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

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)-beta provided by stromal cells. TGF-beta 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 p19(ARF) MFBs or in vivo-activated MFBs derived from physiologically inflamed livers of Mdr2/p19(ARF) 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 beta-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-beta or PDGF signaling. These data suggest that the TGF-beta/PDGF axis is crucial during hepatic tumor-stroma crosstalk, regulating both tumor growth and cancer progression.

journal_name

Oncogene

journal_title

Oncogene

authors

van Zijl F,Mair M,Csiszar A,Schneller D,Zulehner G,Huber H,Eferl R,Beug H,Dolznig H,Mikulits W

doi

10.1038/onc.2009.253

subject

Has Abstract

pub_date

2009-11-12 00:00:00

pages

4022-33

issue

45

eissn

0950-9232

issn

1476-5594

pii

onc2009253

journal_volume

28

pub_type

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