期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 18, 页码 4947-4952出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1524448113
关键词
microfluidics; cancer metastasis; CTC clusters; circulating tumor cell cluster microemboli; capillary microhemodynamics
资金
- NIH [F33-GM109574, R24OD016761, P41 EB002503-11]
- Howard Hughes Medical Institute
- Alex Lemonade Stand Foundation
- Live Like Bella Foundation
- NIH National Institute of Biomedical Imaging and Bioengineering Quantum Grant
Multicellular aggregates of circulating tumor cells (CTC clusters) are potent initiators of distant organ metastasis. However, it is currently assumed that CTC clusters are too large to pass through narrow vessels to reach these organs. Here, we present evidence that challenges this assumption through the use of microfluidic devices designed to mimic human capillary constrictions and CTC clusters obtained from patient and cancer cell origins. Over 90% of clusters containing up to 20 cells successfully traversed 5- to 10-mu m constrictions even in whole blood. Clusters rapidly and reversibly reorganized into single-file chain-like geometries that substantially reduced their hydrodynamic resistances. Xenotransplantation of human CTC clusters into zebrafish showed similar reorganization and transit through capillary-sized vessels in vivo. Preliminary experiments demonstrated that clusters could be disrupted during transit using drugs that affected cellular interaction energies. These findings suggest that CTC clusters may contribute a greater role to tumor dissemination than previously believed and may point to strategies for combating CTC cluster-initiated metastasis.
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