Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 40, Pages 9986-9991Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1803884115
Keywords
protease; circulating tumor cells; cell secretion; microfluidics; liquid biopsy
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Funding
- Vortex Biosciences
- National Cancer Institute (NCI) Innovative Molecular Analysis Technologies (IMAT) Program [R33CA177456]
- NCI Early Detection Research Network NCI [1U01CA214182]
- Merit Review Research Funds from the US Department of Veteran Affairs
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Tumor cells are hypothesized to use proteolytic enzymes to facilitate invasion. Whether circulating tumor cells (CTCs) secrete these enzymes to aid metastasis is unknown. A quantitative and high-throughput approach to assay CTC secretion is needed to address this question. We developed an integrated microfluidic system that concentrates rare cancer cells >100,000-fold from 1 mL of whole blood into similar to 50,000 2-nL drops composed of assay reagents within 15 min. The system isolates CTCs by size, exchanges fluid around CTCs to remove contaminants, introduces a matrix metalloprotease (MMP) substrate, and encapsulates CTCs into microdroplets. We found CTCs from prostate cancer patients possessed above baseline levels of MMP activity (1.7- to 200-fold). Activity of CTCs was generally higher than leukocytes from the same patient (average CTC/leukocyte MMP activity ratio, 2.6 +/- 1.5). Higher MMP activity of CTCs suggests active proteolytic processes that may facilitate invasion or immune evasion and be relevant phenotypic biomarkers enabling companion diagnostics for anti-MMP therapies.
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