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M. Belting

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    MINI 35 - Biology (ID 161)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI35.14 - Microthrombosis Enhances Extravasation via Myeloid Hypoxia-Inducible Factors (ID 94)

      18:30 - 20:00  |  Author(s): M. Belting

      • Abstract
      • Presentation
      • Slides

      Mechanisms that regulate the positive association between thrombosis and pulmonary metastasis are incompletely understood. It was hypothesised that thrombus formation stimulates a hypoxic response, which in turn promotes extravasation. The primary aim was to determine whether thrombosis of the pulmonary microvasculature (T~pm~) increases extravasation via myeloid (neutrophil and macrophage) hypoxia-inducible factor (HIF).

      Pulmonary microthrombosis was induced in wildtype and conditional HIFα knockout mice by administration of intravenous polystyrene microbeads (n=15/group). Murine lung cancer cell extravasation was quantified, and both murine pulmonary and human breast tumors (n=221) were characterised by immunostaining and image analysis.

      T~pm~ was induced in wild type mice via tail vein administration of polystyrene microbeads (15μm diameter, 1000/mouse). T~pm~ led to chronological increases in pulmonary HIF1α expression (P=0.01), HIF2α expression (P<0.01), neutrophil infiltration (P<0.05), and macrophage infiltration (P<0.05; 1-5days post-T~pm~ vs. non-thrombosed vehicle controls, n=8/group/time point); these increases were comparable with changes observed following vena cava thrombosis (assessed via image analysis of immunostained tissue throughout). In wild type mice with circulating Lewis lung cancer cells (LLCs, 1million/mouse i/v), T~pm~ led to increases in pulmonary fibrin deposition (P<0.0001), HIF1α expression (P<0.05), HIF2α expression (P<0.05), and LLC extravasation (P<0.0001; 14days post-LLCs vs. non-thrombosed controls, n=15/group). Using conditional HIFα knockout mice (vs. wild type littermates), it was shown that T~pm~-induced increases in pulmonary fibrin deposition and LLC extravasation were dependent upon HIF1α or HIF2α in neutrophils and macrophages; myeloid HIFs were also responsible for T~pm~-induced increases in pulmonary tumour proliferation and vascularisation (n=15/group). In human tumour samples (n=221), fibrin deposition was positively correlated with HIF2α expression (RS=0.22, P<0.001), while increases in HIF2α were associated with reductions in metastasis-free survival (P<0.05).

      Thrombus formation in mouse pulmonary microvasculature enhances cancer cell extravasation via neutrophil- and macrophage-specific HIF1α or HIF2α. In human tumours, HIF2α is associated with increased fibrin deposition, and reduced survival. Pulmonary microvascular thrombosis can enhance cancer cell dissemination via myeloid cell-specific HIFs.

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