Wang Jiping, Xiao Jiajun, Wen Danping, Wu Xie, Mao Zuohua, Zhang Jin, Ma Duan
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.
Department of Parasitology and Microbiology, Shanghai Medical College, Fudan University, Shanghai, China.
Mol Carcinog. 2016 May;55(5):882-96. doi: 10.1002/mc.22329. Epub 2015 May 6.
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.
组织因子途径抑制物（TFPI）是组织因子（TF）启动的凝血途径的生理性抑制物。循环中的TFPI和肿瘤细胞相关的TFPI均能显著降低肿瘤细胞诱导的凝血激活及肺转移。然而，内皮细胞锚定的TFPI在癌症生物学中的意义在很大程度上仍未被探索。我们利用Cre-LoxP系统和基因失活（GI）策略，构建了内皮细胞中TFPI全长缺失（包括TFPIα和TFPIβ亚型）的小鼠。使用TFPI缺陷小鼠的实验性肺肿瘤转移模型来评估内皮细胞锚定的TFPI在癌症进展中的作用。最后，研究了肺微血管通透性和微环境。TFPI缺陷小鼠存活且可育，与对照同窝小鼠相比，其血浆TFPI水平和肺TFPI水平降低。内皮细胞中的TFPI缺陷通过增加血管通透性和改变肺微环境促进了肺肿瘤转移。我们的观察结果表明，内皮细胞锚定的TFPI控制肺肿瘤转移，并且在很大程度上是通过抑制局部TF诱导的凝血酶生成以及调节小鼠的肺微环境来实现的。
