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Carcinogenesis Advance Access published online on August 4, 2005
Carcinogenesis, doi:10.1093/carcin/bgi202
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 22, 2005
Revised July 27, 2005
Accepted July 28, 2005

CARCINOGENESIS

Non-parenchymal liver cells support the growth advantage in the first stages of hepatocarcinogenesis

Claudia Drucker 1, Wolfram Parzefall 1, Olga Teufelhofer 1, Michael Grusch 1, Adolf Ellinger 2, Rolf Schulte-Hermann 1, and Bettina Grasl-Kraupp 1*

1 Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
2 Department for Anatomy and Cell Biology, Division: Cell Biology and Ultrastructural Research, Medical University of Vienna, Schwarzspanierstraße 13, A-1090 Vienna, Austria

* To whom correspondence should be addressed.
Bettina Grasl-Kraupp, E-mail: bettina.grasl-kraupp{at}meduniwien.ac.at


  Abstract

Hepatocellular carcinoma almost always arise in chronically inflamed livers. We developed a culture model to study the role of non-parenchymal cells (NPCs) for inflammation-driven hepatocarcinogenesis. Rats were treated with the carcinogen N-nitrosomorpholine, which induced initiated hepatocytes expressing the marker placental glutathione-S-transferase (GSTp). After 21 days two preparations of hepatocytes were made: (i) conventional ones (Hep-conv) containing NPCs and (ii) hepatocytes purified of NPCs (Hep-pur). Initiated GSTp-pos hepatocytes were present in both preparations and were cultured along with normal GSTp-neg ones.

Under any culture condition DNA synthesis was ~4-fold higher in GSTp-pos than in GSTp-neg hepatocytes demonstrating the inherent growth advantage of the first stages of hepatocarcinogenesis. Hepatocytes showed ~3-fold lower rates of DNA synthesis in Hep-pur than in Hep-conv, which was elevated above Hep-conv levels by addition of NPC or NPC-supernatant. Pretreatment of NPCs with pro-inflammatory lipopolysaccharide (LPS) further increased DNA-synthesis. Thus, NPCs release soluble growth stimulators. Next we investigated the effect of specific cytokines produced by NPCs. Tumor necrosis factor {alpha} and interleukin 6 barely altered DNA synthesis, while hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), and the heparin-binding epidermal growth factor-like growth factor (HB-EGF) were potent inducers of DNA replication in both, GSTp-neg and GSTp-pos cells.

In conclusion, DNA synthesis of hepatocytes is increased by factors released from NPCs, an effect augmented by LPS-stimulation. NPC-derived cytokines, such as KGF, HGF, and HB-EGF, stimulate DNA synthesis preferentially in initiated hepatocytes, presumably resulting in tumor promotion. Similar mechanisms may contribute to carcinogenesis in human inflammatory liver dieases.

Keywords: hepatocarcinogenesis; inflammation; microenvironment; growth factors.
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