Inflammation in cancer and depression: a starring role for the kynurenine pathway

Sforzini, Luca; Nettis, Maria Antonietta; Mondelli, Valeria; Pariante, Carmine M.

doi:10.1007/s00213-019-05200-8

Cited by 64 publications

(81 citation statements)

References 122 publications

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“…For pediatric brain cancers, non-invasive PET imaging methods that can detect tumors with high sensitivity and specificity have lagged behind adult applications. In this study, we provide evidence that the tryptophan amino acid derivative 1-L-[ 18 ]FETrp, as abnormal tryptophan metabolism in tumors has been linked to the kynurenine inflammatory pathway 28,41,42 . Based on our studies in an immunocompetent, genetically engineered preclinical medulloblastoma model with spontaneous tumor occurrence and intact blood-brain barrier, we now suggest that 1-L-[ 18 F]FETrp, in combination with other commonly used imaging modalities, may have clinical relevance for the diagnosis, metabolic characterization and evaluation of response to treatment of medulloblastoma.…”

Section: Discussionmentioning

confidence: 93%

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Xin

Yue

et al. 2020

Sci Rep

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In vivo positron emission tomography (pet) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[ 18 F]fluoroethyl)-L-tryptophan (1-L-[ 18 f]fetrp) as a pet imaging probe for this common malignant pediatric brain tumor. 1-L-[ 18 F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/ Smo medulloblastoma mice with constitutive actvation of the Smoothened (Smo) receptor using a PerkinElmer G4 PET-X-Ray scanner. Medulloblastoma showed significant and specific accumulation of 1-L-[ 18 F]FETrp. 1-L-[ 18 F]FETrp also showed significantly higher tumor uptake than its D-enantiomer, 1-D-[ 18 F]FETrp. The uptake of 1-L-[ 18 F]FETrp in the normal brain tissue was low, suggesting that 1-L-[ 18 f] fetrp may prove a valuable pet imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors.

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Section: Discussionmentioning

confidence: 93%

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Xin

Yue

et al. 2020

Sci Rep

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“…Depression is probably not only due to emotional distress but also due to immunological mechanisms, which might negatively affect the QoL and increase all-cause mortality (199)(200)(201). Enhanced Trp breakdown as a consequence of immune activation has been proposed to play a crucial role in the development of depression in cancer patients (202)(203)(204).…”

Section: Fatigue and Depression Are Related To Immune Activation In Cmentioning

confidence: 99%

“…It can cross the blood-brain barrier; therefore, reduced Trp availability may contribute to serotonin dysregulation and neurobehavioral manifestations (217,218). However, also the accumulation of downstream metabolites of the Kyn pathway is suggested to trigger neurobehavioral symptoms (204,205).…”

Section: Inflammatory-induced Tryptophan Breakdown Contributes To Thementioning

confidence: 99%

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

et al. 2020

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Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

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“…The kynurenine pathway may be involved in several psychiatric disorders, several of which have been reviewed in detail (144)(145)(146)(154)(155)(156)(157). Perhaps the strongest evidence is for a role in schizophrenia (145,146).…”

Section: Psychiatric Disordersmentioning

confidence: 99%

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

et al. 2020

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The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.

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Inflammation in cancer and depression: a starring role for the kynurenine pathway

Cited by 64 publications

References 122 publications

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

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