title: Endothelial cell-anchored tissue factor pathway inhibitor regulates tumor metastasis to the lung in mice.
abstract: Tissue factor pathway inhibitor (TFPI) is a physiological inhibitor of the tissue factor (TF)-initiated coagulation pathway. Both circulating and tumor cell-associated TFPI significantly reduce tumor cell-induced coagulation activation and lung metastasis. However, the significance of endothelial cell-anchored TFPI in cancer biology remains largely unexplored. We generated mice with full-length disruption of TFPI (including TFPIα and TFPIβ isoforms) in endothelial cells, using a Cre-LoxP system and gene inactivation (GI) strategy. Experimental pulmonary tumor metastasis models were used with TFPI-deficient mice to evaluate the role of endothelial cell-anchored TFPI in cancer progression. Finally, lung microvascular permeability and microenvironment were investigated. TFPI-deficient mice were viable and fertile, and showed decreased plasma TFPI levels and lung TFPI levels as compared with their control littermates. TFPI deficiency in endothelial cells promoted pulmonary tumor metastasis with an increased vascular permeability and altered lung microenvironment. Our observations suggest that endothelial cell-anchored TFPI controls lung tumor metastasis, and does so largely through the inhibition of local TF-induced thrombin generation and the regulation of the lung microenvironment in mice.
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.
authors.forename: Danping
authors.initials: D
authors.lastname: Wen
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.
authors.forename: Xie
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Parasitology and Microbiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zuohua
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.|Children's Hospital, Fudan University, Shanghai, China.
authors.forename: Duan
authors.initials: D
authors.lastname: Ma
mesh_terms: D000818:Animals; D042783:Endothelial Cells; D055785:Gene Knockdown Techniques; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D009374:Neoplasms, Experimental; D059016:Tumor Microenvironment
chemical_list: D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor
keywords: TFPI; conditional knockout; lung microenvironment; microvascular permeability; tumor metastasis