Abstract B7: Hypoxia-inducible factor 1 mediates thrombosis-associated cancer progression

Abstract

Abstract Background. Cancer patients are up to 50 times more likely to suffer from lethal venous thromboembolism compared with non-cancer patients, but mechanisms that regulate the positive correlation between these conditions are unclear. Our primary aim was to test whether hypoxia within cells contained in the thrombus and adjacent vein leads to upregulation of hypoxia-inducible factor 1 (HIF1), which in turn stimulates the production of factors that mediate tumor growth and metastasis. Methods. Systemic or endothelial and myeloid HIF1 levels were altered (via administration of HIF1 agonist L-mimosine or via cre-Tie2 driven HIF1 deletion respectively) in established mouse models of thrombosis and breast cancer (inferior vena cava stenosis or polyoma middle T mutation driven by mouse mammary tumour virus respectively). Protein arrays were used to quantify the expression of 25 factors that regulate coagulation, thrombosis, and cancer progression. Adhesion and migration assays were used to characterise tumor and endothelial cell behaviour on thrombotic surfaces; while endothelial and tumor cell oxygen consumption rate was measured before and after thrombin treatment. Image analysis was also used to quantify intra-tumor thrombus formation. Results. Thrombus formation or upregulation of HIF1 increased the circulating expression of 10 factors that mediate tumor growth and remodelling including vascular endothelial growth factor (VEGF, 2±1 vs 1±0.2pg/ml in controls, n=6/group, P<0.05), hepatocyte growth factor (HGF, 10±5 vs 7±2% in controls, n=8/group, P<0.05), and stromal cell-derived factor 1 (SDF1, 14±6 vs 2±1% in controls, n=8/group, P<0.05). Hypoxia (1% oxygen) tended to attenuate endothelial cell migration on fibrin (100±13 vs 64±10 cells in controls, n=6/group, P=0.05); while HIF1 deletion in Lewis lung cancer cells abolished their hypoxia-induced increase in adhesion onto fibrin (n=5/group, P<0.05). Thrombin administration reduced the oxygen consumption rate of Lewis lung cancer cells (59±13 vs 79±16 pMol/min in controls, n=5/group, P<0.005) but not endothelial cells (P=0.06). Deposition of fibrin in mammary tumours was reduced following endothelial and myeloid HIF1 deletion (5±1 vs 13±3% in controls, n=7/group, P<0.05) and this was associated with reduced tumour size (n=14, R=0.7, P<0.01). Conclusions. HIF1 regulates the progression of venous thrombosis and cancer, and could also be responsible for the positive association between these conditions. Cell and tissue-specific HIF1 is an attractive therapeutic target for treatments that aim to reduce thrombosis-associated cancer progression. Citation Format: Colin E. Evans, Cristina Branco-Price, Julia Humphries, Ashar Wadoodi, Prakash Saha, Jung-whan Kim, Mattias Belting, Alberto Smith, Randall S. Johnson. Hypoxia-inducible factor 1 mediates thrombosis-associated cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B7.