Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions.
Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis. Neutrophils through release of neutrophil extracellular traps (NETs) in response to infections were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. To be able to intervene on this process, understanding the exact molecular nature of these mechanisms is crucial. We therefore hypothesize and demonstrate that β1-integrin is an important factor mediating the interactions between circulating tumor cells and NETs. We show that β1-integrin expression on both cancer cells and NETs is important for the adhesion of circulating tumor cells to NETs both in vitro and in vivo. Using a murine model of intra-abdominal sepsis to mimic the postoperative inflammatory environment, we show that β1-integrin expression is upregulated in the context of inflammation in vivo. Ultimately, we show that this increased early cancer cell adhesion to NETs in vivo and this effect is abrogated when mice are administered DNAse 1. Our data therefore sheds light on the first molecular mechanism by which NETs can trap circulating tumor cells (CTCs), broadening our understanding of this process.
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Sara
S
Najmeh
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Jonathan
J
Cools-Lartigue
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Roni F
0000-0001-7508-020X
RF
Rayes
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Stephen
S
Gowing
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Phil
P
Vourtzoumis
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
France
F
Bourdeau
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Betty
B
Giannias
Meakins-Christie Laboratories, Department of Medicine, McGill University and the McGill University Health Center, Montreal, QC, Canada.
Julie
J
Berube
Meakins-Christie Laboratories, Department of Medicine, McGill University and the McGill University Health Center, Montreal, QC, Canada.
Simon
S
Rousseau
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Lorenzo E
LE
Ferri
Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.
Jonathan D
JD
Spicer
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D049109:Cell Proliferation; D004195:Disease Models, Animal; D065206:Extracellular Traps / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D019012:Integrin beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured
D019012:Integrin beta1; D034741:RNA, Small Interfering