title: Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals.
abstract: Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1β, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cedervall
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Femel
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden. anna-karin.olsson@imbim.uu.se.
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D065206:Extracellular Traps / Q000276:immunology*; D005260:Female; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D016491:Peripheral Vascular Diseases / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines