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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Preclinical Development

A Human Model of Epithelial to Mesenchymal Transition to Monitor Drug Efficacy in Hepatocellular Carcinoma Progression

Franziska van Zijl, Sabine Mall, Georg Machat, Christine Pirker, Robert Zeillinger, Andreas Weinhaeusel, Martin Bilban, Walter Berger and Wolfgang Mikulits
Franziska van Zijl
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Sabine Mall
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Georg Machat
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Christine Pirker
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Robert Zeillinger
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Andreas Weinhaeusel
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Martin Bilban
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Walter Berger
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Wolfgang Mikulits
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DOI: 10.1158/1535-7163.MCT-10-0917 Published May 2011
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Abstract

The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation. Therapeutic agents clinically used against HCC were examined for efficacy by determination of IC50 values. We show that liver cancer cell lines exhibited either an epithelial or mesenchymal phenotype of which the latter showed strong migratory and invasive abilities in vitro. The common cellular origin of both cell types indicated that mesenchymal HCC cells have been derived from epithelial hepatocytes through EMT in the HCC patient. Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells, which were slightly more resistant to cytostatic drugs. Most remarkably, combined treatment with doxorubicin and sorafenib caused increased susceptibility of both HCC cell types resulting in enhanced drug efficacy. Taken together, this EMT model of human HCC allows the identification of molecular mechanisms and the assessment of therapeutic drug efficacy during liver cancer progression in preclinical studies. Mol Cancer Ther; 10(5); 850–60. ©2011 AACR.

This article is featured in Highlights of This Issue, p. 709

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics (http://mct.aacrjournals.org/).

  • Received October 1, 2010.
  • Revision received February 8, 2011.
  • Accepted February 8, 2011.
  • ©2011 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 10 (5)
May 2011
Volume 10, Issue 5
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A Human Model of Epithelial to Mesenchymal Transition to Monitor Drug Efficacy in Hepatocellular Carcinoma Progression
Franziska van Zijl, Sabine Mall, Georg Machat, Christine Pirker, Robert Zeillinger, Andreas Weinhaeusel, Martin Bilban, Walter Berger and Wolfgang Mikulits
Mol Cancer Ther May 1 2011 (10) (5) 850-860; DOI: 10.1158/1535-7163.MCT-10-0917

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A Human Model of Epithelial to Mesenchymal Transition to Monitor Drug Efficacy in Hepatocellular Carcinoma Progression
Franziska van Zijl, Sabine Mall, Georg Machat, Christine Pirker, Robert Zeillinger, Andreas Weinhaeusel, Martin Bilban, Walter Berger and Wolfgang Mikulits
Mol Cancer Ther May 1 2011 (10) (5) 850-860; DOI: 10.1158/1535-7163.MCT-10-0917
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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