• digestive system diseases
• kynurenine
• treatment strategy
• tryptophan metabolism
• tryptophan-2,3-dioxygenase (TDO2)

• 32370888 National Natural Science Foundation of China
• MSPY202101 Minnan Normal University Cultivation Project
• 2022J05180 Fujian Provincial Natural Science Foundation of China
• 2024J08071 Fujian Provincial Natural Science Foundation of China

• Amino acid metabolism
• Cancer stem cell (CSC)
• Glucose metabolism
• Lipid metabolism
• Tumor therapy

• Humans
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Lipid Metabolism
• Glucose/metabolism
• Neoplasms/metabolism
• Neoplasms/pathology
• Amino Acids/metabolism
• Animals

• IRF9
• Macrophage
• PSMA5
• Rheumatoid arthritis

• IDO1
• IL4I1
• amino acid metabolism
• arginine
• cancer immunotherapy
• glutamine
• immunosuppression
• tryptophan

• Humans
• Neoplasms/immunology
• Neoplasms/therapy
• Neoplasms/metabolism
• Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
• Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
• Immunotherapy/methods
• Animals
• Amino Acids/metabolism
• Arginase/metabolism
• Glutaminase/metabolism
• Glutaminase/antagonists & inhibitors
• Tumor Escape
• Nitric Oxide Synthase Type II/metabolism
• Tryptophan Oxygenase/metabolism
• Tryptophan Oxygenase/antagonists & inhibitors
• Molecular Targeted Therapy
• Tumor Microenvironment/immunology
• L-Amino Acid Oxidase

• IDO-1
• TDO2
• Tryptophan metabolism
• aryl hydrocarbon receptor
• cancer stem cells
• hematopoietic stem cells
• human diseases
• induced pluripotent stem cells
• kynurenine pathway
• mesenchymal stromal cells
• neural stem cells

• St. Vincent’s Clinic Foundation
• Multiple Sclerosis Australia
• St Vincent’s Curran Foundation

• Biomarker
• Mechanism
• Metabolic reprogramming
• Treatment strategy
• Tryptophan metabolism

• Humans
• Tryptophan/metabolism
• Gastrointestinal Neoplasms
• Liver/metabolism

• 82200673 National Nature Science Foundation of China
• Z24H160013 Key Nature Science Foundation of Zhejiang province
• zz202306 the Independent Project Fund of the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the National Key Research and Development Program of China

• EMT
• cancer stem-like cells
• esophageal squamous cell carcinoma
• microenvironment
• surface markers

• Ahr
• cancer
• immunoregulation
• kynurenine
• metastasis
• tryptophan pathway

• NRF of Prof Anguelov
• Research Development program of Dr JC Serem
• Research Development program of Dr YN Hlophe
• School of Medicine Research Committee

• AHR
• IDO1
• TDO2
• cancer
• immune evasion
• kynurenine
• proliferation
• tryptophan

• Humans
• Tryptophan/metabolism
• Kynurenine/metabolism
• Neoplasms/genetics
• Neoplasms/therapy
• Tryptophan Oxygenase/genetics
• T-Lymphocytes/metabolism
• Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism

• R01 CA245548 NCI NIH HHS
• R01 GM145744 NIGMS NIH HHS
• T32 GM007062 NIGMS NIH HHS
• T32 GM131945 NIGMS NIH HHS

Tryptophan 2,3-dioxygenase (TDO2) is one of the emerging immune checkpoints. Meanwhile, TDO2 is also a key enzyme in the tryptophan (Trp)–kynurenine (Kyn) signaling pathway. Many studies have evaluated that TDO2 is highly expressed in various malignant tumor patients and plays a prognostic role. However, the sample size of a single prognostic study was small, and the results were still controversial.

We used Stata software and referenced the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement to conduct a meta-analysis on TDO2 and its clinical features and prognosis. We searched the PubMed, Cochrane Library, and Web of Science databases to find publications concerning TDO2 expression in malignant tumor patients up to June 2021. We used the Newcastle–Ottawa Scale (NOS) to evaluate the bias risk of the included literature. Risk ratios (RRs) and hazard ratios (HRs) were used for clinical outcomes, specifically overall survival (OS) and progression-free survival (PFS). In addition, we used data from The Cancer Genome Atlas (TCGA) to verify our conclusions.

Nine studies including 667 patients with malignant tumors were identified. Our results suggested that overexpression of TDO2 was statistically correlated with poor OS and poor PFS (HR = 2.58, 95% CI = 1.52–4.40, p = 0.0005; HR = 2.38, 95% CI = 0.99–5.73, p = 0.05). In terms of clinicopathological characteristics, the overexpression level of TDO2 was statistically correlated with TNM (tumor–node–metastasis) stage (RR = 0.65, 95% CI = 0.48–0.89, p = 0.002) and regional lymph node metastasis (RR = 0.76, 95% CI = 0.59–0.99, p = 0.04). Subgroup analysis revealed the potential sources of heterogeneity. In addition, bioinformatics studies suggested that the level of TDO2 was high in malignant tumors and higher in cancer tissue than in matched paracarcinoma tissue. Gene enrichment analysis showed that TDO2 was closely related to immune response.

Overall, TDO2 may be a biomarker for the survival and prognosis of patients with malignant tumors and a potential therapeutic target in the future.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=260442, identifier (CRD42021260442)

• biological function
• cancer
• clinical application
• miR-1258
• tumor suppressor

Tryptophan 2,3-dioxygenase (TDO) encoded by TDO2, a rate-limiting enzyme in the kynurenine pathway, catabolizes tryptophan to kynurenine, evades immune surveillance, and promotes tumor growth. Although accumulating evidence suggests a crucial role of TDO2 during tumor formation and development, systematic evaluation of TDO2 across human cancers has rarely been reported.

To shed more light on the role of TDO2 in human cancer, we explored the expression profiles of TDO2 and identified its prognostic value in pancancer analysis through TCGA, CCLE, and GTEx databases. We further utilized TCGA data to evaluate the association between TDO2 and tumor immunological features, such as mismatch repair (MMR), tumor immune infiltration, immune checkpoint-related genes, tumor mutational burden (TMB), microsatellite instability (MSI), and DNA methyltransferase (DNMT).

TDO2 exhibited different expression levels in various cancer cell lines. Frequently, TDO2 was detected to be highly expressed in the majority of cancers. In addition, high TDO2 expression was correlated with an unfavorable prognosis for patients in KIRP, LGG, TGCT, and UVM. Moreover, high TDO2 expression level positively correlated with higher immune infiltration, especially dendritic cells. Additionally, there is a close relationship between TDO2 and immune checkpoint-related gene markers, such as LAIR1, CD276, NRP1, CD80, and CD86. Finally, correlation analysis has demonstrated a high-correlation between TDO2 and TMB, MSI, MMR, and DNMT of multiple cancer types.

Therefore, our results suggest that TDO2 can function as a potential prognostic biomarker due to its role in tumor immunity regulation.

In addition to its well-established immunosuppressive actions, tryptophan 2,3-dioxygenase (TDO) appears to elicit direct effects on tumor cell function. Although TDO has been associated with cancer stemness, its involvement in melanoma stem cell biology remains largely unknown. Since we showed that by upregulating TDO, dexamethasone (dex) promotes proliferation and migration of SK-Mel-28 human melanoma cells, we sought to investigate dex effects on melanoma spherogenesis and stemness, and whether these events are mediated by TDO. We demonstrate here that dex significantly upregulates TDO in A375, a more aggressive melanoma cell line, confirming that dex effects are not limited to SK-Mel-28 cells. Moreover, dex stimulates spherogenesis of both cell lines, which is mediated by TDO, evident by its suppression with 680C91, a TDO inhibitor. The formed melanospheres appear to be enriched with embryonic stem cell marker mRNAs, the expression of which is potentiated by dex. Expression of cancer stem cell markers (CD133, CD44, ganglioside GD2) was significantly increased in A375 spheres, as detected by flow cytometry. Taken together, our results suggest that TDO could represent a promising target in the management of melanoma and that dex, routinely used as a co-medication also in advanced melanoma, may stimulate melanoma cell function/tumor-supporting properties, a rather debilitating and undesired side effect.

Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.

• Amino acid metabolism
• Cancer stem cell
• Self-renewal
• Resistance

The impact of germline variants on the regulation of the expression of tumor microenvironment (TME)-based immune response genes remains unclear. Expression quantitative trait loci (eQTL) provide insight into the effect of downstream target genes (eGenes) regulated by germline-associated variants (eVariants). Through eQTL analyses, we illustrated the relationships between germline eVariants, TME-based immune response eGenes, and clinical outcomes. In this study, both RNA sequencing data from primary tumor and germline whole-genome sequencing data were collected from patients with stage III colorectal cancer (CRC). Ninety-nine high-risk subjects were subjected to immune response gene expression analyses. Seventy-seven subjects remained for further analysis after quality control, of which twenty-two patients (28.5%) experienced tumor recurrence. We found that 65 eQTL, including 60 germline eVariants and 22 TME-based eGenes, impacted the survival of cancer patients. For the recurrence prediction model, 41 differentially expressed genes (DEGs) achieved the best area under the receiver operating characteristic curve of 0.93. In total, 19 survival-associated eGenes were identified among the DEGs. Most of these genes were related to the regulation of lymphocytes and cytokines. A high expression of HGF, CCR5, IL18, FCER1G, TDO2, IFITM2, and LAPTM5 was significantly associated with a poor prognosis. In addition, the FCER1G eGene was associated with tumor invasion, tumor nodal stage, and tumor site. The eVariants that regulate the TME-based expression of FCER1G, including rs2118867 and rs12124509, were determined to influence survival and chromatin binding preferences. We also demonstrated that FCER1G and co-expressed genes in TME were related to the aggregation of leukocytes via pathway analysis. By analyzing the eQTL from the cancer genome using germline variants and TME-based RNA sequencing, we identified the eQTL in immune response genes that impact colorectal cancer characteristics and survival.

• Immune cells
• Knockout mice
• Kynurenine
• TDO2
• Tryptophan

Tryptophan 2,3-dioxygnease 2 (TDO2) is specific for metabolizing tryptophan to kynurenine (KYN), which plays a critical role in mediating immune escape of cancer. Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers, its tumor-promoting role in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we observed that TDO2 was overexpressed in ESCC tissues and correlated significantly with lymph node metastasis, advanced clinical stage, and unfavorable prognosis. Functional experiments showed that TDO2 promoted tumor cell proliferation, migration, and colony formation, which could be prevented by inhibition of TDO2 and aryl hydrocarbon receptor (AHR). Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model, tumor burden of C57BL/6 mice with ESCC induced by 4-NQO, enhance the expression of phosphorylated AKT, with subsequent phosphorylation of GSK3β, and polarization of M2 macrophages by upregulating interleukin-8 (IL-8) to accelerate tumor progression in the tumor microenvironment (TME). Collectively, our results discovered that TDO2 could upregulate IL-8 through AKT/GSK3β to direct the polarization of M2 macrophages in ESCC, and suggested that TDO2 could represent as an attractive therapeutic target and prognostic marker to ESCC.

• Esophageal squamous cell carcinoma
• IL-8
• KYN
• M2 macrophage
• Tryptophan 2,3-dioxygenase 2

Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test.

A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry.

A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort.

The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches.

• Cancer stem cell
• PD-L1
• PTEN
• Renal cell carcinoma
• TDO2

• Aged
• Biomarkers, Tumor/metabolism
• Carcinoma, Renal Cell/pathology
• Disease Progression
• Female
• Humans
• Kidney Neoplasms/pathology
• Male
• Retrospective Studies
• Tryptophan Oxygenase/metabolism

Bladder cancer (BC) is the 10th most common cancer in the world. BC with muscle invasion results in a poor prognosis and is usually fatal. Cancer cell metabolism has an essential role in the development and progression of tumors. Expression of tryptophan 2,3‐dioxygenase (TDO2) is associated with tumor progression and worse survival in some other cancers. However, no studies have been performed to uncover the biofunctional roles of TDO2 in BC.

This study aim to investigate the clinicopathologic significance of TDO2 in BC.

TDO2 expression was evaluated by qRT‐PCR and immunohistochemistry in an integrated analysis with the Cancer Genome Atlas (TCGA) and other published datasets. TDO2 overexpression was significantly associated with T classification, N classification, and M classification, tumor stage, recurrence, and basal type, and with the expression of CD44 and aldehyde dehydrogenase 1 (ALDH1) in BC. High TDO2 expression correlated with poor outcome of BC patients. Using BC cell lines with knockdown and forced expression of TDO2, we found that TDO2 was involved in the growth, migration, and invasiveness of BC cells. Moreover, TDO2 was found to be crucial for spheroid formation in BC cells. Importantly, TDO2 promoted BC cells resistance to cetuximab through integration of the EGFR pathway.

Our results indicate that TDO2 might take an essential part in BC progression and could be a potential marker for targeted therapy in BC.

• EGFR
• TDO2
• bladder cancer
• cancer stem cell
• cetuximab
• spheroid formation

Tryptophan 2,3-dioxygenase (TDO2) is a key rate-limiting enzyme in the kynurenine pathway and promotes tumor growth and escape from immune surveillance in different types of cancer. The present study aimed to investigate whether TDO2 serves a role in the development of ovarian cancer. Reverse transcription-quantitative PCR and western blotting were used to detect the expression of TDO2 in different cell lines. The effects of TDO2 overexpression, TDO2 knockdown and TDO2 inhibitor on ovarian cancer cell proliferation, migration and invasion were determined by MTS, colony formation and Transwell assays. The expression of TDO2 in ovarian cancer tissues, normal ovarian tissues and fallopian tube tissues were analyzed using the gene expression data from The Cancer Genome Atlas and Genotype-Tissue Expression project. Immune cell infiltration in cancer tissues was evaluated using the single sample gene set enrichment analysis algorithm. The present study found that Ras^V12-mediated oncogenic transformation was accompanied by the upregulation of TDO2. In addition, it was demonstrated that TDO2 was upregulated in ovarian cancer tissues compared with normal ovarian tissues. TDO2 overexpression promoted proliferation, migration and invasion of ovarian cancer cells, whereas TDO2 knockdown repressed these phenotypes. Treatment with LM10, a TDO2 inhibitor, also repressed the proliferation, migration and invasion of ovarian cancer cells. The present study indicated that TDO2 can be used as a new target for the treatment of ovarian cancer.

• tryptophan 2,3‑dioxygenase
• ovarian cancer
• proliferation
• migration
• invasion

• AHR
• Cancer
• IDO
• Immune system
• Indoximod
• Kynurenine pathway

• Animals
• Antineoplastic Agents/therapeutic use
• Enzyme Inhibitors/therapeutic use
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
• Kynurenine/metabolism
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/pathology
• Signal Transduction
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• Tumor Microenvironment

• Tryptophan 2,3-dioxygenase (TDO2)
• aryl hydrocarbon receptor (AhR)
• epithelial to mesenchymal transition (EMT)
• hepatocellular carcinoma
• metastasis

• P51 OD011104 NIH HHS

In locally advanced rectal cancer patients (LARC), preoperative chemoradiation improves local control and sphincter preservation. The response rate to treatment varies substantially between 20 and 30%, and it is an important prognostic factor. Indeed, nonresponsive patients are subjected to higher rates of local and distant metastases, and worse survival compared to patients with complete response. In the search of predictive biomarkers for response prediction to therapy in LARC patients, we found increased plasma tryptophan levels in nonresponsive patients. On the basis of plasma levels of 5-hydroxy-tryptophan and kynurenine, the activities of tryptophan 5-hydroxylase 1 (TPH1) and indoleamine-2,3-dioxygenases 1 (IDO1)/tryptophan-2,3-dioxygenase (TDO2) have been obtained and data have been correlated with gene expression profiles. We demonstrated that TDO2 overexpression in nonresponsive patients correlates with kynurenine plasma levels. Finally, through the gene expression and targeted metabolomic analysis in paired healthy mucosa-rectal cancer tumor samples, we evaluated the impact of tryptophan catabolism at tissue level in responsive and nonresponsive patients.

• IDO1
• TDO2
• TPH1
• kynurenine pathway
• rectal cancer
• serotonin pathway
• tryptophan

• IDO1
• IDO2
• KYNU
• TDO2
• breast cancer
• cancer immunotherapy
• immune infiltrates

Tryptophan 2,3-dioxygenase (TDO), encoded by the gene TDO2, is an enzyme that catalyses the first and rate-limiting step of tryptophan (Try) degradation in the kynurenine (Kyn) pathway in the liver. Recently, TDO has been demonstrated to be expressed in various human tumours, especially hepatocellular carcinoma (HCC). However, the role of TDO in HCC is still not very clear. Here, we studied the role of TDO in HCC.

We demonstrated that TDO is overexpressed in human HCC tissues and is significantly correlated with malignant phenotype characteristics, including tumour size, tumour differentiation, vascular invasion, etc. Kaplan–Meier analysis showed a poor overall survival rate in patients with TDO-overexpressing tumours. In addition, the effects of TDO on HCC tumour growth and metastasis were detected both in vivo and in vitro. TDO overexpression facilitated HCC cell growth, invasion and migration.

Our results suggest that TDO positively regulates HCC proliferation and invasion and acts as a new prognostic biomarker of HCC.

• 3-dioxygenase
• TDO
• hepatocellular carcinoma
• tryptophan
• tryptophan 2

• immunosurveillance
• cancer metabolism

• Animals
• Enzyme Inhibitors/therapeutic use
• Humans
• Immunotherapy/methods
• Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
• Kynurenine/metabolism
• Mice
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Tryptophan/metabolism
• Tryptophan Oxygenase/antagonists & inhibitors
• Tryptophan Oxygenase/metabolism

• No 754688 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
• No 643638 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
• No 754688 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
• 01ZX1402 Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• 01ZX1402 Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
• University of Costa Rica | Vicerrectoría de Investigación, Universidad de Costa Rica (Vice-Rector for Research at the University of Costa Rica)
• Costa Rica’s Ministry of Science, Technology and Telecommunications (MICITT)

The self-renewal and differentiation potentials of stem cells are dependent on amino acid (AA) metabolism. We review the literature on the metabolic preference of both cancer and noncancer stem cells. The balance in AA metabolism is responsible for maintaining the functionality of noncancer stem cells, and altering the levels of AAs can influence the malignant biological behavior of cancer stem cells. AAs are considered nutrients participating in metabolism and playing a critical role in maintaining the activity of normal stem cells and the effect of therapy of cancer stem cells. Targeting AA metabolism helps inhibit the stemness of cancer stem cells and remodels the function of normal stem cells. This review summarizes the metabolic characteristics and regulation pathways of AA in different stem cells, not only from the nutritional perspective but also from the genomic perspective that have been reported in the recent five years. In addition, we briefly survey new therapeutic modalities that may help eradicate cancer stem cells by exploiting nutrient deprivation. Understanding AA uptake characteristics helps researchers define the preference for AA in different stem cells and enables clinicians make timely interventions to specifically target the cell behavior.

• Cancer
• Disease
• Neurological disorders
• Physiology
• Psychiatric disorders
• Tryptophan