Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation
Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation
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DOI：
10.1158/0008-5472.can-05-3897
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Schneider, Stefan W.
中科院分区：
文献类型：
--
作者：
Goerge, Tobias;Barg, Alexej;Schneider, Stefan W.
在血管系统中，循环肿瘤细胞与内皮细胞相互作用。肿瘤-内皮细胞串扰将血管内环境转变为称为内皮细胞活化（ECA）的促血栓形成、促炎症和细胞粘附状态。在本研究中，我们分析了转移性肿瘤源性可溶性因子将血管内皮转化为促血栓形成和促炎症激活状态的潜力。培养的黑色素瘤和结肠癌细胞（A375、WM 9、A7和HT-29）的上清液诱导大血管和微血管内皮细胞（人脐静脉内皮细胞和人真皮微血管内皮细胞）的急性活化，如细胞内钙通量和血管性血友病因子和白细胞介素-8（急性ECA的所有标志物）的分泌所示。使用特异性蛋白酶激活受体1（PAR 1）抑制剂（RWJ-58259和SCH-79797）可抑制该过程，表明内皮凝血酶受体具有介导作用。肿瘤细胞和培养上清液的免疫荧光、Western印迹分析和胶原酶活性测定揭示了基质金属蛋白酶-1（MMP-1）的存在，MMP-1是最近描述的PARI激活剂。抑制培养的肿瘤细胞上清液中的MMP-1显著减弱ECA。使用分离的人MMP-1（5 nmol/L）的其他研究证明了在肿瘤-内皮通讯中存在功能性MMP-1/PAR 1轴。这些发现显示了肿瘤与内皮细胞串扰的新途径，该途径通过微血管和大血管内皮细胞中的血管内MMP 1/PAR 1轴进行。抑制这种串扰可能是防止肿瘤诱导的ECA并因此防止血栓形成和炎性细胞粘附的有力手段。
In the vascular system, circulating tumor cells interact with endothelial cells. Tumor-endothelial cross-talk transforms the intravascular milieu to a prothrombotic, proinflammatory, and cell-adhesive state called endothelial cell activation (ECA). In the present study, we analyze the potential of metastatic tumor-derived soluble factors to transform the vascular endothelium into a prothrombotic and proinflammatory activated state. Supernatant from cultured melanoma and colon cancer cells (A375, WM9, A7, and HT-29) induced an acute activation of macrovascular and microvascular endothelial cells (human umbilical vein endothelial cells and human dermal microvascular endothelial cells) as shown by intracellular calcium flux and secretion of von Willebrand factor and interleukin-8, all markers of acute ECA. This process was inhibited using specific proteinase-activated receptor 1 (PAR1) inhibitors (RWJ-58259 and SCH-79797), indicating a mediating role for endothelial thrombin receptors. Immunofluorescence, Western blot analysis, and collagenase activity assay of tumor cells and culture supernatant revealed the presence of matrix metalloproteinase-1 (MMP-1), a recently described activator of PARI. Inhibition of MMP-1 in supernatant from cultured tumor cells significantly attenuated ECA. Additional studies using isolated human MMP-1 (5 nmol/L) proved the presence of a functional MMP-1/PAR1 axis in tumor-endothelial communication. These findings show a new pathway of tumor-endothelial cross-talk via an intravascular MMP1/PAR1 axis in microvascular and macrovascular endothelium. Inhibition of this cross-talk may be a powerful means to prevent tumor-induced ECA and thus thrombotic and inflammatory cell adhesion.