An Anti-Wnt5a Antibody Suppresses Metastasis of Gastric Cancer Cells In Vivo by Inhibiting Receptor-Mediated Endocytosis
An Anti-Wnt5a Antibody Suppresses Metastasis of Gastric Cancer Cells In Vivo by Inhibiting Receptor-Mediated Endocytosis
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DOI：
10.1158/1535-7163.mct-11-0682
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发表时间：
2012-02-01
影响因子：
5.7
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
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作者：
Hanaki, Hideaki;Yamamoto, Hideki;Kikuchi, Akira
Wnt 5a是激活Wnt信号传导中的β-连环蛋白非依赖性途径的代表性配体。据报道，Wnt 5a在人胃癌中的表达与侵袭性和不良预后相关，并且Wnt 5a的敲除降低了胃癌细胞在裸鼠中转移的能力。因此，Wnt 5a及其信号通路可能成为胃癌治疗的重要靶点。本研究的目的是检查抗Wnt 5a抗体是否影响胃癌细胞的转移。抗Wnt 5a多克隆抗体（pAb 5a-5）可抑制Wnt 5a高表达胃癌细胞的体外迁移和侵袭能力。以前，已经证明Wnt 5a诱导受体的内化，这是Rac 1的Wnt 5a依赖性激活所必需的。pAb 5a-5抑制Wnt 5a依赖的受体内化，从而抑制Rac 1的Wnt 5a依赖的活化。层粘连蛋白γ 2是Wnt 5a信号转导的靶基因之一，Rac 1参与其表达。pAb 5a-5还抑制层粘连蛋白γ 2的Wnt 5a依赖性表达。在实验性肝转移测定中，将胃癌细胞引入裸鼠的脾脏中。层粘连蛋白γ 2是胃癌细胞体内肝转移所必需的。腹腔注射pAb 5a-5可抑制胃癌细胞的转移能力。这些结果表明，抗Wnt 5a抗体能够抑制Wnt 5a依赖性受体的内化，从而通过抑制Rac 1的活化和层粘连蛋白γ 2的表达来防止胃癌细胞的转移。Mol Cancer Ther; 11（2）;298-307. (C)2011年AACR。
Wnt5a is a representative ligand that activates the beta-catenin-independent pathway in Wnt signaling. It was reported that the expression of Wnt5a in human gastric cancer is associated with aggressiveness and poor prognosis and that knockdown of Wnt5a reduces the ability of gastric cancer cells to metastasize in nude mice. Therefore, Wnt5a and its signaling pathway might be important targets for the therapy of gastric cancer. The aim of this study was to examine whether an anti-Wnt5a antibody affects metastasis of gastric cancer cells. One anti-Wnt5a polyclonal antibody (pAb5a-5) inhibited migration and invasion activities in vitro of gastric cancer cells with a high expression level of Wnt5a. Previously, it was shown that Wnt5a induces the internalization of receptors, which is required for Wnt5a-dependent activation of Rac1. pAb5a-5 inhibited Wnt5a-dependent internalization of receptors, thereby suppressed Wnt5a-dependent activation of Rac1. Laminin gamma 2 is one of target genes of Wnt5a signaling and Rac1 was involved in its expression. pAb5a-5 also inhibited Wnt5a-dependent expression of laminin gamma 2. In an experimental liver metastasis assay, gastric cancer cells were introduced into the spleens of nude mice. Laminin gamma 2 was required for liver metastatic ability of gastric cancer cells in vivo. Furthermore, intraperitoneal injection of pAb5a-5 inhibited the metastatic ability of gastric cancer cells. These results suggest that an anti-Wnt5a antibody was capable of suppressing Wnt5a-dependent internalization of receptors, resulting in the prevention of metastasis of gastric cancer cells by inhibiting the activation of Rac1 and the expression of laminin gamma 2. Mol Cancer Ther; 11(2);298-307. (C) 2011 AACR.