(Vienna, 20th November 2014) One of the most aggressive and common forms of liver cancer is hepatocellular carcinoma. A team of researchers from the Institute of Cancer Research at the MedUni Vienna has now identified the crucial key factor involved in the development and progression of this malignant type of tumour: the AXL receptor supports cancer-promoting processes and slows down cancer-inhibiting factors. This finding could make a targeted therapeutic approach possible in future.
In the Western world, metabolic diseases and infections with hepatitis C are the most common causes of hepatocellular carcinoma (HCC). The team led by Wolfgang Mikulits, Head of the Tumour Progression and Metastasis Research Group at the MedUni Vienna's Institute of Cancer Research (ICR) and member of the Comprehensive Cancer Center (CCC) Vienna, investigated the role of the AXL receptor tyrosine kinase in the context of liver cancer as part of a study. Says Mikulits: "Until now, the function of AXL had been barely investigated at all, which is astonishing since this receptor is shown to have been activated in more than 50 per cent of all HCC patients."
AXL changes signalling pathways
The researchers were able to demonstrate that the expression (presence) and activation of AXL lead to a diversion of signalling pathways, enabling the migration and metastasis of liver cancer cells. As a result, AXL, after binding a 14-3-3 adapter protein, is able to influence the extremely important transforming growth factor (TGF) beta signalling pathway in such a way that it only causes the invasion and metastasis of HCC cells. In contrast to this, AXL inhibits the anti-oncogenic function of TGF-beta. AXL is therefore the crucial key factor in the aggressive development of hepatocellular carcinoma. The analyses of patient samples confirm the experimental data, according to which the high expression of AXL and the activation of TGF-beta is related to a greatly reduced life expectancy for HCC patients.
New therapeutic approach
The discovery that this central switching centre for tumour development promotes it instead of inhibiting it opens up new possibilities for the effective treatment of HCC. By using a highly specific AXL inhibitor, the progression of the cancer could be prevented in a large number of patients. At the University Department of Internal Medicine I at the MedUni Vienna and the Vienna General Hospital, Director Christoph Zielinski has set the course for the first clinical testing phase on HCC patients.
This study, which was financed by the Austrian Science Fund (FWF) and which has recently been published in the international and highly-respected journal "Hepatology", was set up through cooperation between the working group led by Wolfgang Mikulits and Wolfgang Sieghart and Markus Peck-Radosavljevic (both from the University Department of Internal Medicine III, Clinical Department of Gastroenterology and Hepatology).
“Signaling of Axl via 14-3-3zeta activates autocrine transforming growth factor-β signaling in hepatocellular carcinoma”. Patrick Reichl, Mirko Dengler, Franziska van Zijl, Heidemarie Huber, Gerhard Führlinger, Christian Reichel, Wolfgang Sieghart, Markus Peck-Radosavljevic, Markus Grubinger and Wolfgang Mikulits. Hepatology. 2014 Sep 24. doi: 10.1002/hep.27492. [Epub ahead of print]