Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration.
Nat Cancer
; 2(5): 545-562, 2021 05.
Article
en En
| MEDLINE
| ID: mdl-35122017
ABSTRACT
Metastasis is the leading cause of cancer-related deaths, and obesity is associated with increased breast cancer (BC) metastasis. Preclinical studies have shown that obese adipose tissue induces lung neutrophilia associated with enhanced BC metastasis to this site. Here we show that obesity leads to neutrophil-dependent impairment of vascular integrity through loss of endothelial adhesions, enabling cancer cell extravasation into the lung. Mechanistically, neutrophil-produced reactive oxygen species in obese mice increase neutrophil extracellular DNA traps (NETs) and weaken endothelial junctions, facilitating the influx of tumor cells from the peripheral circulation. In vivo treatment with catalase, NET inhibitors or genetic deletion of Nos2 reversed this effect in preclinical models of obesity. Imaging mass cytometry of lung metastasis samples from patients with cancer revealed an enrichment in neutrophils with low catalase levels correlating with elevated body mass index. Our data provide insights into potentially targetable mechanisms that underlie the progression of BC in the obese population.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Neoplasias Pulmonares
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Cancer
Año:
2021
Tipo del documento:
Article
País de afiliación:
Canadá