Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts.
Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts.
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DOI：
10.1371/journal.pone.0009741
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发表时间：
2010-03-17
期刊：
影响因子：
3.7
通讯作者：
Peyruchaud O
中科院分区：
文献类型：
--
作者：
David M;Wannecq E;Descotes F;Jansen S;Deux B;Ribeiro J;Serre CM;Grès S;Bendriss-Vermare N;Bollen M;Saez S;Aoki J;Saulnier-Blache JS;Clézardin P;Peyruchaud O
骨转移是乳腺癌最常见的并发症。目前使用强力抗吸收药物的骨转移治疗只能是姑息性的，这表明骨吸收不依赖于因素控制骨转移的进展。自体趋化蛋白(ATX/NPP2)是一种分泌型蛋白，具有致癌和促转移的双重特性。ATX通过其溶磷脂酶D(LysoPLD)活性控制血液中溶血磷脂酸(LPA)的水平。血小板衍生的LPA促进乳腺癌细胞溶骨性骨转移的进展。我们询问ATX是否参与了骨转移过程。我们通过利用不同溶骨性骨转移小鼠模型上的转基因乳腺癌细胞来表征ATX在溶骨性骨转移形成中的作用。静脉注射强制表达ATX的人乳腺癌MDA-B02细胞(MDA-B02/ATX)到免疫缺陷的BALB/C裸小鼠，可以促进溶骨性骨转移的形成，这是通过增加骨丢失、肿瘤负担和转移部位活跃的破骨细胞数量来判断的。小鼠乳腺癌4T1细胞心内注射诱导免疫活性BALB/C小鼠形成溶骨性骨转移。这些细胞表达活跃的ATX，沉默的ATX表达抑制了溶骨性骨损害的程度，并减少了骨转移部位活跃的破骨细胞的数量。在体外，在存在MDA-B02/ATX细胞条件培养液或重组自体趋化素的情况下，破骨细胞的分化被促进，而重组自体趋化素能被自体趋化蛋白抑制剂vpc8a202阻断。在体外，在活性碳处理的血清中加入LPA，恢复了血清支持RANK-L/mcsf诱导的破骨细胞生成的能力。癌细胞自身趋化蛋白的表达控制着溶骨性骨转移的形成。这项工作展示了LPA作为一种直接刺激肿瘤生长和转移以及破骨细胞分化的新作用。因此，靶向自体趋化蛋白/LPA通路成为改善骨转移患者预后的一种潜在的新的治疗方法。
Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorbtive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2) is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD) activity, ATX controls the level of lysophosphatidic acid (LPA) in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models. Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX) to inmmunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis. Expression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a factor that stimulates directly cancer growth and metastasis, and osteoclast differentiation. Therefore, targeting the autotaxin/LPA track emerges as a potential new therapeutic approach to improve the outcome of patients with bone metastases.
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DOI：
10.1016/0005-2760(89)90112-4
发表时间：
1989-02-20
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
GERRARD, JM;ROBINSON, P
通讯作者：
ROBINSON, P
影响因子：
3.3
作者：
Inoue, M.;Xie, W.;Ueda, H.
通讯作者：
Ueda, H.
影响因子：
8.2
作者：
Boucher, J;Quilliot, D;Saulnier-Blache, JS
通讯作者：
Saulnier-Blache, JS
影响因子：
4.8
作者：
Ferry, G;Tellier, E;Saulnier-Blache, JS
通讯作者：
Saulnier-Blache, JS
影响因子：
15.9
作者：
Minn, AJ;Kang, YB;Massagué, J
通讯作者：
Massagué, J