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      Diverse roles of cell-specific hypoxia-inducible factor 1 in cancer-associated hypercoagulation.

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          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.

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          Author and article information

          Journal
          Blood
          Blood
          American Society of Hematology
          1528-0020
          0006-4971
          Mar 10 2016
          : 127
          : 10
          Affiliations
          [1 ] Department of Physiology, Development and Neuroscience and British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom;
          [2 ] Department of Clinical Sciences, Lund University, Lund, Sweden; and.
          [3 ] Department of Physiology, Development and Neuroscience and.
          [4 ] Department of Physiology, Development and Neuroscience and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
          Article
          blood-2015-09-671982
          10.1182/blood-2015-09-671982
          26702059

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