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Microchip Captures Clusters of Circulating Tumor Cells


Circulating tumor cells (CTCs) are cells that break away from a tumor and move through a cancer patient’s bloodstream. Single CTCs are extremely rare, typically fewer than 1 in 1 billion cells. These cells can take up residence in distant organs, and it is believed that this is one mode by which cancer spreads. Even less common than single CTCs are small groups of CTCs, or clusters. While the existence of CTC clusters has been known for more than 50 years, their prevalence in the blood as well as their role in metastasis has not been thoroughly investigated, mostly because they are so elusive. However, recent advances in biomedical technologies that enable the capture of single CTCs have renewed interest in CTC clusters, which are occasionally captured along with single CTCs.


According to an article published online in Nature Methods Researchers (18 May 2015) a microfluidic chip has been developed that can capture rare clusters of circulating tumor cells from unprocessed blood, which could yield important new insights into how cancer spreads. The work was funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the National Institutes of Health. The new technology — called Cluster-Chip — was developed with support from a Quantum Grant from NIBIB, which funds transformative technological innovation designed to solve major medical problems with a substantial disease burden, such as preventing cancer metastasis or precisely tailoring therapeutics to an individual’s cancer cell biology. When the authors recently used Cluster-Chip to capture and analyze CTC clusters in a group of 60 patients with metastatic breast, prostate, and melanoma cancers, CTC clusters-ranging from two to 19 cells were found in 30-40% of the patients. According to the authors, the presence of these clusters is far more common than was thought in the past and the fact that clusters were seen in this many patients is remarkable.


The chip is designed to slowly push blood through many rows of microscopic triangle-shaped posts. The posts are arranged in such a way that every two posts funnels cells towards the tip of a third post. At the tip, single cells — including blood cells and single CTCs — easily slide to either side of the post and continue through the chip until reaching the next tip; however CTC clusters are left at the tip, hanging in the balance due to forces pulling them down the post in opposite directions. To determine the efficiency of Cluster-Chip, the authors introduced fluorescently tagged cell clusters (ranging from 2-30 cells) into the chip and counted the number of clusters that were captured and the number that flowed through undetected. At a blood flow rate of 2.5ml/hr, the chip captured 99% of clusters containing four or more cells, 70% of three-cell clusters, and 41% of two-cell clusters. Comparison of the clusters under a microscope before and after capture found that the chip had no negative effects on the integrity of the clusters as a whole. The authors next compared the efficiency of their novel chip to two currently-used methods that have had some success capturing CTC clusters. They found that at similar blood flow rates, the Cluster-Chip was significantly more efficient than a filter-based method, which pushes blood through a membrane with pores only large enough to let single cells pass through. The chip was also more efficient than a different microfluidic chip ┬áthat isolates CTCs and occasionally clusters using antibodies that stick to special proteins found on the surface of some tumor cells. The results highlight the importance of the unique Cluster-Chip capture technique, which is based on the structural properties of CTC clusters rather than their size or the presence of surface proteins. This latter property makes the Cluster-Chip well-suited for capturing CTC clusters from a range of cancer types, including those that lose surface proteins during metastasis and those that never express them, such as melanoma.


The authors tested the Cluster-Chip in a small trial of 60 patients with metastatic cancer. In this study, the chip captured CTC clusters in 11 of 27 (40.7%) breast cancer patients, 6 of 20 (30%) melanoma patients, and 4 of 13 (31%) prostate patients. The large number of clusters found in the patient samples suggests a possibly greater role for clusters in the metastatic cascade. To characterize the biology of the clusters, the authors measured a marker of tumor cell proliferation — an indicator of increased invasiveness and poor outcomes — in one breast cancer patient with high numbers of both single CTCs and clusters. Approximately half of the cells in the patient’s clusters were positive for the proliferative marker, demonstrating that clusters can contain both actively proliferating and quiescent cells. The authors also noted the rare presence of non-tumor cells within clusters in less than 5% of patients.


About the National Institute of Biomedical Imaging and Bioengineering: NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at the NIBIB website.



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