Elucidation of tumor microenvironmental via expression of TDO in liver metastasis of colorectal cancer and its clinical application

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10560
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: National Cancer Center Japan
• Principal Investigator: Miyazaki Toshiaki 国立研究開発法人国立がん研究センター, 研究所, 研究員 (50589075)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 大腸がん / 肝転移 / Kynurenine / TDO2

Outline of Final Research Achievements

Cancer stem cells (CSC) represent a small fraction of cancer cells and are associated with malignant traits of cancer such as tumorigenesis and metastasis. Elucidation of the biological nature of CSCs will be important to understand the refractory traits of cancer and to devise new strategies for cancer therapy. In an attempt to identify biochemical alterations associated with metastatic traits of cancer, we compared metabolic profiles of spheroids established from CSCs derived from non-metastatic cancers and metastatic foci. We found that Kynurenine was up-regulated in spheroids derived from metastasized liver. In accordance, levels of TDO2, an enzyme responsible for Kynurenine production, were higher in metastatic CSCs than in non-metastatic ones. TDO2 over-expression promoted liver metastasis and suppressed accumulation of immune cells around the metastatic lesion. These results indicate that TDO2 plays an important role in liver metastasis though Kynurenine production.

Free Research Field

がん幹細胞

Academic Significance and Societal Importance of the Research Achievements

キヌレニンの合成を担うTDO2はがん細胞内で発現が上昇しているが、未だキヌレニンやTDOのin vivoにおける免疫抑制やがん細胞転移の作用メカニズムの解明は十分ではない。本研究によりTDO2は、キヌレニンの産生増加、免疫系の制御を介して、大腸がん転移を促進させることを新たに明らかにした。キヌレニンやTDOがもたらす微小環境変化と転移メカニズムの関係が明らかになることにより、TDOとキヌレニンをターゲットとした診断マーカーならびに、新規分子標的の発見により臨床への応用に貢献することができる可能性があると考える。