Thrombin generation and the pathogenesis of cancer

被引:142
作者
Ruf, Wolfram
Mueller, Barbara M.
机构
[1] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[2] La Jolla Inst Mol Med, San Diego, CA USA
关键词
tissue factor; protease activated receptors; protease signaling; metastasis; angiogenesis;
D O I
10.1055/s-2006-939555
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:61 / 68
页数:8
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