Dynamic analysis of lung metastasis by mouse osteosarcoma LM8: VEGF is a candidate for anti-metastasis therapy.
Dynamic analysis of lung metastasis by mouse osteosarcoma LM8: VEGF is a candidate for anti-metastasis therapy.
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DOI：
10.1007/s10585-012-9543-8
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发表时间：
2013-04
影响因子：
4
通讯作者：
Itoh K
中科院分区：
文献类型：
--
作者：
Tanaka T;Yui Y;Naka N;Wakamatsu T;Yoshioka K;Araki N;Yoshikawa H;Itoh K
骨肉瘤（Osteosarcoma， OS）是最常见的恶性骨肿瘤，其预后取决于肺转移，肺转移是恶性肿瘤多阶段发展的结果。本研究旨在利用同源小鼠自发性高转移性OS LM8和亲本Dunn细胞系，阐明肺转移的关键步骤，寻找新的抑制肺转移的候选分子。我们首先研究了两种细胞系小鼠循环肿瘤细胞（ctc）的时间顺序检测。与Dunn型CTCs相比，LM8型CTCs出现速度更快，速度更快，数量更多。在模拟CTCs血流环境的悬浮培养中，lc8 CTCs培养的细胞比原发部位的细胞具有更高的增殖能力。在低硬度（- 150 Pa，接近肺条件）的3D胶原培养中，LM8细胞的增殖能力也高于Dunn细胞。我们接下来关注的是外渗步骤。与Dunn相比，经内皮细胞迁移实验显示LM8具有更高的迁移能力。我们还发现在与LM8共培养过程中内皮屏障功能受到破坏。此外，LM8分泌高水平的血管内皮生长因子（VEGF），而用小分子酪氨酸激酶抑制剂（pazopanib）抑制VEGF信号可减少LM8对血管屏障的破坏和跨内皮迁移。最后，每日口服帕唑帕尼可降低体内肺转移的发生率和大小。总的来说，这些结果表明抗vegf治疗是骨肉瘤肺转移的候选药物。本文的在线版本（doi:10.1007/s10585-012-9543-8）包含补充材料，仅供授权用户使用。
Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis depends on pulmonary metastases, which arise from multi-step progression of malignant tumors. We herein aimed to clarify the critical step of pulmonary metastasis using the syngeneic mouse spontaneous highly metastatic OS LM8 and parental Dunn cell lines, to identify new candidate molecules to suppress pulmonary metastasis. We first investigated the chronological detection of circulating tumor cells (CTCs) from mice with either cell line. LM8 CTCs appeared faster, at a higher rate and with a greater number compared to Dunn CTCs. Cultured cells from CTCs of LM8 showed higher proliferative ability than cells from the primary site in suspension culture, which mimicked the environment of the bloodstream for CTCs. The proliferative ability of LM8 cells was also higher than that of Dunn cells in 3D collagen culture with low stiffness (−150 Pa; close to conditions in the lung). We next focused on the extravasation step. LM8 showed higher migration ability compared to Dunn with transendothelial migration assay. We also found a disruption in endothelial barrier function throughout co-culture with LM8 using time-lapse imaging. In addition, LM8 secreted high levels of vascular endothelial growth factor (VEGF), while VEGF signal inhibition with a small molecule tyrosine kinase inhibitor (pazopanib) decreased disruption of the vascular barrier and transendothelial migration of LM8. Finally, daily oral administration of pazopanib reduced the rate and size of pulmonary metastasis in vivo. Collectively, these results show anti-VEGF therapy as a candidate for pulmonary metastasis of OS. The online version of this article (doi:10.1007/s10585-012-9543-8) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.77.2.1039
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CIFONE, MA;FIDLER, IJ
通讯作者：
FIDLER, IJ
影响因子：
2
作者：
Miroshnikova YA;Jorgens DM;Spirio L;Auer M;Sarang-Sieminski AL;Weaver VM
通讯作者：
Weaver VM
影响因子：
5.7
作者：
Kumar, Rakesh;Knick, Victoria B.;Cheung, Mui
通讯作者：
Cheung, Mui
影响因子：
45.3
作者：
Kager, L;Zoubek, A;Bielack, SS
通讯作者：
Bielack, SS
影响因子：
45.3
作者：
Cohen, Steven J.;Punt, Cornelis J. A.;Meropol, Neal J.
通讯作者：
Meropol, Neal J.