Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge.
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.
van Zijl
F
F
Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, A-1090 Vienna, Austria.
Mair
M
M
Csiszar
A
A
Schneller
D
D
Zulehner
G
G
Huber
H
H
Eferl
R
R
Beug
H
H
Dolznig
H
H
Mikulits
W
W
D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta