A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow
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Most anti-cancer drug screening assays are currently performed in two dimensions, on flat, rigid surfaces. However, there are increasing indications that three-dimensional (3D) platforms provide a more realistic setting to investigate accurate morphology, growth, and sensitivity of tumor cells to chemical factors. Moreover, interstitial flow plays a pivotal role in tumor growth. Here, we present a microfluidic 3D platform to investigate behaviors of tumor cells in flow conditions with anti-migratory compounds. Our results show that interstitial flow and its direction have significant impact on migration and growth of hepatocellular carcinoma cell lines such as HepG2 and HLE. In particular, HepG2/HLE cells tend to migrate against interstitial flow, and their growth increases in interstitial flow conditions regardless of the flow direction. Furthermore, this migratory activity of HepG2 cells is enhanced when they are co-cultured with human umbilical vein endothelial cells. We also found that migration activity of HepG2 cells attenuates under hypoxic conditions. In addition, the effect of Artemisinin, an anti-migratory compound, on HepG2 cells was quantitatively analyzed. The microfluidic 3D platform described here is useful to investigate more accurately the effect of anti-migratory drugs on tumor cells and the critical influence of interstitial flow than 2D culture models.
Keywords3D cell migration Microfluidics Anti-migratory drugs Interstitial flow
Vascular endothelial growth factor
Basic fibroblast growth factor
Human umbilical vein endothelial cell
We appreciate helpful discussions with Dr. Mariko Ikeda at Keio University. We would also like to thank Ms. Jessie S. Jeon at the Massachusetts Institute of Technology for her help with the manuscript. We acknowledge support to R.S. from Japan Science and Technology Agency and Japan Society for Promotion of Science (22680037, G2212), to R.D.K. from the US National Cancer Institute (R21CA140096), and to S.C. from the Ministry of Education, Science and Technology (2009-00631, 2012-0009565) and the Human Resources Development program (20124010203250).
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