Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer.
Animals
B7-H1 Antigen
/ metabolism
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Cell Line, Tumor
Colonic Neoplasms
/ metabolism
Dioxygenases
/ metabolism
Humans
Kynurenine
Liver Neoplasms
/ metabolism
Mice
Neoplasm Transplantation
Neoplastic Stem Cells
/ metabolism
Receptors, Aryl Hydrocarbon
/ metabolism
Spheroids, Cellular
/ cytology
Tumor Escape
Up-Regulation
Wnt Signaling Pathway
TDO2
aryl hydrocarbon receptor
cancer stem cells
kynurenine
liver metastasis
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
revised:
22
10
2021
received:
12
05
2021
accepted:
25
10
2021
pubmed:
30
10
2021
medline:
13
1
2022
entrez:
29
10
2021
Statut:
ppublish
Résumé
The aryl hydrocarbon receptor (AHR) pathway modulates the immune system in response to kynurenine, an endogenous tryptophan metabolite. IDO1 and TDO2 catalyze kynurenine production, which promotes cancer progression by compromising host immunosurveillance. However, it is unclear whether the AHR activation regulates the malignant traits of cancer such as metastatic capability or cancer stemness. Here, we carried out systematic analyses of metabolites in patient-derived colorectal cancer spheroids and identified high levels of kynurenine and TDO2 that were positively associated with liver metastasis. In a mouse colon cancer model, TDO2 expression substantially enhanced liver metastasis, induced AHR-mediated PD-L1 transactivation, and dampened immune responses; these changes were all abolished by PD-L1 knockout. In patient-derived cancer spheroids, TDO2 or AHR activity was required for not only the expression of PD-L1, but also for cancer stem cell (CSC)-related characteristics and Wnt signaling. TDO2 was coexpressed with both PD-L1 and nuclear β-catenin in colon xenograft tumors, and the coexpression of TDO2 and PD-L1 was observed in clinical colon cancer specimens. Thus, our data indicate that the activation of the TDO2-kynurenine-AHR pathway facilitates liver metastasis of colon cancer via PD-L1-mediated immune evasion and maintenance of stemness.
Identifiants
pubmed: 34714577
doi: 10.1111/cas.15182
pmc: PMC8748246
doi:
Substances chimiques
AHR protein, human
0
B7-H1 Antigen
0
Basic Helix-Loop-Helix Transcription Factors
0
CD274 protein, human
0
Receptors, Aryl Hydrocarbon
0
Kynurenine
343-65-7
Dioxygenases
EC 1.13.11.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
170-181Subventions
Organisme : Japan Society for the Promotion of Science
ID : 16K10560
Organisme : Japan Agency for Medical Research and Development
ID : 19ak0101043h0105
Organisme : Japan Agency for Medical Research and Development
ID : JP19cm0106563h0001
Organisme : National Cancer Center Japan
ID : 31-A-3
Organisme : National Cancer Center Japan
ID : 31-A-4
Organisme : National Cancer Center Japan
ID : 31-A-8
Informations de copyright
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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