
  9. Dieter Schrenk
  10. Michael Weller
  11. Manfred Jugold
  12. Gilles J. Guillemin
  13. Christine L. Miller
  14. Christian Lutz
  15. Bernhard Radlwimmer
  16. Irina Lehmann
  17. Andreas von Deimling
  18. Wolfgang Wick
  19. Michael Platten

Contributions

C.A.O. and U.M.L. contributed equally to this study, designed and performed experiments, analysed data and wrote the paper. F.S. and A.D. analysed protein expression by immunohistochemistry. I.T. cloned constructs and designed experiments. S.T. and I.L. performed nuclear translocation assays. M.O. performed animal experiments. T.S performed immune experiments. L.J. and M.J. performed MRI scans. C.L.M. and G.J.G. provided antibodies and designed experiments. D.S. performed and analysed EROD and DRE–luciferase assays. C.L. synthesized the TDO inhibitor. M.W. and W.W. were involved in study design and data interpretation. B.R. analysed microarray data. M.P. and C.A.O. conceptualized the study, interpreted data, designed experiments and wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence toMichael Platten.

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Competing interests

The authors declare no competing financial interests.

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Opitz, C., Litzenburger, U., Sahm, F. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.Nature 478, 197–203 (2011). https://doi.org/10.1038/nature10491

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Editorial Summary

Tumour promotion by kynurenine

The tryptophan catabolite kynurenine (Kyn) and tryptophan degradation by indoleamine-2,3-dioxygenases have previously been implicated in suppressing an antitumour immune response. Michael Platten and colleagues now identify tryptophan-2,3-dioxygenase (TDO) as the enzyme expressed in gliomas and other cancers that converts tryptophan to Kyn. Kyn is an endogenous ligand for the aryl hydrocarbon receptor (AHR), acting directly on glioma cells to promote tumorigenesis. TDO expression in cancer cells also suppresses an AHR-mediated immune response. In human glioblastomas, the expression of TDO and AHR-regulated genes are associated with more advanced stages and poorer clinical outcome.

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