Pham Q.T.a,b· Taniyama D.a· Akabane S.a· Takashima T.a· Maruyama R.a· Sekino Y.c· Sentani K.a· Yasui W.a· Oue N.a

Author affiliations

aDepartment of Molecular Pathology, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
bDepartment of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
cDepartment of Urology, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan

Log in to MyKarger to check if you already have access to this content.

Buy FullText & PDF Unlimited re-access via MyKarger Unrestricted printing, no saving restrictions for personal use read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.

Save over 20% compared to the individual article price.

Learn more

Rent/Cloud Rent for 48h to view Buy Cloud Access for unlimited viewing via different devices Synchronizing in the ReadCube Cloud Printing and saving restrictions apply Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe Access to all articles of the subscribed year(s) guaranteed for 5 years Unlimited re-access via Subscriber Login or MyKarger Unrestricted printing, no saving restrictions for personal use read more

Subcription rates

Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview

Received: November 16, 2021
Accepted: February 06, 2022
Published online: June 09, 2022

Number of Print Pages: 12
Number of Figures: 4
Number of Tables: 3

ISSN: 1015-2008 (Print)
eISSN: 1423-0291 (Online)

For additional information: https://www.karger.com/PAT

Abstract

Introduction: Tryptophan metabolism has been shown to be involved in tumor development. Two main tryptophan-degrading enzymes, tryptophan 2,3-dioxygenase (TDO2) and indoleamine 2,3-dioxygenase 1 (IDO1), may potently promote cancer cell survival and distant metastasis in diverse types of cancer, such as lung and breast cancer. IDO1 overexpression is an independent prognosticator in gastric cancer (GC). This work aimed to uncover the expression of TDO2 and its clinicopathologic significance in GC. Methods: TDO2 expression was evaluated in public data of The Cancer Genome Atlas cohort STAD and in two different GC cohorts. Correlation between TDO2 and immune cell infiltrates as well as PD-L1 tumor staining was investigated. The biofunction of TDO2 was examined with MTT, colony formation, and spheroid formation assays by RNA interference. Results: TDO2 expression was correlated with both progressive disease and clinical outcome, and its expression was an independent predictor of prognosis in GC. TDO2 expression was correlated with infiltration of immune cells and tumor expression of PD-L1. Inhibition of TDO2 expression suppressed cell proliferation, colony formation, and cell invasion of GC cells. Additionally, suppression of TDO2 expression inhibited spheroid body-formation and viability of GC organoids. Conclusion: Our data show that TDO2 might be a crucial marker for predicting prognosis and targeted therapy in GC.

© 2022 S. Karger AG, Basel

References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. Services CfCCaI. Cancer statistics: National Cancer Center. 2020. Available from: http://ganjoho.jp/reg_stat/statistics/index.html. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22. Tirino G, Pompella L, Petrillo A, Laterza MM, Pappalardo A, Caterino M, et al. What’s new in gastric cancer: the therapeutic implications of molecular classifications and future perspectives. Int J Mol Sci. 2018;19(9):2659. Katai H, Ishikawa T, Akazawa K, Isobe Y, Miyashiro I, Oda I, et al. Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001–2007). Gastric Cancer. 2018;21(1):144–54. Xin Yu J, Hodge JP, Oliva C, Neftelinov ST, Hubbard-Lucey VM, Tang J. Trends in clinical development for PD-1/PD-L1 inhibitors. Nat Rev Drug Discov. 2020;19(3):163–4. Kono K, Nakajima S, Mimura K. Current status of immune checkpoint inhibitors for gastric cancer. Gastric Cancer. 2020;23(4):565–78. Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017;14(1):11–31. Counihan JL, Grossman EA, Nomura DK. Cancer metabolism: current understanding and therapies. Chem Rev. 2018;118(14):6893–923. Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy: challenges and opportunities. Trends Pharmacol Sci. 2018;39(3):307–25. Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019;18(5):379–401. Tang D, Yue L, Yao R, Zhou L, Yang Y, Lu L, et al. P53 prevent tumor invasion and metastasis by down-regulating IDO in lung cancer. Oncotarget. 2017;8(33):54548–57. Hsu YL, Hung JY, Chiang SY, Jian SF, Wu CY, Lin YS, et al. Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget. 2016;7(19):27584–98. Smith C, Chang MY, Parker KH, Beury DW, DuHadaway JB, Flick HE, et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2012;2(8):722–35. D’Amato NC, Rogers TJ, Gordon MA, Greene LI, Cochrane DR, Spoelstra NS, et al. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res. 2015;75(21):4651–64. Liu H, Shen Z, Wang Z, Wang X, Zhang H, Qin J, et al. Increased expression of IDO associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma. Sci Rep. 2016;6(1):21319. Pham QT, Oue N, Sekino Y, Yamamoto Y, Shigematsu Y, Sakamoto N, et al. TDO2 overexpression is associated with cancer stem cells and poor prognosis in esophageal squamous cell carcinoma. Oncology. 2018;95(5):297–308. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4. Pham QT, Oue N, Yamamoto Y, Shigematsu Y, Sekino Y, Sakamoto N, et al. The expression of BTS-2 enhances cell growth and invasiveness in renal cell carcinoma. Anticancer Res. 2017;37(6):2853–60. Sentani K, Imai T, Kobayashi G, Hayashi T, Sasaki N, Oue N, et al. Histological diversity and molecular characteristics in gastric cancer: relation of cancer stem cell-related molecules and receptor tyrosine kinase molecules to mixed histological type and more histological patterns. Gastric Cancer. 2021;24(2):368–81. Vasaikar SV, Straub P, Wang J, Zhang B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2017;46(D1):D956–63. Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2015;44(8):e71. Arienti C, Pignatta S, Tesei A. Epidermal growth factor receptor family and its role in gastric cancer. Front Oncol. 2019;9:1308. Quoc Thang P, Daiki T, Yohei S, Shintaro A, Takashi B, Go K, et al. BMC Cancer. 2021. Sumitomo M, Takahara K, Zennami K, Nagakawa T, Maeda Y, Shiogama K, et al. Tryptophan 2,3-dioxygenase in tumor cells is associated with resistance to immunotherapy in renal cell carcinoma. Cancer Sci. 2021;112(3):1038–47. Doi T, Piha-Paul SA, Jalal SI, Saraf S, Lunceford J, Koshiji M, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol. 2018;36(1):61–7. Böger C, Behrens HM, Mathiak M, Krüger S, Kalthoff H, Röcken C. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget. 2016;7(17):24269–83. Tahara T, Shibata T, Okamoto Y, Yamazaki J, Kawamura T, Horiguchi N, et al. Mutation spectrum of TP53 gene predicts clinicopathological features and survival of gastric cancer. Oncotarget. 2016;7(27):42252–60. Ye MX, Zhang Y, Gao HJ, Xu Y, Jing PY, Wu JX, et al. Activation of the aryl hydrocarbon receptor leads to resistance to EGFR TKIs in non-small cell lung cancer by activating src-mediated bypass signaling. Clin Cancer Res. 2018;24(5):1227–39. Li L, Wang T, Li S, Chen Z, Wu J, Cao W, et al. TDO2 promotes the EMT of hepatocellular carcinoma through Kyn-AhR pathway. Front Oncol. 2021;10:562823. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203. Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frederick R, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2012;109(7):2497–502. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23(10):1124–34. Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci. 2019;234:116781. Takaishi S, Okumura T, Tu S, Wang SSW, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27(5):1006–20. Bartfeld S, Clevers H. Stem cell-derived organoids and their application for medical research and patient treatment. J Mol Med. 2017;95(7):729–38. Ukai S, Honma R, Sakamoto N, Yamamoto Y, Pham QT, Harada K, et al. Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell. Oncogene. 2020;39(50):7265–78. Article / Publication Details

First-Page Preview

Received: November 16, 2021
Accepted: February 06, 2022
Published online: June 09, 2022

Number of Print Pages: 12
Number of Figures: 4
Number of Tables: 3

ISSN: 1015-2008 (Print)
eISSN: 1423-0291 (Online)

For additional information: https://www.karger.com/PAT

Copyright / Drug Dosage / Disclaimer Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.