Ruf Wolfram, Mueller Barbara M
Scripps Research Institute and the La Jolla Institute for Molecular Medicine, San Diego, California 92037, USA.
Semin Thromb Hemost. 2006 Apr;32 Suppl 1:61-8. doi: 10.1055/s-2006-939555.
Advanced cancer is associated with a hypercoagulable state that is triggered by tissue factor (TF). TF-initiated thrombin generation is crucial for metastasis through fibrin and platelet deposition, as well as thrombin-dependent protease-activated receptor (PAR) 1 signaling. Surprisingly, PAR2, which is not cleaved by thrombin, appears to cosignal with PAR1 to elicit thrombin effects in metastatic tumor cells. In contrast to TF-driven thrombin pathways in metastasis, direct TF signaling plays a role in angiogenesis-dependent tumor growth. In TF cytoplasmic-domain-deleted mice, PAR2-dependent angiogenesis and tumor growth is enhanced, demonstrating a role for host cell TF signaling. In tumor cells, TF-factor VIIa (FVIIa) activates PAR2 and thereby regulates proangiogenic growth factor expression as well as integrins involving crosstalk with the TF cytoplasmic domain. In addition to thrombin-PAR signaling in metastasis and TF-FVIIa-PAR2 signaling in tumor growth, it is likely that additional protease pathways will prove to be crucial activators of PARs in cancer. Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on specific features of the local tumor microenvironment.
晚期癌症与由组织因子（TF）引发的高凝状态相关。TF启动的凝血酶生成对于通过纤维蛋白和血小板沉积以及凝血酶依赖性蛋白酶激活受体（PAR）1信号传导的转移至关重要。令人惊讶的是，不被凝血酶切割的PAR2似乎与PAR1共同发出信号，以在转移性肿瘤细胞中引发凝血酶效应。与转移中TF驱动的凝血酶途径相反，直接TF信号传导在血管生成依赖性肿瘤生长中起作用。在TF胞质结构域缺失的小鼠中，PAR2依赖性血管生成和肿瘤生长增强，表明宿主细胞TF信号传导的作用。在肿瘤细胞中，TF-因子VIIa（FVIIa）激活PAR2，从而调节促血管生成生长因子的表达以及涉及与TF胞质结构域相互作用的整合素。除了转移中的凝血酶-PAR信号传导和肿瘤生长中的TF-FVIIa-PAR2信号传导外，很可能其他蛋白酶途径将被证明是癌症中PARs的关键激活剂。跨膜丝氨酸蛋白酶以及基质金属蛋白酶是调节转移、肿瘤扩展和依赖于局部肿瘤微环境特定特征的血管生成辅助途径的主要候选者。
