Tags

Type your tag names separated by a space and hit enter

Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation.
Signal Transduct Target Ther. 2020 Jul 10; 5(1):117.ST

Abstract

Tumor cells transform into endothelial cells by epithelial-to-mesenchymal transition, which is characterized by vasculogenic mimicry (VM). VM not only accelerates tumor progression but also increases drug-induced resistance. However, very little is currently known about the molecular determinants that enable VM. Targeting VM might bring a new breakthrough in cancer treatment. Thrombin is the key enzyme of the blood coagulation system and could contribute to tumor progression. Nevertheless, the association between thrombin and VM formation remains largely unknown. We found that VM was associated with the overall survival of non-small-cell lung cancer (NSCLC) patients, and that thrombin expression was closely related to VM formation. This research revealed that thrombin induced VM formation via PAR-1-mediated NF-κB signaling cascades. The novel thrombin inhibitors r-hirudin and DTIP inhibited VM formation and spontaneous metastases in subcutaneous tumors. Clinical pathological analysis confirmed that NSCLC patients with thrombin-positive/PAR-1-high expression had the poorest prognosis and were the most likely to form VM. The promotional activity of thrombin in VM formation and tumor metastasis was abolished in PAR-1-deficient NSCLC cells. The EGFR inhibitor gefitinib had no effect on VM and increased VEGF expression in tumors. The combination therapy of DTIP and gefitinib achieved a better therapeutic effect than either agent alone. This study is the first to illustrate that thrombin substantially contributes, together with PAR-1, to VM formation and to illustrate that VM might be a target of r-hirudin and DTIP to suppress tumor progression. The anticoagulants r-hirudin and DTIP could be employed for antitumor therapy. Combination therapy with DTIP with an EGFR inhibitor might achieve superior therapeutic effects.

Authors+Show Affiliations

Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. wanghj98@hotmail.com. Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China. wanghj98@hotmail.com.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China. 15111010026@fudan.edu.cn. The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. 15111010026@fudan.edu.cn. Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China. 15111010026@fudan.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32647187

Citation

Zhao, Bing, et al. "Thrombin Is a Therapeutic Target for Non-small-cell Lung Cancer to Inhibit Vasculogenic Mimicry Formation." Signal Transduction and Targeted Therapy, vol. 5, no. 1, 2020, p. 117.
Zhao B, Wu M, Hu Z, et al. Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation. Signal Transduct Target Ther. 2020;5(1):117.
Zhao, B., Wu, M., Hu, Z., Ma, Y., Qi, W., Zhang, Y., Li, Y., Yu, M., Wang, H., & Mo, W. (2020). Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation. Signal Transduction and Targeted Therapy, 5(1), 117. https://doi.org/10.1038/s41392-020-0167-1
Zhao B, et al. Thrombin Is a Therapeutic Target for Non-small-cell Lung Cancer to Inhibit Vasculogenic Mimicry Formation. Signal Transduct Target Ther. 2020 Jul 10;5(1):117. PubMed PMID: 32647187.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation. AU - Zhao,Bing, AU - Wu,Mengfang, AU - Hu,Zhihuang, AU - Ma,Yixin, AU - Qi,Wang, AU - Zhang,Yanling, AU - Li,Yaran, AU - Yu,Min, AU - Wang,Huijie, AU - Mo,Wei, Y1 - 2020/07/10/ PY - 2019/10/14/received PY - 2020/03/29/accepted PY - 2020/03/17/revised PY - 2020/7/11/entrez PY - 2020/7/11/pubmed PY - 2020/7/11/medline SP - 117 EP - 117 JF - Signal transduction and targeted therapy JO - Signal Transduct Target Ther VL - 5 IS - 1 N2 - Tumor cells transform into endothelial cells by epithelial-to-mesenchymal transition, which is characterized by vasculogenic mimicry (VM). VM not only accelerates tumor progression but also increases drug-induced resistance. However, very little is currently known about the molecular determinants that enable VM. Targeting VM might bring a new breakthrough in cancer treatment. Thrombin is the key enzyme of the blood coagulation system and could contribute to tumor progression. Nevertheless, the association between thrombin and VM formation remains largely unknown. We found that VM was associated with the overall survival of non-small-cell lung cancer (NSCLC) patients, and that thrombin expression was closely related to VM formation. This research revealed that thrombin induced VM formation via PAR-1-mediated NF-κB signaling cascades. The novel thrombin inhibitors r-hirudin and DTIP inhibited VM formation and spontaneous metastases in subcutaneous tumors. Clinical pathological analysis confirmed that NSCLC patients with thrombin-positive/PAR-1-high expression had the poorest prognosis and were the most likely to form VM. The promotional activity of thrombin in VM formation and tumor metastasis was abolished in PAR-1-deficient NSCLC cells. The EGFR inhibitor gefitinib had no effect on VM and increased VEGF expression in tumors. The combination therapy of DTIP and gefitinib achieved a better therapeutic effect than either agent alone. This study is the first to illustrate that thrombin substantially contributes, together with PAR-1, to VM formation and to illustrate that VM might be a target of r-hirudin and DTIP to suppress tumor progression. The anticoagulants r-hirudin and DTIP could be employed for antitumor therapy. Combination therapy with DTIP with an EGFR inhibitor might achieve superior therapeutic effects. SN - 2059-3635 UR - https://www.unboundmedicine.com/medline/citation/32647187/Thrombin_is_a_therapeutic_target_for_non-small-cell_lung_cancer_to_inhibit_vasculogenic_mimicry_formation L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32647187/ DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.