Sorafenib treatment during partial hepatectomy reduces tumorgenesis in an inflammation-associated liver cancer model

Tamar Zahavi, Tali Lanton, Mali Salmon Divon, Asher Salmon, Tamar Peretz, Eithan Galun, Jonathan H. Axelrod, Amir Sonnenblick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The long-term prognosis after resection of hepatocellular carcinoma (HCC), which is one of the treatment options for early-stage HCC, remains unsatisfactory as a result of a high incidence of disease recurrence. Recent studies performed in murine models revealed a link between liver regeneration under chronic inflammation and hepatic tumorigenesis. Sorafenib is a potent drug for advanced HCC with multikinase inhibition activity. We propose that inhibition of signal transduction pathways which are activated during hepatectomy, using Sorafenib, will reduce accelerated tumorigenesis. To test this hypothesis, we studied the Mdr2-knockout (KO) mouse strain, a model of inflammation-associated cancer, which underwent partial hepatectomy (PHx) at three months of age, with or without Sorafenib. Here we show that Sorafenib treatment during PHx inhibited different signal transduction pathways at the multikinase levels, but did not result in increased morbidity or mortality. At the early stages after PHx, Sorafenib treatment had no effect on the course of proliferation, apoptosis and DNA repair in the regenerating liver, but resulted in decreased stellate cells activation and inflammatory response. Finally, we show that Sorafenib treatment during PHx at three months of age resulted in decreased fibrosis and tumor formation at 8.5 months. In conclusion our study indicates that short-term Sorafenib treatment during PHx is safe and effective in inhibiting inflammation-associated cancer, and is therefore a potential strategy for recurrence prevention in patients with early-stage HCC treated with PHx.

Original languageAmerican English
Pages (from-to)4860-4870
Number of pages11
JournalOncotarget
Volume7
Issue number4
DOIs
StatePublished - 2016
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by the Morasha program of the Israel Science foundation grant No. 1728/11 (A.S.), the Israel cancer association grant No. 2014-0001 (A.S.), the Deutsche Forschungsgemeinschaft (DFG) SFB841 project C3 (E.G.) and by the I-CORE ISF center of excellence (E.G.)''.

Keywords

  • Hepatectomy
  • Liver cancer
  • Mdr2 knockout
  • Sorafenib
  • Stellate cells

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