Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy.
Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy.
复制标题
人类抗体对Wnt信号的失活，该抗体识别肝癌治疗的Glypican-3硫酸盐链。
DOI：
10.1002/hep.26996
复制
发表时间：
2014-08
期刊：
影响因子：
13.5
通讯作者：
Ho, Mitchell
中科院分区：
文献类型：
--
作者：
Gao, Wei;Kim, Heungnam;Feng, Mingqian;Phung, Yen;Xavier, Charles P.;Rubin, Jeffrey S.;Ho, Mitchell
Wnt信号传导对于癌症发病机制是重要的，并且通常在肝细胞癌（HCC）中上调。硫酸乙酰肝素蛋白聚糖（HSPG）作为Wnt活化的共受体或调节剂起作用。磷脂酰肌醇蛋白聚糖-3（GPC 3）是一种在HCC中高度表达的HSPG，它可以将Wnt蛋白吸引到细胞表面并促进细胞增殖。因此，GPC 3已成为肝癌的候选治疗靶点。虽然目前正在临床前和临床研究中评估针对GPC 3的单克隆抗体，但没有一种抗体显示出对Wnt信号传导的影响。在这里，我们首先记录了Wnt 3a、多种Wnt受体和GPC 3在几种HCC细胞系中的表达，并证明GPC 3增强了这些细胞中Wnt 3a/β-catenin信号传导的活性。然后，我们报告了HS 20的鉴定，HS 20是一种针对GPC 3的人单克隆抗体，其优先识别GPC 3的硫酸乙酰肝素链，包括硫酸化和非硫酸化部分。HS 20阻断了Wnt 3a与GPC 3的相互作用，阻断了Wnt 3a/β-catenin信号通路。此外，HS 20在体外抑制Wnt 3a依赖的细胞增殖和裸鼠中的HCC异种移植物生长。此外，HS 20在小鼠中没有可检测到的不期望的毒性。综上所述，我们的结果表明，主要靶向GPC 3的硫酸肝素链的单克隆抗体抑制HCC细胞中的Wnt/β-连环蛋白信号传导，并具有有效的体内抗肿瘤活性。在这里，我们提供了针对蛋白聚糖硫酸乙酰肝素的抗体的第一个例子之一，该抗体在阻断Wnt信号传导和HCC生长方面显示出功效，这表明了肝癌治疗的新策略。
Wnt signaling is important for cancer pathogenesis and is often upregulated in hepatocellular carcinoma (HCC). Heparan sulfate proteoglycans (HSPGs) function as co-receptors or modulators of Wnt activation. Glypican-3 (GPC3) is a HSPG that is highly expressed in HCC, where it can attract Wnt proteins to the cell surface and promote cell proliferation. Thus, GPC3 has emerged as a candidate therapeutic target in liver cancer. While monoclonal antibodies to GPC3 are currently being evaluated in preclinical and clinical studies, none have shown an effect on Wnt signaling. Here, we first document the expression of Wnt3a, multiple Wnt receptors and GPC3 in several HCC cell lines, and demonstrate that GPC3 enhanced the activity of Wnt3a/β-catenin signaling in these cells. Then, we report the identification of HS20, a human monoclonal antibody against GPC3, which preferentially recognized the heparan sulfate chains of GPC3, both the sulfated and non-sulfated portions. HS20 disrupted the interaction of Wnt3a and GPC3 and blocked Wnt3a/β-catenin signaling. Moreover, HS20 inhibited Wnt3a-dependent cell proliferation in vitro and HCC xenograft growth in nude mice. In addition, HS20 had no detectable undesired toxicity in mice. Taken together, our results show that a monoclonal antibody primarily targeting the heparin sulfate chains of GPC3 inhibited Wnt/β-catenin signaling in HCC cells and had potent anti-tumor activity in vivo. Here, we provide one of the first examples of an antibody directed against the heparan sulfate of a proteoglycan that showed efficacy in blocking Wnt signaling and HCC growth, suggesting a novel strategy for liver cancer therapy.
登录
查看更多内容
影响因子：
6.4
作者：
Ho, Mitchell;Feng, Mingqian;Fisher, Robert J.;Rader, Christoph;Pastan, Ira
通讯作者：
Pastan, Ira
DOI：
10.1016/j.bbrc.2012.02.069
发表时间：
2012-03-23
影响因子：
3.1
作者：
Liu, Shiyuan;Li, Yumin;Zeng, Xiangting
通讯作者：
Zeng, Xiangting
影响因子：
11.2
作者：
Ishiguro, Takahiro;Sugimoto, Masamichi;Yamada-Okabe, Hisafumi
通讯作者：
Yamada-Okabe, Hisafumi
影响因子：
2.9
作者：
Rozenberg, GF;Espada, J;Bertolesi, GE
通讯作者：
Bertolesi, GE
影响因子：
8.4
作者：
Ho, Mitchell;Kim, Heungnam
通讯作者：
Kim, Heungnam