Darmmikrobiom bei primären Hirntumoren

 

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ZUSAMMENFASSUNG

Primäre Hirntumoren kommen weniger häufig vor als andere Tumorentitäten. Das Glioblastom ist der häufigste primäre Hirntumor bei Erwachsenen und hat eine sehr schlechte Prognose. Die Pathophysiologie vieler Hirntumoren ist nur unzureichend verstanden. Eine kurative Therapie existiert bis auf wenige Ausnahmen nicht. Bei einigen soliden und hämatologischen Tumoren konnte in den letzten Jahren ein Zusammenhang zwischen Tumorentstehung und -progression mit Veränderungen im intestinalen Mikrobiom festgestellt werden. Zusammenhänge zwischen Mikrobiota und primären Hirntumoren wurden hingegen nicht publiziert.

In der vorliegenden Arbeit werden Mechanismen dargestellt, die bei einer möglichen Interaktion zwischen Mikrobiom und Hirntumoren eine Rolle spielen können. Dabei steht die Schranke vom Darmepithel zum peripheren Blut und vom peripheren Blut zum Gehirn im Mittelpunkt des Interesses. Im Hinblick auf die Darm-Blutschranke sind Interaktionen zwischen Mikrobiom und Immunphänotyp sowie Metaboliten im peripheren Blut bekannt. Im Hinblick auf die Blut-Hirnschranke bestehen mögliche Assoziationen des Immunphänotyps und der Metaboliten im peripheren Blut mit der Immuninfiltration im Gehirn und der Induktion pathogeneserelevanter Signalkaskaden.

ABSTRACT

Primary brain tumours have a low incidence in comparison to other tumours. Glioblastoma is the most common primary brain tumour and has a poor prognosis. The underlying pathophysiology of many brain tumours is only poorly understood. With some exceptions, there is no curative therapy. In the past years, several associations between tumour development and progression of various solid and haematological tumour entities and alterations of the intestinal microbiome have been identified. However, so far there are no publications describing a relation between microbiota and primary brain tumours.

In this review, we describe important mechanisms that are supposed to play a role in a possible interaction between microbiota and brain tumours. We focus on the barriers between gut and peripheral blood and between peripheral blood and brain. With regard to the barrier between gut and peripheral blood, interactions of the intestinal microbiome with the immune phenotype and metabolites in the blood have been described. With regard to the blood-brain-barrier, we discuss possible relations between the peripheral immune phenotype or metabolites in the blood and the immune infiltration in the brain as well as the induction of tumorigenic signaling pathways.

• Literatur

• 1 Ostrom QT, Gittleman H, Truitt G. et al CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in, 2011–2015. Neuro-Oncology 2018; 20: iv1-iv86 doi:10.1093/neuonc/noy131
  CrossrefPubMedGoogle Scholar
• 2 Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clinical Cancer Research 2013; 19: 764-72 doi:10.1158/1078-0432.CCR-12-3002
  CrossrefPubMedGoogle Scholar
• 3 Stupp R, Taillibert S, Kanner A. et al Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA 2017; 318: 2306-16 doi:10.1001/jama.2017.18718
  CrossrefPubMedGoogle Scholar
• 4 Zhuang L, Chen H, Zhang S. et al Intestinal Microbiota in Early Life and Its Implications on Childhood Health. Genomics Proteomics Bioinformatics 2019; 17: 13-25 doi:10.1016/j.gpb.2018.10.002
  CrossrefPubMedGoogle Scholar
• 5 Sochocka M, Donskow-Lysoniewska K, Diniz BS. et al The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer’s Disease – a Critical Review. Mol Neurobiol 2019; 56: 1841-51 doi:10.1007/s12035-018-1188-4
  CrossrefPubMedGoogle Scholar
• 6 Gareau MG, Wine E, Rodrigues DM. et al Bacterial infection causes stress-induced memory dysfunction in mice. Gut 2011; 60: 307-317 doi:10.1136/gut.2009.202515
  CrossrefPubMedGoogle Scholar
• 7 Bagga D, Reichert JL, Koschutnig K. et al Probiotics drive gut microbiome triggering emotional brain signatures. Gut Microbes 2018; 9: 486-96 doi:10.1080/19490976.2018.1460015
  PubMedGoogle Scholar
• 8 MacFabe DF, Cain NE, Boon F. et al Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behavioural Brain Research 2011; 217: 47-54 doi:10.1016/j.bbr.2010.10.005
  CrossrefPubMedGoogle Scholar
• 9 Cheung SG, Goldenthal AR, Uhlemann AC. et al Systematic Review of Gut Microbiota and Major Depression. Front Psychiatry 2019; 10: 34 doi:10.3389/fpsyt.2019.00034
  CrossrefPubMedGoogle Scholar
• 10 Valles-Colomer M, Falony G, Darzi Y. et al The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol 2019; 4: 623-32 doi:10.1038/s41564-018-0337-x
  CrossrefPubMedGoogle Scholar
• 11 Breen DP, Halliday GM, Lang AE. Gut-brain axis and the spread of alpha-synuclein pathology: Vagal highway or dead end?. Mov Disord 2019; 34: 307-16 doi:10.1002/mds.27556
  CrossrefPubMedGoogle Scholar
• 12 Lee YK, Menezes JS, Umesaki Y. et al Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Sciences of the United States of America 2011; 108 (Suppl. 01) 4615-22 doi:10.1073/pnas.1000082107
  CrossrefPubMedGoogle Scholar
• 13 Erny D, Hrabe de Angelis AL, Jaitin D. et al Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015; 18: 965-77 doi:10.1038/nn.4030
  CrossrefPubMedGoogle Scholar
• 14 Baj A, Moro E, Bistoletti M. et al Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis. Int J Mol Sci 2019 doi:10.3390/ijms20061482
  PubMedGoogle Scholar
• 15 Chen GY. The Role of the Gut Microbiome in Colorectal Cancer. Clin Colon Rectal Surg 2018; 31: 192-8 doi:10.1055/s-0037-1602239
  Article in Thieme ConnectPubMedGoogle Scholar
• 16 Castellarin M, Warren RL, Freeman JD. et al Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Research 2012; 22: 299-306 doi:10.1101/gr.126516.111
  CrossrefPubMedGoogle Scholar
• 17 Kostic AD, Chun E, Robertson L. et al Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013; 14: 207-15 doi:10.1016/j.chom.2013.07.007
  CrossrefPubMedGoogle Scholar
• 18 Yang L, Lu X, Nossa CW. et al Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 2009; 137: 588-97 doi:10.1053/j.gastro.2009.04.046
  CrossrefPubMedGoogle Scholar
• 19 Dapito DH, Mencin A, Gwak G-Y. et al Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer cell 2012; 21: 504-16 doi:10.1016/j.ccr.2012.02.007
  CrossrefPubMedGoogle Scholar
• 20 Fernández MF, Reina-Pérez I, Astorga JM. et al Breast Cancer and Its Relationship with the Microbiota. Int J Environ Res Public Health 2018 doi:10.3390/ijerph15081747
  PubMedGoogle Scholar
• 21 Schwabe RF, Jobin C. The microbiome and cancer. Nature reviews. Cancer 2013; 13: 800-12 doi:10.1038/nrc3610
  Google Scholar
• 22 Yoshimoto S, Loo TM, Atarashi K. et al Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499: 97-101 doi:10.1038/nature12347
  Google Scholar
• 23 Wu S, Morin PJ, Maouyo D. et al Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology 2003; 124: 392-400 doi:10.1053/gast.2003.50047
  CrossrefPubMedGoogle Scholar
• 24 Grivennikov S, Karin E, Terzic J. et al IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer cell 2009; 15: 103-13 doi:10.1016/j.ccr.2009.01.001
  CrossrefPubMedGoogle Scholar
• 25 Rubinstein MR, Wang X, Liu W. et al Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 2013; 14: 195-206 doi:10.1016/J.CHOM.2013.07.012
  CrossrefPubMedGoogle Scholar
• 26 Pandiyan P, Bhaskaran N, Zou M. et al Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa. Front Immunol 2019; 10: 426 doi:10.3389/fimmu.2019.00426
  CrossrefPubMedGoogle Scholar
• 27 Faith JJ, Ahern PP, Ridaura VK. et al Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Science translational medicine 2014; 6: 220ra11 doi:10.1126/scitranslmed.3008051
  CrossrefPubMedGoogle Scholar
• 28 Louveau A, Smirnov I, Keyes TJ. et al Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523: 337-41 doi:10.1038/nature14432
  Google Scholar
• 29 Bartholomäus I, Kawakami N, Odoardi F. et al Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 2009; 462: 94-8 doi:10.1038/nature08478
  Google Scholar
• 30 von Hanwehr RI, Hofman FM, Taylor CR. et al Mononuclear lymphoid populations infiltrating the microenvironment of primary CNS tumors. Characterization of cell subsets with monoclonal antibodies. J Neurosurg 1984; 60: 1138-47 doi:10.3171/jns.1984.60.6.1138
  CrossrefPubMedGoogle Scholar
• 31 Atarashi K, Tanoue T, Shima T. et al Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331: 337-41 doi:10.1126/science.1198469
  CrossrefPubMedGoogle Scholar
• 32 Furusawa Y, Obata Y, Fukuda S. et al Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504: 446-50 doi:10.1038/nature12721
  CrossrefPubMedGoogle Scholar
• 33 Pandiyan P, Zheng L, Ishihara S. et al CD4 + CD25 + Foxp3 + regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4 + T cells. Nat Immunol 2007; 8: 1353-62 doi:10.1038/ni1536
  CrossrefPubMedGoogle Scholar
• 34 Ivanov II, Atarashi K, Manel N. et al Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139: 485-98 doi:10.1016/j.cell.2009.09.033
  CrossrefPubMedGoogle Scholar
• 35 Round JL, Lee SM, Li J. et al The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011; 332: 974-7 doi:10.1126/science.1206095
  CrossrefPubMedGoogle Scholar
• 36 Mazmanian SK, Liu CH, Tzianabos AO. et al An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005; 122: 107-18 doi:10.1016/j.cell.2005.05.007
  CrossrefPubMedGoogle Scholar
• 37 Viaud S, Daillere R, Boneca IG. et al Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ. 2015; 22: 199-214 doi:10.1038/cdd.2014.56
  PubMedGoogle Scholar
• 38 Schirmer M, Smeekens SP, Vlamakis H. et al Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell 2016; 167: 1125-1136.e8 doi:10.1016/j.cell.2016.10.020
  CrossrefPubMedGoogle Scholar
• 39 Chen Z, Feng X, Herting CJ. et al Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma. Cancer Research 2017; 77: 2266-78 doi:10.1158/0008-5472.CAN-16-2310
  CrossrefPubMedGoogle Scholar
• 40 Fecci PE, Mitchell DA, Whitesides JF. et al Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 2006; 66: 3294-302 doi:10.1158/0008-5472.CAN-05-3773
  CrossrefPubMedGoogle Scholar
• 41 Lohr J, Ratliff T, Huppertz A. et al Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-beta. Clin Cancer Res 2011; 17: 4296-308 doi:10.1158/1078-0432.CCR-10-2557
  CrossrefPubMedGoogle Scholar
• 42 Han S, Ma E, Wang X. et al Rescuing defective tumor-infiltrating T-cell proliferation in glioblastoma patients. Oncology Letters 2016; 12: 2924-9 doi:10.3892/ol.2016.4944
  CrossrefPubMedGoogle Scholar
• 43 Badie B, Schartner JM. Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery 2000; 46: 957-61 discussion 961–2. doi:10.1097/00006123-200004000-00035
  PubMedGoogle Scholar
• 44 Dutoit V, Herold-Mende C, Hilf N. et al Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 2012; 135: 1042-54 doi:10.1093/brain/aws042
  CrossrefPubMedGoogle Scholar
• 45 Beckhove P, Warta R, Lemke B. et al Rapid T cell-based identification of human tumor tissue antigens by automated two-dimensional protein fractionation. J Clin Invest 2010; 120: 2230-42 doi:10.1172/JCI37646
  CrossrefPubMedGoogle Scholar
• 46 Albulescu R, Codrici E, Popescu ID. et al Cytokine patterns in brain tumour progression. Mediators Inflamm 2013; 2013: 979748 doi:10.1155/2013/979748
  PubMedGoogle Scholar
• 47 Nijaguna MB, Patil V, Hegde AS. et al An Eighteen Serum Cytokine Signature for Discriminating Glioma from Normal Healthy Individuals. PloS one 2015; 10: e0137524 doi:10.1371/journal.pone.0137524
  CrossrefPubMedGoogle Scholar
• 48 Asseman C, Mauze S, Leach MW. et al An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999; 190: 995-1004 doi:10.1084/jem.190.7.995
  CrossrefPubMedGoogle Scholar
• 49 Nakamura K, Kitani A, Fuss I. et al TGF-beta 1 plays an important role in the mechanism of CD4 + CD25 + regulatory T cell activity in both humans and mice. Journal of immunology 2004; 172: 834-42 doi:10.4049/jimmunol.172.2.834
  CrossrefPubMedGoogle Scholar
• 50 Tai X, van Laethem F, Pobezinsky L. et al Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells. Blood 2012; 119: 5155-63 doi:10.1182/blood-2011-11-388918
  CrossrefPubMedGoogle Scholar
• 51 Crane CA, Ahn BJ, Han SJ. et al Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro Oncol 2012; 14: 584-95 doi:10.1093/neuonc/nos014
  CrossrefPubMedGoogle Scholar
• 52 Wainwright DA, Balyasnikova IV, Chang AL. et al IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clinical Cancer Research 2012; 18: 6110-21 doi:10.1158/1078-0432.CCR-12-2130
  CrossrefPubMedGoogle Scholar
• 53 Heimberger AB, Abou-Ghazal M, Reina-Ortiz C. et al Incidence and prognostic impact of FoxP3 + regulatory T cells in human gliomas. Clin Cancer Res 2008; 14: 5166-72 doi:10.1158/1078-0432.CCR-08-0320
  CrossrefPubMedGoogle Scholar
• 54 Zou JP, Morford LA, Chougnet C, Dix AR, Brooks AG, Torres N. et al Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. J Immunol 1999; 162: 4882-92
  PubMedGoogle Scholar
• 55 Seliger C, Leukel P, Moeckel S. et al Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro. PloS one 2013; 8: e78935 doi:10.1371/journal.pone.0078935
  CrossrefPubMedGoogle Scholar
• 56 Silginer M, Burghardt I, Gramatzki D. et al The aryl hydrocarbon receptor links integrin signaling to the TGF-beta pathway. Oncogene 2016; 35: 3260-71 doi:10.1038/onc.2015.387
  CrossrefPubMedGoogle Scholar
• 57 Tanabe K, Matsushima-Nishiwaki R, Yamaguchi S. et al Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells. J Neuroinflammation 2010; 7: 16 doi:10.1186/1742-2094-7-16
  CrossrefPubMedGoogle Scholar
• 58 Zheng X, Zhou K, Zhang Y. et al Food withdrawal alters the gut microbiota and metabolome in mice. FASEB J 2018; 32: 4878-88 doi:10.1096/fj.201700614R
  CrossrefPubMedGoogle Scholar
• 59 Garnier D, Renoult O, Alves-Guerra M-C. et al Glioblastoma Stem-Like Cells, Metabolic Strategy to Kill a Challenging Target. Front Oncol 2019; 9: 118 doi:10.3389/fonc.2019.00118
  CrossrefPubMedGoogle Scholar
• 60 Kelly CJ, Zheng L, Campbell EL. et al Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe 2015; 17: 662-71 doi:10.1016/j.chom.2015.03.005
  CrossrefPubMedGoogle Scholar
• 61 Arpaia N, Campbell C, Fan X. et al Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504: 451-5 doi:10.1038/nature12726
  CrossrefPubMedGoogle Scholar
• 62 Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science 2017 doi:10.1126/science.aaf9794
  PubMedGoogle Scholar
• 63 Lee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev 2010; 34: 426-44 doi:10.1111/j.1574-6976.2009.00204.x
  CrossrefPubMedGoogle Scholar
• 64 Yano JM, Yu K, Donaldson GP. et al Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015; 161: 264-76 doi:10.1016/j.cell.2015.02.047
  CrossrefPubMedGoogle Scholar
• 65 Clarke G, Grenham S, Scully P. et al The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013; 18: 666-73 doi:10.1038/mp.2012.77
  PubMedGoogle Scholar
• 66 Desbonnet L, Garrett L, Clarke G. et al The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat. Journal of Psychiatric Research 2008; 43: 164-74 doi:10.1016/j.jpsychires.2008.03.009
  CrossrefPubMedGoogle Scholar
• 67 Valladares R, Bojilova L, Potts AH. et al Lactobacillus johnsonii inhibits indoleamine 2,3-dioxygenase and alters tryptophan metabolite levels in BioBreeding rats. FASEB J 2013; 27: 1711-20 doi:10.1096/fj.12-223339
  CrossrefPubMedGoogle Scholar
• 68 Raison CL, Dantzer R, Kelley KW. et al CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 2010; 15: 393-403 doi:10.1038/mp.2009.116
  PubMedGoogle Scholar
• 69 Wikoff WR, Anfora AT, Liu J. et al Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 2009; 106: 3698-703 doi:10.1073/pnas.0812874106
  CrossrefPubMedGoogle Scholar
• 70 Opitz CA, Litzenburger UM, Sahm F. et al An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011; 478: 197-203 doi:10.1038/nature10491
  Google Scholar
• 71 Pilotte L, Larrieu P, Stroobant V. et al Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A 2012; 109: 2497-502 doi:10.1073/pnas.1113873109
  CrossrefPubMedGoogle Scholar
• 72 Uyttenhove C, Pilotte L, Theate I. et al Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003; 9: 1269-74 doi:10.1038/nm934
  CrossrefPubMedGoogle Scholar
• 73 Fallarino F, Grohmann U, You S. et al The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 2006; 176: 6752-61 doi:10.4049/jimmunol.176.11.6752
  CrossrefPubMedGoogle Scholar
• 74 Favre D, Mold J, Hunt PW. et al Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2010; 2: 32ra36 doi:10.1126/scitranslmed.3000632
  PubMedGoogle Scholar
• 75 Frumento G, Rotondo R, Tonetti M. et al Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 2002; 196: 459-68 doi:10.1084/jem.20020121
  CrossrefPubMedGoogle Scholar
• 76 Fallarino F, Grohmann U, Vacca C. et al T cell apoptosis by tryptophan catabolism. Cell Death Differ 2002; 9: 1069-77 doi:10.1038/sj.cdd.4401073
  CrossrefPubMedGoogle Scholar
• 77 Mezrich JD, Fechner JH, Zhang X. et al An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 2010; 185: 3190-8 doi:10.4049/jimmunol.0903670
  CrossrefPubMedGoogle Scholar
• 78 Rothhammer V, Mascanfroni ID, Bunse L. et al Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 2016; 22: 586-97 doi:10.1038/nm.4106
  CrossrefPubMedGoogle Scholar
• 79 Quintana FJ, Basso AS, Iglesias AH. et al Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 453: 65-71 doi:10.1038/nature06880
  Google Scholar
• 80 Opitz CA, Litzenburger UM, Opitz U. et al The indoleamine-2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan upregulates IDO1 in human cancer cells. PloS one 2011; 6: e19823 doi:10.1371/journal.pone.0019823
  CrossrefPubMedGoogle Scholar
• 81 Vezzani A, Gramsbergen JB, Speciale C. et al Production of quinolinic acid and kynurenic acid by human glioma. Adv Exp Med Biol 1991; 294: 691-5 doi:10.1007/978-1-4684-5952-4_95
  PubMedGoogle Scholar
• 82 Alberati-Giani D, Ricciardi-Castagnoli P, Köhler C. et al Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells. J Neurochem 1996; 66: 996-1004 doi:10.1046/j.1471-4159.1996.66030996.x
  PubMedGoogle Scholar
• 83 D’Amato NC, Rogers TJ, Gordon MA. et al A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res 2015; 75: 4651-64 doi:10.1158/0008-5472.CAN-15-2011
  CrossrefPubMedGoogle Scholar
• 84 McCord M, Mukouyama YS, Gilbert MR. et al Targeting WNT Signaling for Multifaceted Glioblastoma Therapy. Front Cell Neurosci 2017; 11: 318 doi:10.3389/fncel.2017.00318
  CrossrefPubMedGoogle Scholar
• 85 Carro MS, Lim WK, Alvarez MJ. et al The transcriptional network for mesenchymal transformation of brain tumours. Nature 2010; 463: 318-25 doi:10.1038/nature08712
  Google Scholar
• 86 West AJ, Tsui V, Stylli SS. et al The role of interleukin-6-STAT3 signalling in glioblastoma. Oncol Lett 2018; 16: 4095-104 doi:10.3892/ol.2018.9227
  PubMedGoogle Scholar
• 87 Ferguson SD, Srinivasan VM, Heimberger AB. The role of STAT3 in tumor-mediated immune suppression. J Neurooncol 2015; 123: 385-94 doi:10.1007/s11060-015-1731-3
  CrossrefPubMedGoogle Scholar
• 88 Leidgens V, Seliger C, Jachnik B. et al Ibuprofen and Diclofenac Restrict Migration and Proliferation of Human Glioma Cells by Distinct Molecular Mechanisms. PloS one 2015; 10: e0140613 doi:10.1371/journal.pone.0140613
  CrossrefPubMedGoogle Scholar
• 89 Yamini B. NF-kappaB, Mesenchymal Differentiation and Glioblastoma. Cells 2018 doi:10.3390/cells7090125
  PubMedGoogle Scholar
• 90 Gray GK, McFarland BC, Nozell SE. et al NF-kappaB and STAT3 in glioblastoma: therapeutic targets coming of age. Expert Rev Neurother 2014; 14: 1293-306 doi:10.1586/14737175.2014.964211
  CrossrefPubMedGoogle Scholar
• 91 Monsalve FA, Pyarasani RD, Delgado-Lopez F. et al Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm 2013; 2013: 549627 doi:10.1155/2013/549627
  PubMedGoogle Scholar
• 92 Ellis HP, Kurian KM. Biological Rationale for the Use of PPARgamma Agonists in Glioblastoma. Front Oncol 2014; 4: 52 doi:10.3389/fonc.2014.00052
  PubMedGoogle Scholar
• 93 Grommes C, Conway DS, Alshekhlee A. et al Inverse association of PPARgamma agonists use and high grade glioma development. J Neurooncol 2010; 100: 233-9 doi:10.1007/s11060-010-0185-x
  CrossrefPubMedGoogle Scholar
• 94 Maleki Vareki S, Rytelewski M, Figueredo R. et al Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin. Oncotarget 2014; 5: 2778-91 doi:10.18632/oncotarget.1916
  CrossrefPubMedGoogle Scholar
• 95 Fulda S, Kogel D. Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. Oncogene 2015; 34: 5105-13 doi:10.1038/onc.2014.458
  CrossrefPubMedGoogle Scholar
• 96 Joseph JV, Conroy S, Tomar T. et al TGF-β is an inducer of ZEB1-dependent mesenchymal transdifferentiation in glioblastoma that is associated with tumor invasion. Cell Death & Disease 2014; 5: e1443 doi:10.1038/cddis.2014.395
  CrossrefPubMedGoogle Scholar
• 97 Bhat KPL, Balasubramaniyan V, Vaillant B. et al Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer cell 2013; 24: 331-346 doi:10.1016/j.ccr.2013.08.001
  CrossrefPubMedGoogle Scholar
• 98 Rutledge WC, Kong J, Gao J. et al Tumor-Infiltrating Lymphocytes in Glioblastoma Are Associated with Specific Genomic Alterations and Related to Transcriptional Class. Clinical Cancer Research 2013; 19: 4951-4960 doi:10.1158/1078-0432.CCR-13-0551
  CrossrefPubMedGoogle Scholar