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Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors

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Abstract

Introduction

There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment.

Methods

We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites. In addition, we utilized commercially available small-molecules to pharmacologically modulate IDO1, IDO2, TDO2, and AhR in patient-derived glioma and meningioma cell lines (n = 9 each).

Results

We observed a positive trend between the grade of the tumor and the average immunohistochemical staining score for IDO1, IDO2, and TDO2, with TDO2 displaying the strongest immunostaining. AhR immunostaining was present in all grades of gliomas and meningiomas, with the greatest staining intensity noted in glioblastomas. Immunocytochemical staining showed a positive trend between nuclear localization of AhR and histologic grade in both gliomas and meningiomas, suggesting increased AhR activation with higher tumor grade. Unlike enzyme inhibition, AhR antagonism markedly diminished patient-derived tumor cell viability, regardless of tumor type or grade, following in vitro drug treatments.

Conclusions

Collectively, these results suggest that AhR may offer a novel and robust therapeutic target for a patient population with highly limited treatment options.

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Acknowledgements

The study was supported, in part, by the following Grants: 1F31CA210682-01A1 (A.R.G.) from the National Cancer Institute; 4T32CA009531-30 (A.R.G.) from the National Cancer Institute; R25GM058905 (A.R.G.) from the National Institute of General Medical Sciences; R01CA123451 (C.J. and S.M.) from the National Cancer Institute; the Fund for Medical Research and Education, Wayne State University School of Medicine (S.M.); a Strategic Research Initiative Grant from Karmanos Cancer Institute (S.M.); and The Office of the Vice President for Research, Wayne State University (S.M.). The Biobanking and Correlative Sciences Core is supported, in part, by the National Institute of Health Center Grant P30CA022453 to the Karmanos Cancer Institute at Wayne State University. We wish to thank the patients who graciously donated their tumor tissue for this study.

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Authors and Affiliations

  1. Department of Neurosurgery, Wayne State University, Detroit, MI, USA

    Anthony R. Guastella, Sharon K. Michelhaugh, Neil V. Klinger, Hassan A. Fadel, Sam Kiousis, Csaba Juhász & Sandeep Mittal

  2. Department of Oncology, Wayne State University, Detroit, MI, USA

    Anthony R. Guastella, Rouba Ali-Fehmi, William J. Kupsky & Sandeep Mittal

  3. Department of Pathology, Wayne State University, Detroit, MI, USA

    Rouba Ali-Fehmi & William J. Kupsky

  4. Department of Neurology, Wayne State University, Detroit, MI, USA

    Csaba Juhász

  5. Department of Pediatrics, Wayne State University, Detroit, MI, USA

    Csaba Juhász

  6. Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA

    Sandeep Mittal

  7. PET Center and Translational Imaging Laboratory, Children’s Hospital of Michigan, Detroit, MI, USA

    Csaba Juhász

  8. Karmanos Cancer Institute, Detroit, MI, USA

    Csaba Juhász & Sandeep Mittal

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  1. Anthony R. Guastella
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Supplemental Figure 1

. Immunohistochemical staining of positive controls. Immunostaining for the stated antibody were performed on the following tissues: lymph node (IDO1) and liver (IDO2, TDO2, and AhR). Images are 20× magnification, with scale bar of 100 μm. (TIF 3387 KB)

Supplemental Figure 2

. Immunocytochemical staining of patient-derived cells. Cultured patient-derived glioma and meningioma cells were plated onto 8-well chamber slides. When cells were at a sufficient density, cells were fixed in formalin for 30 min. Immunocytochemical staining was performed as described in the Methods section. Cells were stained for the three rate-limiting enzymes of the kynurenine pathway (indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase 2 (TDO2)), as well as the aryl hydrocarbon receptor (AhR). IDO1 showed lower staining in gliomas than in meningiomas. IDO2 and TDO2 showed staining in all tumor sections, with TDO2 having the greatest staining intensity. Unlike in the tissue staining, cellular staining of AhR was greatest in the highest grade of each tumor type. Furthermore, cellular staining showed that higher grade tumors also had abundant nuclear staining of AhR. Images are representative of the average staining score for the cell type and antibody used and are 20× magnification, with scale bar of 100 μm. (TIF 31141 KB)

Supplemental Figure 3

. Representative primary antibody immunocytochemical negative controls are shown for each of the tumor types and histological grades. Images are 20x magnification, with scale bar of 100 µm. (TIF 1031 KB)

Supplemental Figure 4

. Drug combination study of high-grade gliomas and meningiomas. Cultured patient-derived grade IV glioblastoma (n = 3) and grade III meningioma cell lines (n = 3) were treated in triplicate for 48 hrs with the listed drug combinations. Drugs used were as follows: IDO1 – epacadostat (20 nM); IDO2 – tenatoprazole (4 µM); and TDO2 – 680C91 (2 µM). After treatment, cell viability was measured via MTT assay. Cell viability is represented as percent control and plotted with a box and whiskers plot using the Tukey method. No combination of the rate-limiting enzyme inhibitors produced a significant loss of cell viability. (TIF 1608 KB)

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Guastella, A.R., Michelhaugh, S.K., Klinger, N.V. et al. Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors. J Neurooncol 139, 239–249 (2018). https://doi.org/10.1007/s11060-018-2869-6

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