title: Diverse roles of cell-specific hypoxia-inducible factor 1 in cancer-associated hypercoagulation.
abstract: Despite the increased risk of thrombosis in cancer patients compared with healthy individuals, mechanisms that regulate cancer-induced hypercoagulation are incompletely understood. The aim of this study was to investigate whether cell-specific hypoxia-inducible factor (HIF) 1α regulates cancer-associated hypercoagulation, using in vitro clotting assays and in vivo cancer models. In mouse lung and mammary tumor cells, hypoxia led to increases in cell adhesion, clotting, and fibrin deposition; these increases were eliminated in HIF1α null cells. Increased levels of HIF1α were also associated with increased tissue factor expression in human breast tumor samples. Conversely, deletion of endothelial (but not myeloid) cell-specific HIF1α doubled pulmonary fibrin deposition, and trebled thrombus formation compared with wildtype littermates in tumor-bearing mice. Our data suggest that tumor and endothelial cell-specific HIF1α may have opposing roles in cancer-associated coagulation and thrombosis. Off-target effects of manipulating the HIF1 axis in cancer patients should be carefully considered when managing thrombotic complications.
authors.affiliation: Department of Physiology, Development and Neuroscience and British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Colin E
authors.initials: CE
authors.lastname: Evans
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden; and.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden; and.
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
authors.affiliation: Department of Physiology, Development and Neuroscience and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Branco
authors.affiliation: Department of Physiology, Development and Neuroscience and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019851:Thrombophilia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit