Research ArticleCancer Diagnostics

Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells

Science Translational Medicine  03 Apr 2013:
Vol. 5, Issue 179, pp. 179ra47
DOI: 10.1126/scitranslmed.3005616

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Positive and Negative Outcomes

Usually people want the good news first, to help cope with the bad news that inevitably follows. However, patients will soon desire both the positive and the negative outcomes together, according to the latest study by Ozkumur and colleagues. These authors have developed a multistage microfluidic device that is capable of sorting rare circulating tumor cells (CTCs) that are either positive or negative for the surface antigen epithelial cell adhesion molecule (EpCAM).

EpCAM+ cells found in the bloodstream have long defined the typical CTC. Many sorting technologies have been developed to enumerate EpCAM+ CTCs in cancer patient’s blood; however, these cells are not always detectable in cancers with low EpCAM expression, like triple-negative breast cancer or melanoma. Ozkumur et al. engineered an automated platform, called the “CTC-iChip,” that captured both EpCAM+ and EpCAM cancer cells in clinical samples using a series of debulking, inertial focusing, and magnetic separation steps. The sorted CTCs could then be interrogated using standard clinical protocols, such as immunocytochemistry. The authors tested the “positive mode” of their device using whole blood from patients with prostate, lung, breast, pancreatic, and colorectal cancers. After successfully separating out the EpCAM+ CTCs, they confirmed that the cells were viable and had high-quality RNA for molecular analysis, in one example, detecting the EML4-ALK gene fusion in lung cancer. Using the “negative mode” of their device, the authors were able to capture EpCAM CTCs from patients with metastatic breast cancer, pancreatic cancer, and melanoma. The isolated CTCs showed similar morphology when compared with primary tumor tissue from these patients, suggesting that the microfluidic device can be used for clinical diagnoses—delivering both positive and negative news at once.

Ozkumur et al. also demonstrated that CTCs isolated using the iChip could be analyzed on the single-cell level. One such demonstration with 15 CTCs from a prostate cancer patient reveals marked heterogeneity in the expression of mesenchymal and stem cell markers as well as typical prostate cancer–related antigens. The CTC-iChip can therefore process large volumes of patient blood to obtain not just EpCAM+ CTCs but also the EpCAM ones, thus giving a broader picture of an individual’s cancer status and also allowing the device to be used for more cancer types. With the ability to further analyze the molecular characteristics of CTCs, this CTC-iChip could be a promising addition to current diagnostic tools used in the clinic.