Department of Molecular Pathology, Nara Medical University, Nara, Japan.
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Japan.
Cancer Sci. 2020 May;111(5):1840-1850. doi: 10.1111/cas.14361. Epub 2020 Mar 18.
Triple negative breast cancer (TNBC) is characterized by highly aggressive phenotype, limited treatment options and a poor prognosis. In the present study, we examined the therapeutic effect of anti-claudin (CLDN)-4 extracellular domain antibody, 4D3, on TNBC. When the expression of CLDN4 and CLDN1 in invasive ductal carcinoma (IDC) was examined in 114 IDC (78 cases from 2004 to 2009 in a single center and 36 cases of tissues array), CLDN1 had lower expression than CLDN4 and was correlated with histological grade. In contrast, expression of CLDN4 was correlated with histological grade, receptor subtype, and stage. CLDN4 expression in human IDC cell lines MCF-7 (luminal subtype) and MDA-468 (TNBC) was at the same level. In both cells, paclitaxel (PTX)-induced growth suppression was enhanced by 4D3. Furthermore, 4D3 increased both intracellular PTX concentration (in both cells) and apoptosis. In the mouse model, 4D3 promoted the antitumor effect of PTX on subcutaneous tumors and reduced lung metastasis. The combination of PTX and 4D3 reduced M2 macrophages and mesenchymal stem cells in the tumor. 4D3 also reduced stemness of the tumors and increased the intratumoral pH. Moreover, concurrent treatment with 4D3, PTX and tamoxifen, or with PTX and tamoxifen in MDA-468 also showed the same level of antitumor activity and survival as MCF-7. Furthermore, in a bone metastasis model, combination of PTX and bisphosphonate with 4D3 promoted tumor growth in both cells. Thus, CLDN4 targeting of the antibody facilitated existing therapeutic effects.
三阴性乳腺癌（TNBC）的特点是侵袭性强、治疗选择有限且预后不良。在本研究中，我们研究了抗紧密连接蛋白（CLDN）-4 细胞外结构域抗体 4D3 对 TNBC 的治疗效果。在对 114 例浸润性导管癌（IDC）（2004 年至 2009 年在单一中心的 78 例和组织微阵列的 36 例）中 CLDN4 和 CLDN1 的表达进行检测时，CLDN1 的表达低于 CLDN4，且与组织学分级相关。相反，CLDN4 的表达与组织学分级、受体亚型和分期相关。人 IDC 细胞系 MCF-7（管腔亚型）和 MDA-468（TNBC）中 CLDN4 的表达水平相同。在这两种细胞中，4D3 增强了紫杉醇（PTX）诱导的生长抑制。此外，4D3 增加了细胞内 PTX 浓度（在两种细胞中）和细胞凋亡。在小鼠模型中，4D3 促进了 PTX 对皮下肿瘤的抗肿瘤作用，并减少了肺转移。PTX 和 4D3 联合减少了肿瘤中的 M2 巨噬细胞和间充质干细胞。4D3 还降低了肿瘤的干性，并增加了肿瘤内的 pH 值。此外，4D3 与 PTX 和他莫昔芬同时治疗，或在 MDA-468 中与 PTX 和他莫昔芬同时治疗，也显示出与 MCF-7 相同的抗肿瘤活性和生存率。此外，在骨转移模型中，PTX 和双膦酸盐与 4D3 的联合治疗促进了两种细胞的肿瘤生长。因此，抗体对 CLDN4 的靶向作用增强了现有的治疗效果。
