Tumor MMP-1 activates endothelial PAR1 to facilitate vascular intravasation and metastatic dissemination.
Tumor MMP-1 activates endothelial PAR1 to facilitate vascular intravasation and metastatic dissemination.
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DOI：
10.1158/0008-5472.can-12-4495
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发表时间：
2013-07-15
期刊：
影响因子：
11.2
通讯作者：
Quigley JP
中科院分区：
文献类型：
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作者：
Juncker-Jensen A;Deryugina EI;Rimann I;Zajac E;Kupriyanova TA;Engelholm LH;Quigley JP
浸润，即原发性肿瘤细胞主动进入脉管系统，仍然是转移级联中研究最少的步骤。蛋白酶介导的肿瘤细胞逃逸和基质侵袭代表了广泛接受的导致内渗步骤的过程。然而，直接促进肿瘤细胞血管渗透的分子因素尚未确定。在本研究中，通过使用人 HEp3 表皮样癌的高度播散性变体 HEp3-hi/diss 分析了胶原蛋白溶解蛋白酶 MMP-1 在癌细胞内渗和转移中的体内作用。虽然天然获得性或实验诱导的 MMP-1 缺陷显着抑制了 HEp3-hi/diss 内渗，但向 MMP-1 沉默的原发性肿瘤补充重组 MMP-1 可以恢复其受损的血管传播。令人惊讶的是，MMP-1 产生和活性的消除并没有显着影响 HEp3-hi/diss 迁移或基质侵袭，表明 MMP-1 依赖性细胞内渗的非胶原蛋白溶解机制。为了支持这种非胶原蛋白溶解机制，HEp3-hi/diss 细胞中的 MMP-1 沉默调节了新型微肿瘤模型中血管生成脉管系统的微结构和完整性。与此同时，MMP-1 缺陷导致肿瘤内血管通透性、肿瘤细胞内渗和转移扩散水平降低。利用 HEp3-hi/diss 细胞的 PAR1 缺陷，我们进一步证明内皮 PAR1 是一个假定的非肿瘤细胞/非基质靶标，癌产生的 MMP-1 激活它可调节内皮通透性和跨内皮迁移。特定 PAR1 拮抗剂在活体动物中的抑制作用也表明肿瘤中 MMP-1 依赖性血管通透性的机制涉及内皮 PAR1 激活。总之，我们的研究结果从机制上强调了肿瘤 MMP-1/内皮 PAR1 轴对侵袭性癌细胞表现出的实际血管内渗事件的贡献。
Intravasation, the active entry of primary tumor cells into the vasculature, remains the least studied step in the metastatic cascade. Protease-mediated escape and stromal invasion of tumor cells represent widely-accepted processes leading up to the intravasation step. However, molecular factors that contribute directly to tumor cell vascular penetration have not been identified. In this study, the in vivo role of the collagenolytic protease, MMP-1, in cancer cell intravasation and metastasis was analyzed by employing a highly-disseminating variant of human HEp3 epidermoid carcinoma, HEp3-hi/diss. Whereas naturally-acquired or experimentally-induced MMP-1 deficiency substantially suppressed HEp3-hi/diss intravasation, supplementation of recombinant MMP-1 to MMP-1-silenced primary tumors, restored their impaired vascular dissemination. Surprisingly, abrogation of MMP-1 production and activity did not affect significantly HEp3-hi/diss migration or matrix invasion, suggesting non-collagenolytic mechanisms underlying MMP-1-dependent cell intravasation. In support of such non-collagenolytic mechanisms, MMP-1 silencing in HEp3-hi/diss cells modulated the microarchitecture and integrity of the angiogenic vasculature in a novel microtumor model. Concomitantly, MMP-1 deficiency led to decreased levels of intratumoral vascular permeability, tumor cell intravasation and metastatic dissemination. Taking advantage of PAR1 deficiency of HEp3-hi/diss cells, we further demonstrate that endothelial PAR1 is a putative non-tumor-cell/non-matrix target, activation of which by carcinoma-produced MMP-1 regulates endothelial permeability and transendothelial migration. The inhibitory effects of specific PAR1 antagonists in live animals have also indicated that the mechanisms of MMP-1-dependent vascular permeability in tumors involve endothelial PAR1 activation. Together, our findings mechanistically underscore the contribution of a tumor MMP-1/endothelial PAR1 axis to actual intravasation events manifested by aggressive carcinoma cells.