Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model
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Zhuo Zhang1, Hiroe Shiratsuchi2, Jules Lin3, Guoan Chen3, Rishindra M. Reddy3, Ebrahim Azizi2,4, Shamileh Fouladdel2,4, Andrew C. Chang3, Lin Lin3, Hui Jiang7, Meghna Waghray3,4,5, Gary Luker8, Diane M. Simeone3,4,5, Max S. Wicha2,4, David G. Beer3, Nithya Ramnath2,6, Sunitha Nagrath1,4
1Department of Chemical Engineering, Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109
2Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
3Department of Surgery, University of Michigan, Ann Arbor, MI 48109
4Translational Oncology Program, University of Michigan, Ann Arbor, MI 48109
5Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109
6Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105
7Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109
8Department of Radiology, Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109
Nithya Ramnath, e-mail: firstname.lastname@example.org
Sunitha Nagrath, e-mail: email@example.com
Keywords: expansion of CTCs, early stage lung cancer, microfluidic co-culture
Received: October 10, 2014 Accepted: October 11, 2014 Published: December 01, 2014
The potential utility of circulating tumor cells (CTCs) to guide clinical care in oncology patients has gained momentum with emerging micro- and nanotechnologies. Establishing the role of CTCs in tumor progression and metastasis depends both on enumeration and on obtaining sufficient numbers of CTCs for downstream assays. The numbers of CTCs are few in early stages of cancer, limiting detailed molecular characterization. Recent attempts in the literature to culture CTCs isolated from metastatic patients using monoculture have had limited success rates of less than 20%. Herein, we have developed a novel in-situ capture and culture methodology for ex-vivo expansion of CTCs using a three dimensional co-culture model, simulating a tumor microenvironment to support tumor development. We have successfully expanded CTCs isolated from 14 of 19 early stage lung cancer patients. Expanded lung CTCs carried mutations of the TP53 gene identical to those observed in the matched primary tumors. Next-generation sequencing further revealed additional matched mutations between primary tumor and CTCs of cancer-related genes. This strategy sets the stage to further characterize the biology of CTCs derived from patients with early lung cancers, thereby leading to a better understanding of these putative drivers of metastasis.
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