Neutralization of TNFα in tumor with a novel nanobody potentiates paclitaxel-therapy and inhibits metastasis in breast cancer. (1st February 2017)

• Record Type: Journal Article
• Authors: Ji, Xuemei; Peng, Zhengxin; Li, Xiaorui; Yan, Zhonghui; Yang, Yue; Qiao, Zheng; Liu, Yu
• Is Part Of: Cancer letters. Volume 386(2017)
• Page Start: 24
• Page End: 34
• Publication Date: 2017-02-01
• Subjects: Breast cancer -- TNFa nanobody -- Tumor inflammatory environment -- Metastasis and invasion -- EMT; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.10.031
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Researchers have suggested that inflammatory factors in the tumor environment can promote cancer invasion and metastasis, stimulating cancer progression. Thus, novel strategies that target cytokines and modulate the tumor microenvironment may emerge as important approaches for treating metastatic breast cancer. Specific neutralization of pathogenic TNF signaling using a TNFα antibody has gained increasing attention. Considering this, a selective human TNFα neutralized antibody was generated based on nanobody technology. A TNFα-specific nanobody was produced in Pichia pastoris with a molecular mass of 15 kDa and affinity constant of 2.05 nM. In the proliferation experiment, the TNFα nanobody could inhibit the proliferation of the breast cancer cell line MCF-7 induced by hTNFα in a dose-dependent manner. In the microinvasion model, the TNFα nanobody could inhibit the migration of the breast cancer cell lines MCF-7, MDA-MB-231 and the invasiveness of MDA-MB-231 induced by hTNFα in a dose-dependent manner. Drug administration of the combination of paclitaxel with the TNFα nanobody in vivo significantly enhanced the efficacy against 4T-1 breast tumor proliferation and lung metastasis; meanwhile, E-cadherin tumor epithelial marker expression was upregulated, supporting the anti-tumor therapeutic relevance of paclitaxel and the TNFα nanobody on EMT. This study highlights the importance of neutralizing low TNFα levels in the tumor microenvironment to sensitize the chemotherapeutic response, which has attractive potential for clinical applications. Highlights: Novel TNFα nanobody was generated with high affinity and low molecular weight. TNFα nanobody inhibited increased migration and invasiveness of MCF-7 and MDA-MB-231. Combining Taxol with TNFα nanobody enhanced anti-tumor efficacy. TNFα nanobody inhibited mice 4T-1 tumor EMT. TNFα nanobody penetrated into and neutralized TNFα interior tumor.