Säfholm Annette, Tuomela Johanna, Rosenkvist Jeanette, Dejmek Janna, Härkönen Pirkko, Andersson Tommy
Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
Clin Cancer Res. 2008 Oct 15;14(20):6556-63. doi: 10.1158/1078-0432.CCR-08-0711.
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.
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.
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%.
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.
乳腺癌治疗中一个固有的问题是，当前的治疗方法未能特异性地靶向原发性肿瘤中乳腺癌细胞的扩散。临床研究结果表明，原发性乳腺肿瘤中Wnt-5a蛋白表达的缺失预示着肿瘤扩散更快，体外分析显示其通过抑制肿瘤细胞迁移来实现这一点。因此，我们假设恢复Wnt-5a信号传导可能是一种抑制乳腺癌转移的新治疗策略。
我们使用体外技术表明，4T1小鼠乳腺癌细胞对使用我们新型的模拟Wnt-5a的六肽Foxy-5恢复Wnt-5a信号传导的反应，与人类乳腺癌细胞相同。因此，我们随后可以在将4T1细胞接种到小鼠体内后，研究其对癌症转移扩散的体内作用。
体外分析显示，重组Wnt-5a和源自Wnt-5a的Foxy-5肽均损害了4T1乳腺癌细胞的迁移和侵袭，而不影响其凋亡或增殖。体内实验表明，腹腔注射Foxy-5可使接种的4T1乳腺癌细胞从乳腺脂肪垫转移至肺和肝脏的转移率降低70%至90%。
这些数据提供了原理证明，即恢复乳腺癌细胞中的Wnt-5a信号传导是一种通过靶向细胞运动来损害乳腺肿瘤转移的新方法。与现有疗法相结合，这种方法代表了一种治疗乳腺癌患者的潜在新治疗策略。
