Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain.
Humans
Female
Toll-Like Receptor 4
/ metabolism
Myeloid Differentiation Factor 88
/ genetics
Interleukin-6
/ metabolism
Adaptor Proteins, Signal Transducing
/ metabolism
Breast Neoplasms
/ genetics
Brain
/ pathology
Brain Neoplasms
/ drug therapy
Adaptor Proteins, Vesicular Transport
/ metabolism
Tumor Microenvironment
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
21
02
2022
accepted:
30
09
2022
revised:
31
08
2022
pubmed:
13
10
2022
medline:
16
11
2022
entrez:
12
10
2022
Statut:
ppublish
Résumé
Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.
Identifiants
pubmed: 36224342
doi: 10.1038/s41388-022-02496-3
pii: 10.1038/s41388-022-02496-3
pmc: PMC9652147
doi:
Substances chimiques
Toll-Like Receptor 4
0
Myeloid Differentiation Factor 88
0
Interleukin-6
0
Adaptor Proteins, Signal Transducing
0
Adaptor Proteins, Vesicular Transport
0
TLR4 protein, human
0
Banques de données
figshare
['10.6084/m9.figshare.16685680.v1']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5008-5019Informations de copyright
© 2022. The Author(s).
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