Background: Circulating tumor cells (CTCs) have shown prognostic relevance in many cancer types. However, the\nmajority of current CTC capture methods rely on positive selection techniques that require a priori knowledge\nabout the surface protein expression of disseminated CTCs, which are known to be a dynamic population.\nMethods: We developed a microfluidic CTC capture chip that incorporated a nanoroughened glass substrate for\ncapturing CTCs from blood samples. Our CTC capture chip utilized the differential adhesion preference of cancer\ncells to nanoroughened etched glass surfaces as compared to normal blood cells and thus did not depend on\nthe physical size or surface protein expression of CTCs.\nResults: The microfluidic CTC capture chip was able to achieve a superior capture yield for both epithelial cell\nadhesion molecule positive (EpCAM+) and EpCAM- cancer cells in blood samples. Additionally, the microfluidic\nCTC chip captured CTCs undergoing transforming growth factor beta-induced epithelial-to-mesenchymal\ntransition (TGF-�²-induced EMT) with dynamically down-regulated EpCAM expression. In a mouse model of\nhuman breast cancer using EpCAM positive and negative cell lines, the number of CTCs captured correlated\npositively with the size of the primary tumor and was independent of their EpCAM expression. Furthermore,\nin a syngeneic mouse model of lung cancer using cell lines with differential metastasis capability, CTCs were\ncaptured from all mice with detectable primary tumors independent of the cell linesâ�� metastatic ability.\nConclusions: The microfluidic CTC capture chip using a novel nanoroughened glass substrate is broadly applicable to\ncapturing heterogeneous CTC populations of clinical interest independent of their surface marker expression and\nmetastatic propensity. We were able to capture CTCs from a non-metastatic lung cancer model, demonstrating\nthe potential of the chip to collect the entirety of CTC populations including subgroups of distinct biological and\nphenotypical properties. Further exploration of the biological potential of metastatic and presumably non-metastatic\nCTCs captured using the microfluidic chip will yield insights into their relevant differences and their effects on tumor\nprogression and cancer outcomes.
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