Abstract 184: Pulmonary Microvascular Thrombosis Enhances Extravasation via Myeloid Hypoxia-Inducible Factors
Introduction: Mechanisms that regulate the positive association between thrombosis and 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 (Tpm) increases extravasation via myeloid (neutrophil and macrophage) hypoxia-inducible factor (HIF).
Methods and Results: Tpm was induced in wild type mice via tail vein administration of polystyrene microbeads (15μm diameter, 1000/mouse). Tpm 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-Tpm 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), Tpm 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 Tpm-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 Tpm-induced increases in pulmonary tumour proliferation and vascularisation (n=15/group). In human breast tumour microarrays (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 (HR=1.1, P<0.05).
Conclusions: Thrombus formation in mouse pulmonary microvasculature enhances cancer cell extravasation via neutrophil- and macrophage-specific HIF1α or HIF2α. In human breast tumours, HIF2α is associated with increased fibrin deposition, and reduced survival. Pulmonary microvascular thrombosis can enhance cancer cell dissemination via myeloid cell-specific HIFs.
Author Disclosures: C.E. Evans: None. C. Branco-Price: None. A. Prodger: None. A. Palazon: None. P. Tyrakis: None. H. Rundqvist: None. P. Bendahl: None. M. Belting: None. R.S. Johnson: None.
- © 2015 by American Heart Association, Inc.