Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma.
Glioblastoma
IGFBP6
Lactate
Microenvironment
Microglia
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Jan 2023
Jan 2023
Historique:
received:
17
12
2021
accepted:
25
04
2022
pubmed:
3
6
2022
medline:
7
1
2023
entrez:
2
6
2022
Statut:
ppublish
Résumé
Lactic acidosis has been reported in solid tumor microenvironment (TME) including glioblastoma (GBM). In TME, several signaling molecules, growth factors and metabolites have been identified to induce resistance to chemotherapy and to sustain immune escape. In the early phases of the disease, microglia infiltrates TME, contributing to tumorigenesis rather than counteracting its growth. Insulin-like Growth Factor Binding Protein 6 (IGFBP6) is expressed during tumor development, and it is involved in migration, immune-escape and inflammation, thus providing an attractive target for GBM therapy. Here, we aimed at investigating the crosstalk between lactate metabolism and IGFBP6 in TME and GBM progression. Our results show that microglia exposed to lactate or IGFBP6 significantly increased the Monocarboxylate transporter 1 (MCT1) expression together with genes involved in mitochondrial metabolism. We, also, observed an increase in the M2 markers and a reduction of inducible nitric oxide synthase (iNOS) levels, suggesting a role of lactate/IGFBP6 metabolism in immune-escape activation. GBM cells exposed to lactate also showed increased levels of IGFBP6 and vice-versa. Such a phenomenon was coupled with a IGFBP6-mediated sonic hedgehog (SHH) ignaling increase. We, finally, tested our hypothesis in a GBM zebrafish animal model, where we observed an increase in microglia cells and igfbp6 gene expression after lactate exposure. Our results were confirmed by the analysis of human transcriptomes datasets and immunohistochemical assay from human GBM biopsies, suggesting the existence of a lactate/IGFBP6 crosstalk in microglial cells, so that IGFBP6 expression is regulated by lactate production in GBM cells and in turn modulates microglia polarization.
Identifiants
pubmed: 35654889
doi: 10.1007/s00262-022-03215-3
pii: 10.1007/s00262-022-03215-3
pmc: PMC9813126
doi:
Substances chimiques
Insulin-Like Growth Factor Binding Protein 6
0
Lactic Acid
33X04XA5AT
Hedgehog Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-20Subventions
Organisme : Piano di Incentivi per la ricerca di Ateneo
ID : 2020/2022 Linea di intervento 2 (G.L.V.).
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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