title: Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci.
abstract: In mouse models of lung metastasis, before the appearance of significant metastases, localized changes in vascular permeability have been observed, which appear to set the stage for tumour growth. However, it is unclear whether this is also true in human patients. Here, we show that MD-2, a coreceptor for Toll-like receptor 4 that has a key role in the innate immune response, triggers the formation of regions of hyperpermeability in mice by upregulating C-C chemokine receptor type 2 (CCR2) expression. The CCR2-CCL2 system induces the abundant secretion of permeability factors such as serum amyloid A3 and S100A8. Disruption of MD-2 or CCR2 abrogates the formation of hyperpermeable regions, resulting in reduced tumour cell homing. Furthermore, fibrinogen, which is processed during permeability-mediated coagulation, is also localized in areas of elevated CCR2 expression in tumour-bearing human lungs. Our findings raise the possibility that CCR2 upregulation might represent a marker for regions of increased susceptibility to metastatic homing in lung cancer.
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Tokyo 162-8666, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Hiratsuka
authors.forename: Sachie
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomita
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akashi-Takamura
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kijima
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maru
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D009924:Organ Culture Techniques; D054390:Receptors, CCR2; D009418:S100 Proteins / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D018836:Inflammation Mediators; D051218:Lymphocyte Antigen 96; D054390:Receptors, CCR2; D009418:S100 Proteins; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; D051197:Toll-Like Receptor 4; D005340:Fibrinogen; D051416:Focal Adhesion Protein-Tyrosine Kinases