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Hepatic tumor–stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge

Oncogene volume 28, pages 4022–4033 (2009)Cite this article

Abstract

The tumor–stroma crosstalk is a dynamic process fundamental in tumor development. In hepatocellular carcinoma (HCC), the progression of malignant hepatocytes frequently depends on transforming growth factor (TGF)-β provided by stromal cells. TGF-β induces an epithelial to mesenchymal transition (EMT) of oncogenic Ras-transformed hepatocytes and an upregulation of platelet-derived growth factor (PDGF) signaling. To analyse the influence of the hepatic tumor–stroma crosstalk onto tumor growth and progression, we co-injected malignant hepatocytes and myofibroblasts (MFBs). For this, we either used in vitro-activated p19ARF MFBs or in vivo-activated MFBs derived from physiologically inflamed livers of Mdr2/p19ARF double-null mice. We show that co-transplantation of MFBs with Ras-transformed hepatocytes strongly enhances tumor growth. Genetic interference with the PDGF signaling decreases tumor cell growth and maintains plasma membrane-located E-cadherin and β-catenin at the tumor–host border, indicating a blockade of hepatocellular EMT. We further generated a collagen gel-based three dimensional HCC model in vitro to monitor the MFB-induced invasion of micro-organoid HCC spheroids. This invasion was diminished after inhibition of TGF-β or PDGF signaling. These data suggest that the TGF-β/PDGF axis is crucial during hepatic tumor–stroma crosstalk, regulating both tumor growth and cancer progression.

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Acknowledgements

Mdr2 null mice were kindly provided by Dr Ilan Stein. We thank Dr Takako Sasaki for the fibulin-2 antibody. This work was supported by the Austrian Science Fund, FWF, grant numbers P19598-B13 (to WM) and SFB F28 (to RE, HB and WM), the ‘Hochschuljubiläumsstiftung der Stadt Wien’ (to WM), the Herzfelder Family Foundation (to WM), and the European Union, FP7 Health Research, project number HEALTH-F4-2008-202047 (to WM).

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Authors and Affiliations

  1. Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

    F van Zijl, D Schneller, G Zulehner, H Huber & W Mikulits

  2. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    M Mair & R Eferl

  3. Research Institute of Molecular Pathology, Vienna, Austria

    A Csiszar & H Beug

  4. Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria

    H Dolznig

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  1. F van Zijl
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  2. M Mair
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  6. H Huber
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Correspondence to W Mikulits.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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van Zijl, F., Mair, M., Csiszar, A. et al. Hepatic tumor–stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene 28, 4022–4033 (2009). https://doi.org/10.1038/onc.2009.253

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