Genome-wide expression profiling revealed overexpression of the gene encoding frizzled homologue 10 (FZD10), a cell-surface receptor for molecules in the Wnt pathway, as a potential contributor to synovial sarcomas (SS). Northern blotting and immunohistochemical staining confirmed that expression levels of FZD10 were very high in nearly all SS tumors and cell lines examined but absent in most normal organs or in some cancers arising in other tissues. Treatment of human SS cells with small-interfering RNA (siRNA) to FZD10 decreased the amount of its product and suppressed growth of SS cells. Moreover, a polyclonal antibody specifically recognizing the extracellular domain (ECD) of FZD10 was markedly effective in mediating ADCC against FZD10-overexpressing synovial sarcoma cells in vitro. Injection of the antibody into SS xenografts in nude mice attenuated tumor growth, and TUNEL assays revealed clusters of apoptotic cells in antibody-treated xenografts. Taken together, these findings suggest that a humanized antibody against FZD10 might be a promising treatment for patients with tumors that overexpress FZD10; minimal or no adverse reactions would be expected because FZD10 protein is not abundant in vital organs.Oncogene (2005) 24, 6201-6212. doi:10.1038/sj.onc.1208780; published online 27 June 2005.