Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling.
Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling.
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DOI：
10.1186/1476-4598-5-69
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发表时间：
2006-12-08
期刊：
影响因子：
37.3
通讯作者：
Davis GE
中科院分区：
文献类型：
--
作者：
Fisher KE;Pop A;Koh W;Anthis NJ;Saunders WB;Davis GE
溶血磷脂酸（LPA）和1-磷酸鞘氨醇（S1 P）是与肿瘤扩散有关的生物活性脂质信号分子。膜型基质金属蛋白酶1（MT 1-MMP）是一种膜系胶原酶，被认为通过细胞外基质降解参与肿瘤侵袭。在这项研究中，我们研究了LPA和S1 P调节的肿瘤细胞迁移的二维（2D）和三维（3D）胶原基质的侵袭的分子要求，特别是评估了MT 1-MMP在这个过程中的作用。在Boyden小室测定中，LPA刺激而S1 P抑制大多数肿瘤细胞系的迁移。相反，HT 1080纤维肉瘤细胞迁移响应这两种脂质。HT 1080细胞也显著地侵入3D胶原基质（在48小时内~700 μm）以响应任一脂质。靶向LPA 1和Rac 1或S1 P 1、Rac 1和Cdc 42的siRNA分别特异性抑制LPA或S1 P诱导的HT 1080侵袭。对LPA诱导的HT 1080在2D基质与3D基质上的运动性的分析显示，合成MMP抑制剂仅在细胞导航3D基质时显著降低侵袭的距离（~125 μm对~45 μm）和速度（~0.09 μm/min对~0.03 μm/min），这表明MMP仅在侵袭中起作用。此外，金属蛋白酶组织抑制剂（TIMP）-2，-3和-4，但不是TIMP-1，阻止脂质激动剂诱导的侵袭表明膜型（MT）-MMP的作用。此外，MT 1-MMP在几种肿瘤细胞系中的表达与LPA诱导的侵袭直接相关。用MT 1-MMP cDNA转染在LPA存在下既不表达MT 1-MMP也不侵入的HEK 293，随后响应于LPA侵入。当HT 1080细胞接种在胶原基质之上或之内时，靶向MT 1-MMP而非其他MMP的siRNA抑制脂质激动剂诱导的侵袭，从而确立了MT 1-MMP在该过程中的必要作用。LPA是MT 1-MMP依赖性肿瘤细胞侵袭3D胶原基质的基本调节剂。相比之下，S1 P在大多数情况下似乎充当抑制性刺激，而仅刺激选定的肿瘤细胞系。MT 1-MMP仅在肿瘤细胞通过3D屏障时需要，而在细胞在2D基质上迁移时不需要。我们证明，肿瘤细胞需要协调调节LPA/S1 P受体和Rho GTPases迁移，此外，需要MT 1-MMP，以便在肿瘤进展过程中侵入胶原基质。
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive lipid signaling molecules implicated in tumor dissemination. Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a membrane-tethered collagenase thought to be involved in tumor invasion via extracellular matrix degradation. In this study, we investigated the molecular requirements for LPA- and S1P-regulated tumor cell migration in two dimensions (2D) and invasion of three-dimensional (3D) collagen matrices and, in particular, evaluated the role of MT1-MMP in this process. LPA stimulated while S1P inhibited migration of most tumor lines in Boyden chamber assays. Conversely, HT1080 fibrosarcoma cells migrated in response to both lipids. HT1080 cells also markedly invaded 3D collagen matrices (~700 μm over 48 hours) in response to either lipid. siRNA targeting of LPA1 and Rac1, or S1P1, Rac1, and Cdc42 specifically inhibited LPA- or S1P-induced HT1080 invasion, respectively. Analysis of LPA-induced HT1080 motility on 2D substrates vs. 3D matrices revealed that synthetic MMP inhibitors markedly reduced the distance (~125 μm vs. ~45 μm) and velocity of invasion (~0.09 μm/min vs. ~0.03 μm/min) only when cells navigated 3D matrices signifying a role for MMPs exclusively in invasion. Additionally, tissue inhibitors of metalloproteinases (TIMPs)-2, -3, and -4, but not TIMP-1, blocked lipid agonist-induced invasion indicating a role for membrane-type (MT)-MMPs. Furthermore, MT1-MMP expression in several tumor lines directly correlated with LPA-induced invasion. HEK293s, which neither express MT1-MMP nor invade in the presence of LPA, were transfected with MT1-MMP cDNA, and subsequently invaded in response to LPA. When HT1080 cells were seeded on top of or within collagen matrices, siRNA targeting of MT1-MMP, but not other MMPs, inhibited lipid agonist-induced invasion establishing a requisite role for MT1-MMP in this process. LPA is a fundamental regulator of MT1-MMP-dependent tumor cell invasion of 3D collagen matrices. In contrast, S1P appears to act as an inhibitory stimulus in most cases, while stimulating only select tumor lines. MT1-MMP is required only when tumor cells navigate 3D barriers and not when cells migrate on 2D substrata. We demonstrate that tumor cells require coordinate regulation of LPA/S1P receptors and Rho GTPases to migrate, and additionally, require MT1-MMP in order to invade collagen matrices during neoplastic progression.
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影响因子：
4
作者：
Kostenis, E
通讯作者：
Kostenis, E
DOI：
10.1152/ajpcell.2000.278.3.c612
发表时间：
2000-03-01
影响因子：
5.5
作者：
Lee, H;Goetzl, EJ;An, SZ
通讯作者：
An, SZ
影响因子：
64.5
作者：
Hotary, KB;Allen, ED;Weiss, SJ
通讯作者：
Weiss, SJ
DOI：
10.1083/jcb.149.6.1309
发表时间：
2000-06-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hotary K;Allen E;Punturieri A;Yana I;Weiss SJ
通讯作者：
Weiss SJ
影响因子：
11.2
作者：
Deryugina, EI;Zijlstra, A;Quigley, JP
通讯作者：
Quigley, JP