Tissue factor in cancer progression and angiogenesis.
Tissue factor in cancer progression and angiogenesis.
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DOI：
10.1016/s0049-3848(10)70010-4
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发表时间：
2010-04
影响因子：
7.5
通讯作者：
Schaffner, Florence
中科院分区：
文献类型：
--
作者：
Ruf, Wolfram;Yokota, Naho;Schaffner, Florence
癌细胞组织因子（TF）的组成性表达触发局部和全身的凝血级联激活，是癌症相关血栓形成的主要原因。原发性乳腺癌活检显示TF和蛋白酶激活受体（PAR） 2的显著上调，以及与癌症复发相关的TF细胞质结构域磷酸化升高。涉及PAR2和整合素的TF信号在血管生成和肿瘤进展中具有多重作用。非凝固、选择性剪接形式的TF保留了整合素结合位点，在沉积到肿瘤基质后，通过连接内皮整合素αvβ3和α6β1刺激血管生成。在肿瘤细胞上，全长TF与层粘连蛋白结合β1整合素组成相关，支持TF- viia - par2信号传导，导致促血管生成和免疫调节细胞因子和生长因子的上调。缺乏PAR2，而不是凝血酶受体PAR1，可以延缓小鼠自发性乳腺癌的发展和血管生成开关。此外，通过选择性抗体抑制TF- viia - par2信号传导抑制人异种移植乳腺癌的生长和血管生成，而不是通过阻断TF启动的凝血来抑制。因此，阻断TF信号是一种潜在的抗血管生成策略，不会增加与TF凝血途径长期抑制相关的出血风险。
Constitutive expression of tissue factor (TF) by cancer cells triggers local and systemic activation of the coagulation cascade and is a major cause of cancer associated thrombosis. Primary breast cancer biopsies show a marked upregulation of TF and protease activated receptor (PAR) 2, as well as increased TF cytoplasmic domain phosphorylation that is correlated with cancer relapse. TF signaling involving PAR2 and integrins has multiple effects on angiogenesis and tumor progression. The non-coagulant, alternatively spliced form of TF retains an integrin-binding site and, upon deposition into the tumor stroma, stimulates angiogenesis by ligating endothelial integrins αvβ3 and α6β1. On tumor cells, full-length TF is constitutively associated with laminin-binding β1 integrins that support TF-VIIa-PAR2 signaling leading to upregulation of pro-angiogenic and immune modulatory cytokines and growth factors. Deficiency of PAR2, but not of the thrombin receptor PAR1, delays spontaneous breast cancer development and the angiogenic switch in mice. In addition, human xenograft breast cancer growth and angiogenesis is suppressed by selective antibody inhibition of TF-VIIa-PAR2 signaling, but not by blocking TF initiated coagulation. Thus, interruption of TF signaling represents a potential anti-angiogenic strategy that does not carry an increased risk of bleeding associated with prolonged inhibition of the TF coagulation pathway.