Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.
Nature
; 533(7604): 493-498, 2016 05 26.
Article
em En
| MEDLINE
| ID: mdl-27225120
ABSTRACT
Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Encefálicas
/
Astrócitos
/
Junções Comunicantes
/
Nucleotídeos Cíclicos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Nature
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos