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

Guastella, Anthony R.; Michelhaugh, Sharon K.; Klinger, Neil V.; Fadel, Hassan; Kiousis, Sam; Ali-Fehmi, Rouba; Kupsky, William J.; Juhász, Csaba; Mittal, Sandeep

doi:10.1007/s11060-018-2869-6

Cited by 38 publications

(43 citation statements)

References 47 publications

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“…Although the aberrant activation of KP and expression patterns of the first rate-limiting KP enzyme in gliomas have been previously reported, 5,9,10,13,[31][32][33][34] the systemic and comprehensive studies of the expression, activity, and individual function of IDO1 and its isozymes in gliomas are very limited.…”

Section: Discussionmentioning

confidence: 99%

“…Similar results have been observed for IDO1, IDO2, and TDO mRNA expression in the TCGA database 35 and IDO1/TDO protein expression of paraffin-embedded tissue sections from glioma patients. 13,31,32,34 Compared with IDO1/TDO, the function of IDO2 has been less studied. IDO2 plays a nonredundant role in Trp metabolism 36 and a nonredundant immunosuppressive role different from that of IDO1 and TDO.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is a recent report showing that the expression of IDO2 was positively correlated with the grades of glioma. 34 A previous study using bioinformatical analysis of the Rembrandt or TCGA database showed that high IDO1/TDO mRNA expression was associated with poor prognosis in patients with glioma. 13,35,40 Herein, for the first time, it was found that glioma patients with positive IDO1/TDO protein expression had shorter overall survival.…”

Section: Discussionmentioning

confidence: 99%

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Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn–AhR–AQP4 signaling pathway

Xing

Tao

et al. 2020

Sig Transduct Target Ther

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Indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO) initiate the first step of the kynurenine pathway (KP), leading to the transformation of L-tryptophan (Trp) into L-kynurenine (Kyn) and other downstream metabolites. Kyn is known as an endogenous ligand of the aryl hydrocarbon receptor (AhR). Activation of AhR through TDO-derived Kyn is a novel mechanism to support tumor growth in gliomas. However, the role of IDO1 and IDO2 in this mechanism is still unknown. Herein, by using clinical samples, we found that the expression and activity of IDO1 and/or TDO (IDO1/TDO) rather than IDO2 were positively correlated with the pathologic grades of gliomas. The expression of IDO1/TDO rather than IDO2 was positively correlated with the Ki67 index and overall survival. The expression of IDO1/TDO was positively correlated with the expression of aquaporin 4 (AQP4), implying the potential involvement of IDO1/TDO in glioma cell motility. Mechanistically, we found that IDO1/TDO accounted for the release of Kyn, which activated AhR to promote cell motility via the Kyn-AhR-AQP4 signaling pathway in U87MG glioma cells. RY103, an IDO1/TDO dual inhibitor, could block the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway and exert anti-glioma effects in GL261 orthotopic glioma mice. Together, our results showed that the IDO1/ TDO-Kyn-AhR-AQP4 signaling pathway is a new mechanism underlying the malignancy of gliomas, and suggest that both IDO1 and TDO might be valuable therapeutic targets for gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn–AhR–AQP4 signaling pathway

Xing

Tao

et al. 2020

Sig Transduct Target Ther

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“…The growth pattern of astrocytomas in the brain consists of invasive or local invasive growth, and as the invasiveness increases, the tumour grade increases and the survival rate decreases (10). At present, the conventional treatment is primarily surgical resection supplemented by radiotherapy and chemotherapy (11). There are a number of surgical methods for astrocytoma, including excisional biopsy (EB), subtotal resection (STR), gross resection (GR), partial resection (PR) and gross total resection (GTR).…”

Section: Introductionmentioning

confidence: 99%

Advantages of gross total resection in patients with astrocytoma: A population‑based study

Mao

2020

Oncol Lett

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The present study aimed to investigate the association between surgical methods and survival outcomes in patients with astrocytoma. Patients diagnosed with astrocytoma between January 2004 and December 2015 were identified using the Surveillance, Epidemiology and End Results database. Kaplan-Meier curves and Cox regression were used to analyze the effects of surgical methods on overall survival (OS) and cancer-specific survival (CSS). Among 42,224 eligible patients with astrocytoma, 11,427 (27.1%) patients did not receive surgery, 7,661 (18.1%) received excisional biopsy (EB), 5,520 (13.1%) received a subtotal resection (STR), 6,037 (14.3%) received a gross resection (GR), 5,314 (12.6%) received a partial resection (PR) and 6,265 (14.8%) received a gross total resection (GTR). Patients who underwent GR had the longest survival time (17.00 months). However, over time, the proportion of patients who underwent STR or GR increased, whereas the proportion of patients who did not undergo surgery, PR or GTR decreased. Furthermore, surgical method was an independent prognostic factor for OS and CSS for the patients with astrocytoma. Multivariate Cox regression showed that GTR was associated with the more favorable OS [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.77-0.83; P<0.001] and CSS (HR, 0.80; 95% CI, 0.77-0.83; P<0.001) times compared with EB. Moreover, similar results were observed in subgroup analyses based on summary stage and grade. In the present study, it was demonstrated that GTR was one of the effective surgical methods for improved OS and CSS time in patients with astrocytoma. However, among the American astrocytoma population, the proportion of patients who underwent GTR decreased. It is necessary to further advocate for the efficacy of GTR.

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“…IDO1 and TDO2 activity can lead to an immunosuppressed tumor microenvironment that promotes progression of glioblastoma (24). Production of KYN increases the occupancy of the aryl hydrocarbon receptor, thus enhancing the invasiveness of human glioblastoma cells (24,25).…”

Section: Introductionmentioning

confidence: 99%

Multimodal neuroimaging of gliomatosis cerebri: a case series of four patients

Bonomi

John

Patel

et al. 2020

Acta Radiologica Open

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In the latest World Health Organization classification of brain tumors, gliomatosis cerebri has been redefined to varying subsets of diffuse gliomas; however, the term is still used to describe gliomas with infiltrative growth into three or more cerebral lobes. These tumors are frequently misdiagnosed and difficult to treat due to their atypical presentation using structural imaging modalities including computed tomography and T1/T2-weighted magnetic resonance imaging (MRI). In this retrospective case series, we compared clinical MRI to amino acid positron emission tomography (PET) to assess the potential value of PET in the assessment of the extent of tumor involvement and in monitoring disease progression. We report the clinical course and serial multimodal imaging findings of four patients. Each patient presented at varying points in disease progression with widespread glioma brain involvement and was evaluated at least once by amino acid PET using alpha-[11C]methyl-L-tryptophan ([11C]-AMT). Increased uptake of [11C]-AMT was detected in a subset of non-enhancing brain lesions and detected tumor invasion before MRI signs of tumor in some regions. Increased uptake of [11C]-AMT was also detected in tumorous regions not detected by perfusion MRI or MR spectroscopy. Metabolic response to treatment was also observed in two patients. Overall, these data are consistent with and expand upon previous reports using other amino acid PET tracers in gliomatosis and show the potential added value of this imaging modality to clinical MRI in the detection and monitoring of these diffusely infiltrative tumors.

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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

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

Cited by 38 publications

References 47 publications

Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn–AhR–AQP4 signaling pathway

Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn–AhR–AQP4 signaling pathway

Advantages of gross total resection in patients with astrocytoma: A population‑based study

Multimodal neuroimaging of gliomatosis cerebri: a case series of four patients

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