CSPG4 Protein as a New Target for the Antibody-Based Immunotherapy of Triple-Negative Breast Cancer
CSPG4 Protein as a New Target for the Antibody-Based Immunotherapy of Triple-Negative Breast Cancer
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DOI：
10.1093/jnci/djq343
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发表时间：
2010-10-01
影响因子：
10.3
通讯作者：
Ferrone, Soldano
中科院分区：
文献类型：
--
作者：
Wang, Xinhui;Osada, Takuya;Ferrone, Soldano
背景细胞表面蛋白聚糖硫酸软骨素蛋白聚糖4（CSPG 4）是基于单克隆抗体（mAb）的多种癌症免疫治疗的潜在靶点。缺乏对三阴性乳腺癌（TNBC）的有效治疗促使我们检查CSPG 4是否在TNBC中表达并且可以用CSPG 4特异性mAb靶向。方法在44个原发性TNBC病变中，在TNBC细胞系HS 578 T、MDA-MB-231、MDA-MB-435和SUM 149中，以及12例转移性乳腺癌患者胸腔积液中的肿瘤细胞。在体外测试CSPG 4特异性mAb 225.28对TNBC细胞的生长、粘附和迁移的影响。在小鼠乳腺癌模型中测试mAb 225.28诱导肿瘤转移消退（n = 7只小鼠）和抑制自发转移和肿瘤复发（n = 12只小鼠/组）的能力。还在细胞系和小鼠模型中研究了mAb 225.28抗肿瘤作用的机制。结果CSPG 4蛋白在44个原发性TNBC病灶中的32个（72.7%）、TNBC细胞系和12例转移性乳腺癌患者胸腔积液中的肿瘤细胞中优先表达。CSPG 4特异性mAb 225.28在体外统计学上显著抑制TNBC细胞的生长、粘附和迁移。mAb 225.28在TNBC细胞衍生的实验肺转移模型中诱导73.1%的肿瘤转移消退（mAb 225.28 vs对照，转移性结节的平均面积= 44590.8 vs 165950.8 μ m（2）;平均差= 121360.0 μ m（2），95%可信区间= 91010.7 ~ 151709.4 μ m（2）; P < .001）。此外，mAb 225.28在原位异种移植小鼠模型中统计学显著降低自发性肺转移和肿瘤复发。CSPG 4的抗肿瘤作用机制包括增加肿瘤细胞的凋亡和减少有丝分裂活性，降低肿瘤微环境中的血管密度，以及减少参与细胞存活、增殖和转移的信号通路的激活。CSPG 4特异性mAb的抗肿瘤活性由多种机制介导，包括抑制对TNBC细胞存活、增殖和转移至关重要的信号传导途径。
Background The cell surface proteoglycan, chondroitin sulfate proteoglycan 4 (CSPG4), is a potential target for monoclonal antibody (mAb)-based immunotherapy for many types of cancer. The lack of effective therapy for triple-negative breast cancer (TNBC) prompted us to examine whether CSPG4 is expressed in TNBC and can be targeted with CSPG4-specific mAb.Methods CSPG4 protein expression was assessed in 44 primary TNBC lesions, in TNBC cell lines HS578T, MDA-MB-231, MDA-MB-435, and SUM149, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. The effect of CSPG4-specific mAb 225.28 on growth, adhesion, and migration of TNBC cells was tested in vitro. The ability of mAb 225.28 to induce regression of tumor metastases (n = 7 mice) and to inhibit spontaneous metastasis and tumor recurrence (n = 12 mice per group) was tested in breast cancer models in mice. The mechanisms responsible for the antitumor effect of mAb 225.28 were also investigated in the cell lines and in the mouse models. All statistical tests were two-sided.Results CSPG4 protein was preferentially expressed in 32 of the 44 (72.7%) primary TNBC lesions tested, in TNBC cell lines, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. CSPG4-specific mAb 225.28 statistically significantly inhibited growth, adhesion, and migration of TNBC cells in vitro. mAb 225.28 induced 73.1% regression of tumor metastasis in a TNBC cell-derived experimental lung metastasis model (mAb 225.28 vs control, mean area of metastatic nodules = 44590.8 vs 165950.8 mu m(2); difference of mean = 121360.0 mu m(2), 95% confidence interval = 91010.7 to 151709.4 mu m(2); P < .001). Additionally, mAb 225.28 statistically significantly reduced spontaneous lung metastases and tumor recurrences in an orthotopic xenograft mouse model. The mechanisms responsible for antitumor effect included increased apoptosis and reduced mitotic activity in tumor cells, decreased blood vessel density in the tumor microenvironment, and reduced activation of signaling pathways involved in cell survival, proliferation and metastasis.Conclusions This study identified CSPG4 as a new target for TNBC. The antitumor activity of CSPG4-specific mAb was mediated by multiple mechanisms, including the inhibition of signaling pathways crucial for TNBC cell survival, proliferation, and metastasis.