Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice
Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice
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DOI：
10.1096/fj.13-248641
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发表时间：
2014-06-01
期刊：
影响因子：
4.8
通讯作者：
Brindley, David N.
中科院分区：
文献类型：
--
作者：
Benesch, Matthew G. K.;Tang, Xiaoyun;Brindley, David N.
自分泌运动因子是一种分泌型酶，产生大多数细胞外溶血磷脂酸，其刺激6种G蛋白偶联受体。溶血磷脂酸促进癌细胞存活、生长、迁移、侵袭、转移以及对化疗和放疗的抗性。本研究探讨了抑制自分泌运动因子是否能减少乳腺肿瘤的生长和转移。我们使用了一种新的自分泌运动因子抑制剂（ONO-8430506; IC 90 =100 nM），与溶剂处理的小鼠相比，24小时内血浆自分泌运动因子活性降低>60%，不饱和溶血磷脂酸浓度降低>75%。在注射20，000个BALB/c小鼠4 T1或4 T1 - 12 B癌细胞后，在乳腺癌的同基因原位小鼠模型中测定ONO-8430506对肿瘤生长的影响。我们首次表明，抑制autotaxin减少初始肿瘤生长和随后的肺转移性结节都由60%相比，车辆治疗的小鼠。值得注意的是，与乳腺脂肪垫相比，4 T1细胞表达的自分泌运动因子可以忽略不计。肿瘤生长使未治疗小鼠脂肪垫中的自分泌运动素活性增加了2倍。我们的研究结果强调了肿瘤与环境相互作用的重要性，以及自分泌运动因子在促进乳腺癌生长和转移中的作用。我们还确定，自分泌运动因子抑制可以提供一种新的治疗方法来阻断溶血磷脂酸在癌症中的不良作用。
Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G-protein-coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO-8430506; IC90=100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle-treated mice. The effects of ONO-8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1-12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle-treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2-fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer.