title: Nanoroughened adhesion-based capture of circulating tumor cells with heterogeneous expression and metastatic characteristics.
abstract: Circulating tumor cells (CTCs) have shown prognostic relevance in many cancer types. However, the majority of current CTC capture methods rely on positive selection techniques that require a priori knowledge about the surface protein expression of disseminated CTCs, which are known to be a dynamic population.
  
  
  
  We developed a microfluidic CTC capture chip that incorporated a nanoroughened glass substrate for capturing CTCs from blood samples. Our CTC capture chip utilized the differential adhesion preference of cancer cells to nanoroughened etched glass surfaces as compared to normal blood cells and thus did not depend on the physical size or surface protein expression of CTCs.
  
  
  
  The microfluidic CTC capture chip was able to achieve a superior capture yield for both epithelial cell adhesion molecule positive (EpCAM+) and EpCAM- cancer cells in blood samples. Additionally, the microfluidic CTC chip captured CTCs undergoing transforming growth factor beta-induced epithelial-to-mesenchymal transition (TGF-β-induced EMT) with dynamically down-regulated EpCAM expression. In a mouse model of human breast cancer using EpCAM positive and negative cell lines, the number of CTCs captured correlated positively with the size of the primary tumor and was independent of their EpCAM expression. Furthermore, in a syngeneic mouse model of lung cancer using cell lines with differential metastasis capability, CTCs were captured from all mice with detectable primary tumors independent of the cell lines' metastatic ability.
  
  
  
  The microfluidic CTC capture chip using a novel nanoroughened glass substrate is broadly applicable to capturing heterogeneous CTC populations of clinical interest independent of their surface marker expression and metastatic propensity. We were able to capture CTCs from a non-metastatic lung cancer model, demonstrating the potential of the chip to collect the entirety of CTC populations including subgroups of distinct biological and phenotypical properties. Further exploration of the biological potential of metastatic and presumably non-metastatic CTCs captured using the microfluidic chip will yield insights into their relevant differences and their effects on tumor progression and cancer outcomes.
authors: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.|Department of Mechanical and Aerospace Engineering, New York University, New York, NY, 10012, USA.
authors: Weiqiang
authors: W
authors: Chen
authors: Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, 48109, USA.|Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, 48109, USA.
authors: Steven G
authors: SG
authors: Allen
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
authors: Ajaya Kumar
authors: AK
authors: Reka
authors: Department of Mechanical and Aerospace Engineering, New York University, New York, NY, 10012, USA.
authors: Weiyi
authors: W
authors: Qian
authors: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors: Shuo
authors: S
authors: Han
authors: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.|School of Advanced Engineering, Beihang University, Beijing, 100191, China.
authors: Jianing
authors: J
authors: Zhao
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
authors: Liwei
authors: L
authors: Bao
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA. vkeshamo@med.umich.edu.|University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA. vkeshamo@med.umich.edu.
authors: Venkateshwar G
authors: VG
authors: Keshamouni
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA. smerajve@umich.edu.|University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA. smerajve@umich.edu.
authors: Sofia D
authors: SD
authors: Merajver
authors: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. jpfu@umich.edu.|Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. jpfu@umich.edu.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA. jpfu@umich.edu.|Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI, 48109, USA. jpfu@umich.edu.
authors: Jianping
authors: J
authors: Fu
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods*; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D016212:Transforming Growth Factor beta
keywords: Adhesion; Breast cancer; Circulating tumor cells; Lung cancer; Metastasis; Microfluidics