The Wnt-5a-Derived Hexapeptide Foxy-5 Inhibits Breast Cancer Metastasis In vivo by Targeting Cell Motility
The Wnt-5a-Derived Hexapeptide Foxy-5 Inhibits Breast Cancer Metastasis In vivo by Targeting Cell Motility
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DOI：
10.1158/1078-0432.ccr-08-0711
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发表时间：
2008-10-15
影响因子：
11.5
通讯作者：
Andersson, Tommy
中科院分区：
文献类型：
--
作者：
Safholm, Annette;Tuomela, Johanna;Andersson, Tommy
目的：乳腺癌治疗的一个固有问题是，目前的治疗方法不能特异性地靶向乳腺癌细胞从原发肿瘤的扩散。临床研究表明，Wnt-5a蛋白在乳腺原发肿瘤中的表达缺失预示着肿瘤的更快扩散，体外分析表明其是通过抑制肿瘤细胞的迁移来实现的。因此，我们假设重组Wnt-5a信号可能是抑制乳腺癌转移的一种新的治疗策略。实验设计：我们使用体外技术证明4T1小鼠乳腺癌细胞对Wnt-5a信号重组有反应，使用我们的新型Wnt-5a模拟六肽Foxy-5，与人类乳腺癌细胞的方式相同。因此，我们随后可以在体内研究4T1细胞接种小鼠后对癌症转移扩散的影响。结果：体外分析显示，重组Wnt-5a和Wnt-5a衍生的Foxy-5肽均能抑制4T1乳腺癌细胞的迁移和侵袭，但不影响细胞凋亡和增殖。体内实验表明，注射Foxy-5可抑制接种后的4T1乳腺癌细胞从乳腺脂肪垫向肺和肝脏转移70% ~ 90%。结论：这些数据从原理上证明了乳腺癌细胞中Wnt-5a信号的重构是一种通过靶向细胞运动抑制乳腺癌肿瘤转移的新途径。结合现有的治疗方法，这种方法代表了一种潜在的治疗乳腺癌患者的新治疗策略。
Purpose: An inherent problem in breast cancer treatment is that current therapeutic approaches fail to specifically target the dissemination of breast cancer cells from the primary tumor. Clinical findings show that the loss of Wnt-5a protein expression in the primary breast tumor predicts a faster tumor spread, and in vitro analyses reveal that it does so by inhibiting tumor cell migration. Therefore, we hypothesized that the reconstitution of Wnt-5a signaling could be a novel therapeutic strategy to inhibit breast cancer metastasis.Experimental Design: We used in vitro techniques to show that 4T1 mouse breast cancer cells responded to the reconstitution of Wnt-5a signaling using our novel Wnt-5a mimicking hexapeptide, Foxy-5, in the same way as human breast cancer cells. Therefore, we could subsequently study its effect in vivo on the metastatic spread of cancer following the inoculation of 4T1 cells into mice.Results: In vitro analyses revealed that both recombinant Wnt-5a and the Wnt-5a-derived Foxy-5 peptide impaired migration and invasion without affecting apoptosis or proliferation of 4T1 breast cancer cells. The in vivo experiments show that i.p. injections of Foxy-5 inhibited metastasis of inoculated 4T1 breast cancer cells from the mammary fat pad to the lungs and liver by 70% to 90%.Conclusions: These data provide proof of principle that the reconstitution of Wnt-5a signaling in breast cancer cells is a novel approach to impair breast tumor metastasis by targeting cell motility. In combination with existing therapies, this approach represents a potential novel therapeutic strategy for the treatment of breast cancer patients.