Therapeutic potential of antibodies against FZD10, a cell-surface protein, for synovial sarcomas
Therapeutic potential of antibodies against FZD10, a cell-surface protein, for synovial sarcomas
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DOI：
10.1038/sj.onc.1208780
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发表时间：
2005-09-01
期刊：
影响因子：
8
通讯作者：
Nakamura, Y
中科院分区：
文献类型：
--
作者：
Nagayama, S;Fukukawa, C;Nakamura, Y
全基因组表达专家。Ling揭示了编码卷曲同源10(FZD10)的基因的过度表达，FZD10是Wnt通路中分子的细胞表面受体，是滑膜肉瘤(SS)的潜在贡献者。Northern印迹和免疫组织化学染色证实，FZD10在几乎所有SS肿瘤和细胞系中都有很高的表达水平，但在大多数正常器官或其他组织发生的一些肿瘤中不表达。FZD10用小干扰RNA(SiRNA)作用于人SS细胞后，其产物的量减少，生长受到抑制。此外，识别FZD10胞外区(ECD)的多克隆抗体对体外高表达FZD10的滑膜肉瘤细胞具有明显的抗癌活性。将抗体注射到裸鼠的SS异种移植瘤中可以抑制肿瘤的生长，TUNEL检测显示抗体处理的异种移植瘤中有成簇的凋亡细胞。综上所述，这些发现表明，针对FZD10的人源化抗体可能是一种有希望的治疗方法，用于过度表达FZD10的肿瘤患者；预计不良反应最小或没有，因为FZD10蛋白在重要器官中并不丰富。
Genome-wide expression pro. ling 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 over-express FZD10; minimal or no adverse reactions would be expected because FZD10 protein is not abundant in vital organs.