Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration.
Sheri A C McDowellRobin B E LuoAzadeh ArabzadehSamuel DoréNicolas C BennettValérie BretonElham KarimiMorteza RezanejadRyan R YangKatherine D LachMarianne Samir Makboul IssacBozena SamborskaLucas J M PerusDan MoldoveanuYuhong WeiBenoit FisetRoni F RayesIan R WatsonLawrence KazakMarie-Christine GuiotPierre O FisetJonathan D SpicerAndrew J DannenbergLogan A WalshAbdel Razaq Ahmad A AlyasinPublished in: Nature cancer (2021)
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.
Keyphrases
- weight loss
- insulin resistance
- metabolic syndrome
- adipose tissue
- type diabetes
- weight gain
- body mass index
- oxidative stress
- high fat diet induced
- bariatric surgery
- reactive oxygen species
- endothelial cells
- high fat diet
- squamous cell carcinoma
- small cell lung cancer
- single cell
- stem cells
- physical activity
- single molecule
- high resolution
- gene expression
- obese patients
- nitric oxide
- dna damage
- mesenchymal stem cells
- ischemia reperfusion injury
- bone marrow
- electronic health record
- smoking cessation
- nitric oxide synthase
- heat shock protein
- combination therapy
- induced apoptosis
- deep learning