Title:
Wnt5a as a molecular target for cancer therapy

Akira Kikuchi, MD & PhD
Department of Molecular Biology and Biochemistry,
Graduate School of Medicine, Osaka University

Abstract:
The genetics of cancer and development have converged in the identification of intra- and extra-cellular signaling pathways that are aberrantly regulated in cancer and are also central to embryonic pattering. The Wnt signaling pathway has provided an outstanding example of this. There are 19 Wnt genes in human and mouse genomes. Some of Wnt proteins activate a non-canonical Wnt pathway (also referred to as the β-catenin-independent pathway) that primary modulates cell movement and polarity. Since Wnt5a is a representative ligand that activates the ?-catenin-independent pathway and has been suggested to be involved in human diseases, we analyzed how Wnt5a regulates its signaling and whether its abnormality is associated with tumorigenesis.
Wnt5a bound to Fz2 and Ror1/2 on cell surface and induced the internalization of the receptors in a clathrin-dependent manner. Wnt5a-induecd receptor-mediated endocytosis was necessary for the activation of small G protein Rac. These demonstrate sharp contrast to the findings that Wnt3a activates the β-catenin-dependent pathway through the caveolin-dependent endocytosis of LRP6. In addition, heparan sulfate proteoglycan (HSPG) affected Wnt5a signaling. Therefore, the interaction of Wnt5a with its receptors and other factors such as HSPG is highly complex.
Immunohistochemical analyses with anti-Wnt5a antibody revealed that Wnt5a is overexpressed in about 30% of 237 gastric cancer and 98 prostate cancer cases. The positivity of Wnt5a expression was correlated with poor prognosis of gastric cancer and relapse of prostate cancer. Knockdown of Wnt5a in gastric cancer cells or intraperitoneal injection of anti-Wnt5a antibody suppressed their liver metastatic ability in nude mice. These results suggest Wnt5a is a good therapeutic target for gastric cancer. In this seminar, I will discuss about possibility of anti-Wnt5a antibody as a molecular target for therapeutic use.

References:
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