title: Urokinase exerts antimetastatic effects by dissociating clusters of circulating tumor cells.
abstract: Clusters of circulating tumor cells (CTC) exhibit more robust metastatic properties than single CTC. Thus, understanding the distinct behaviors of CTC clusters and how CTC clustering is regulated may offer new insights into how to limit metastasis. In this study, we utilized an in vivo confocal system to observe the clustering behavior of CTC in real time, finding that the number of clusters increased proportionally with the growth of the primary tumor. Our experiments also indicated that the flow rate of the CTC clusters in blood vessels was relatively slower than single CTC due to increased vessel wall adhesion. Depending on disease stage, 5% to 10% of total CTC in circulation were in clusters, with this proportion increasing to >24% within lung metastases examined. Notably, in the 4T1 mouse model of breast cancer metastasis, we found that injecting host animals with urokinase-type plasminogen activator, a clinical thrombolytic agent, was effective at preventing the assembly of CTC clusters and prolonging overall host survival by approximately 20% relative to control animals. Our results suggest a tractable approach to limit metastasis by suppressing the formation or stability of CTC clusters circulating in the blood of cancer patients.
authors.affiliation: Wonkwang Institute of Integrative Biomedical Science and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk, Korea. Imaging Science-Based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Cheonbuk, Korea. Advanced Institute of Convergence Technology, Seoul National University, Suwon, Gyenggi-do, Korea. jinwoochoi@wku.ac.kr khy1646@wku.ac.kr syun@hms.harvard.edu.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Biomedical Engineering Center, Asan Institute for Life Sciences, Asan Medical Center and University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Jun Ki
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Wonkwang Institute of Integrative Biomedical Science and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk, Korea.
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Pilhan
authors.initials: P
authors.lastname: Kim
authors.affiliation: Imaging Science-Based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Cheonbuk, Korea. Department of Radiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea. jinwoochoi@wku.ac.kr khy1646@wku.ac.kr syun@hms.harvard.edu.
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. jinwoochoi@wku.ac.kr khy1646@wku.ac.kr syun@hms.harvard.edu.
authors.forename: Seok Hyun
authors.initials: SH
authors.lastname: Yun
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000187:drug effects* / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D005343:Fibrinolytic Agents; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator