Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration

Abstract

Obesity enhances BC extravasation by modifying the endothelium. To investigate the effects of obesity on cancer extravasation, we used a syngeneic BC cell line derived from the C57BL6 mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model combined with a diet-induced obesity (DIO) model. Wild type (WT) C57BL6 female mice were enrolled on a low-fat (LF) (10% kcal) or high-fat (HF) (60% kcal) diet for 15 weeks (Fig. 1a,b) 10 , followed by tail vein injection of fluorescently labeled BC cells

Neutrophil phenotypes and functions in cancer: A consensus statement

“…Early studies have shown that cancer-induced NETs act largely within the circulation, where they facilitate cancer-associated thrombosis ( Demers et al, 2012 ; Hell et al, 2016 ; Thalin et al, 2016 ; Thomas et al, 2015 ) and sequester circulating tumor cells to escort metastases ( Cools-Lartigue et al, 2013 ). Subsequent studies revealed that NETs affect essentially every step of the metastatic cascade, including primary tumor progression ( Guglietta et al, 2016 ), invasion and migration ( Park et al, 2016 ), survival in the circulation ( Spiegel et al, 2016 ; Szczerba et al, 2019 ; Teijeira et al, 2020 ), chemotaxis to secondary niches ( Yang et al, 2020 ), extravasation ( McDowell et al, 2021 ; Spiegel et al, 2016 ), metastatic colonization ( Wculek and Malanchi, 2015 ; Yang et al, 2020 ), and outgrowth of metastatic tumor cells ( Albrengues et al, 2018 ; Xiao et al, 2021 ). However, a remaining knowledge gap is how tumors trigger NETosis—Is this a direct consequence of tumor-derived factors?…”

“…In the non-tumor bearing setting, obesity stimulates myelopoiesis to yield elevated neutrophils and Gr1 + cells in multiple organs ( Nagareddy et al, 2014 ; Xia et al, 2011 ). Lung neutrophils from obese and lean mice have a highly divergent transcriptome, with a significant enrichment in pathways related to oxidative stress in obese hosts coinciding with enhanced NETosis ( McDowell et al, 2021 ). In cancer, both genetic- and diet-induced obesity models have elevated peripheral and pulmonary neutrophils that promote breast cancer metastasis to the lung in a GM-CSF–dependent manner ( McDowell et al, 2021 ; Quail et al, 2017 ).…”

“…Lung neutrophils from obese and lean mice have a highly divergent transcriptome, with a significant enrichment in pathways related to oxidative stress in obese hosts coinciding with enhanced NETosis ( McDowell et al, 2021 ). In cancer, both genetic- and diet-induced obesity models have elevated peripheral and pulmonary neutrophils that promote breast cancer metastasis to the lung in a GM-CSF–dependent manner ( McDowell et al, 2021 ; Quail et al, 2017 ). Similar findings have been reported in murine models of high fat diet–induced hypercholesterolemia, where the cholesterol metabolite 27-hydroxycholesterol supports neutrophil recruitment to distal sites to promote metastasis ( Baek et al, 2021 ; Baek et al, 2017 ; Ma et al, 2020 ).…”

Circadian regulation of innate immunity in animals and humans and implications for human disease

“…In higher animals, the presence of cells with oxidative killing (e.g. neutrophils) can lead to tissue damage [51,67]. Given this oxidative stress, and the origin of the clock as an oxidative stress buffer, circadian modulation of innate immunity has been proposed and studied, in animals.…”

Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels

“…More recent data indicate that NETs can directly eliminate melanoma cells, suggesting a tumor-suppressive effect ( 20 ). Recent studies investigating the impact of NETs on breast cancer cell dissemination indicate that NET release (also termed “NETosis”) is associated with trapping and extravasation of blood circulating cancer cells ( 21 ). It was also reported that NETs are able to enhance the motility of breast cancer cells, promoting their recruitment into premetastatic livers ( 22 ).…”