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A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow

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Abstract

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.

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Abbreviations

2D:

Two dimensional

HCC:

Hepatocellular carcinoma

ART:

Artemisinin

PDMS:

Poly-dimethylsiloxane

VEGF:

Vascular endothelial growth factor

bFGF:

Basic fibroblast growth factor

HUVEC:

Human umbilical vein endothelial cell

PBS:

Phosphate-buffered saline

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Acknowledgments

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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Authors and Affiliations

  1. School of Integrated Design Engineering, Keio University, Yokohama, Japan

    Johann Kalchman, Kazuo Tanishita & Ryo Sudo

  2. Department of System Design Engineering, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

    Shingo Fujioka, Kazuo Tanishita & Ryo Sudo

  3. Ecole Centrale de Lille, Villeneuve-d’Ascq, France

    Johann Kalchman

  4. School of Mechanical Engineering, Korea University, Seoul, Korea

    Seok Chung

  5. Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    Yamato Kikkawa

  6. Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

    Toshihiro Mitaka

  7. Departments of Mechanical Engineering and Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA

    Roger D. Kamm

Authors
  1. Johann Kalchman
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  2. Shingo Fujioka
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  3. Seok Chung
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  4. Yamato Kikkawa
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  5. Toshihiro Mitaka
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  6. Roger D. Kamm
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  7. Kazuo Tanishita
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  8. Ryo Sudo
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Corresponding author

Correspondence to Ryo Sudo.

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Kalchman, J., Fujioka, S., Chung, S. et al. A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow. Microfluid Nanofluid 14, 969–981 (2013). https://doi.org/10.1007/s10404-012-1104-6

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  • DOI: https://doi.org/10.1007/s10404-012-1104-6

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