Therapeutic Discovery An Anti-Wnt5a Antibody Suppresses Metastasis of Gastric Cancer Cells In Vivo by Inhibiting Receptor-Mediated Endocytosis

Wnt5a is a representative ligand that activates the b-catenin–independent pathway inWnt signaling. It was reported that the expression of Wnt5a in human gastric cancer is associated with aggressiveness and poor prognosis and that knockdown ofWnt5a reduces the ability of gastric cancer cells to metastasize in nudemice. Therefore, Wnt5a and its signaling pathway might be important targets for the therapy of gastric cancer. The aim of this studywas to examinewhether an anti-Wnt5a antibody affectsmetastasis 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 ofWnt5a. Previously, it was shown thatWnt5a 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 g2 is one of target genes of Wnt5a signaling and Rac1 was involved in its expression. pAb5a-5 also inhibited Wnt5adependent expression of laminin g2. In an experimental liver metastasis assay, gastric cancer cells were introduced into the spleens of nudemice. Laminin g2 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 g2. Mol Cancer Ther; 11(2); 1–10. 2011 AACR.