High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells.
High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells.
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DOI：
10.1371/journal.pone.0164830
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yonekura K
中科院分区：
文献类型：
--
作者：
Fujita H;Gomori A;Fujioka Y;Kataoka Y;Tanaka K;Hashimoto A;Suzuki T;Ito K;Haruma T;Yamamoto-Yokoi H;Harada N;Sakuragi M;Oda N;Matsuo K;Inada M;Yonekura K
大约25-40%的肺癌患者表现出骨转移。骨修饰剂可减少骨相关事件（SRE），但不能显著改善总生存率。因此，迫切需要新的治疗方法。在本研究中，我们在肿瘤诱导的骨病模型中研究了TAS-115（一种VEGF和HGF受体（MET）靶向激酶抑制剂）的抗肿瘤作用。A549-Luc-BM 1细胞是一种由转基因A549人肺腺癌细胞（A549-Luc）克隆而成的趋骨细胞，将其植入小鼠胫骨内（IT）后，产生了与肿瘤进展相关的侵袭性骨破坏。TAS-115显著降低IT肿瘤生长和骨破坏。组织学分析显示TAS-115处理后肿瘤血管减少，这可能通过VEGF抑制介导。此外，TAS-115治疗后肿瘤周围的破骨细胞数量减少。体外研究表明，TAS-115可抑制破骨细胞中HGF、VEGF和巨噬细胞集落刺激因子（M-CSF）诱导的信号通路。此外，TAS-115可抑制猫麦克多诺肉瘤癌基因（FMS）激酶以及M-CSF和NF-κB配体受体激活剂（RANKL）诱导的破骨细胞分化。因此，破骨细胞中的VEGF/MET/FMS-三重抑制可能有助于TAS-115的强效疗效。舒尼替尼（VEGF/FMS抑制）与克唑替尼（MET抑制）联合给药对骨破坏的抑制疗效与TAS-115相当，这一事实也支持这一观点。总之，TAS-115通过阻断VEGF激酶抑制肿瘤生长，还可能通过抑制VEGF/MET/FMS激酶抑制骨破坏，这导致TAS-115在A549-Luc-BM 1骨病模型中具有强效疗效。因此，TAS-115有望成为肺癌骨转移患者的一种新疗法。
Approximately 25–40% of patients with lung cancer show bone metastasis. Bone modifying agents reduce skeletal-related events (SREs), but they do not significantly improve overall survival. Therefore, novel therapeutic approaches are urgently required. In this study, we investigated the anti-tumor effect of TAS-115, a VEGFRs and HGF receptor (MET)-targeted kinase inhibitor, in a tumor-induced bone disease model. A549-Luc-BM1 cells, an osteo-tropic clone of luciferase-transfected A549 human lung adenocarcinoma cells (A549-Luc), produced aggressive bone destruction associated with tumor progression after intra-tibial (IT) implantation into mice. TAS-115 significantly reduced IT tumor growth and bone destruction. Histopathological analysis showed a decrease in tumor vessels after TAS-115 treatment, which might be mediated through VEGFRs inhibition. Furthermore, the number of osteoclasts surrounding the tumor was decreased after TAS-115 treatment. In vitro studies demonstrated that TAS-115 inhibited HGF-, VEGF-, and macrophage-colony stimulating factor (M-CSF)-induced signaling pathways in osteoclasts. Moreover, TAS-115 inhibited Feline McDonough Sarcoma oncogene (FMS) kinase, as well as M-CSF and receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Thus, VEGFRs/MET/FMS-triple inhibition in osteoclasts might contribute to the potent efficacy of TAS-115. The fact that concomitant dosing of sunitinib (VEGFRs/FMS inhibition) with crizotinib (MET inhibition) exerted comparable inhibitory efficacy for bone destruction to TAS-115 also supports this notion. In conclusion, TAS-115 inhibited tumor growth via VEGFR-kinase blockade, and also suppressed bone destruction possibly through VEGFRs/MET/FMS-kinase inhibition, which resulted in potent efficacy of TAS-115 in an A549-Luc-BM1 bone disease model. Thus, TAS-115 shows promise as a novel therapy for lung cancer patients with bone metastasis.
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影响因子：
2.1
作者：
Knudsen, BS;Gmyrek, GA;Woude, GFV
通讯作者：
Woude, GFV
DOI：
10.1007/978-1-62703-989-5_11
发表时间：
2014-01-01
期刊：
SKELETAL DEVELOPMENT AND REPAIR: METHODS AND PROTOCOLS
影响因子：
--
作者：
Kawamoto, Tadafumi;Kawamoto, Komei
通讯作者：
Kawamoto, Komei
DOI：
10.1016/j.bbrc.2006.09.076
发表时间：
2006-11-17
影响因子：
3.1
作者：
Adamopoulos, Iannis E.;Xia, Zhidao;Athanasou, Nicholas A.
通讯作者：
Athanasou, Nicholas A.
影响因子：
4.3
作者：
Mukai, Shoichiro;Yorita, Kenji;Kawagoe, Yukari;Katayama, Yuichi;Nakahara, Kozue;Kamibeppu, Toyoharu;Sugie, Satoru;Tukino, Hiromasa;Kamoto, Toshiyuki;Kataoka, Hiroaki
通讯作者：
Kataoka, Hiroaki
影响因子：
11.5
作者：
Coleman, Robert E.
通讯作者：
Coleman, Robert E.