University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
J Natl Cancer Inst. 2010 Oct 6;102(19):1496-512. doi: 10.1093/jnci/djq343. Epub 2010 Sep 17.
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.
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.
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 μm(2); difference of mean = 121360.0 μm(2), 95% confidence interval = 91010.7 to 151709.4 μm(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.
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.
细胞表面蛋白聚糖，硫酸软骨素蛋白聚糖 4（CSPG4），是一种针对多种癌症的单克隆抗体（mAb）为基础的免疫疗法的潜在靶点。缺乏有效的三阴性乳腺癌（TNBC）治疗促使我们研究 CSPG4 是否在 TNBC 中表达，并且可以用 CSPG4 特异性 mAb 进行靶向治疗。
评估了 44 例原发性 TNBC 病变、TNBC 细胞系 HS578T、MDA-MB-231、MDA-MB-435 和 SUM149 以及 12 例转移性乳腺癌患者胸腔积液中的肿瘤细胞中 CSPG4 蛋白的表达。在体外测试 CSPG4 特异性 mAb 225.28 对 TNBC 细胞生长、粘附和迁移的影响。在乳腺癌小鼠模型中测试 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（每组 n = 12 只小鼠）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。所有统计检验均为双侧检验。
在 44 例原发性 TNBC 病变中，有 32 例（72.7%）检测到 CSPG4 蛋白优先表达，在 TNBC 细胞系中以及在 12 例转移性乳腺癌患者的胸腔积液中的肿瘤细胞中检测到 CSPG4 蛋白优先表达。CSPG4 特异性 mAb 225.28 可显著抑制 TNBC 细胞的体外生长、粘附和迁移。mAb 225.28 在 TNBC 细胞衍生的实验性肺转移模型中诱导 73.1%的肿瘤转移消退（mAb 225.28 与对照组相比，转移性结节的平均面积为 44590.8μm2 与 165950.8μm2；差异均值为 121360.0μm2，95%置信区间为 91010.7 至 151709.4μm2；P <.001）。此外，mAb 225.28 还可显著降低原位异种移植小鼠模型中的自发性肺转移和肿瘤复发。抗肿瘤作用的机制包括肿瘤细胞凋亡增加和有丝分裂活性降低、肿瘤微环境中血管密度降低以及参与细胞存活、增殖和转移的信号通路活性降低。
本研究将 CSPG4 鉴定为 TNBC 的一个新靶点。CSPG4 特异性 mAb 的抗肿瘤活性是通过多种机制介导的，包括抑制 TNBC 细胞存活、增殖和转移的关键信号通路。
