The human protein EGFR controls cell growth. It has mutated in case of many cancer cells or exists in excessive numbers. For this reason it serves as a point of attack for target-oriented therapies. A study group at the Comprehensive Cancer Centre of Medical University of Vienna and AKH Vienna under the guidance of Maria Sibilia from the Institute for Cancer Research has now discovered that the risk of this protein does not -- as previously assumed -- depend on its presence within the tumor cell, but rather from its activity in the cells adjacent to the tumor. EGFR can play a major role in stimulating the tumor in the macrophages (immune cells) of the liver during the formation of the dangerous liver carcinoma.
The EGF Receptor (Epidermal Growth Factor Receptor, EGFR) is a protein which, as a transmembrane receptor, controls a multitude of vital processes in the cell. In human beings, the EGF Receptor is present in many cells types and plays an important role in many types of cancer. It is present in various kinds of tumors in excessive amounts and/or in mutated form, which causes the tumor cells to grow and multiply. For this reason the EGFR serves as a point of attack in many treatment strategies. In the process, its function is inhibited with the objective of slowing down the growth of the tumor cell.
The liver cell carcinoma (hepatocellular carcinoma, short HCC) is one of the most frequent malignant tumors worldwide. Approximately six percent of all cancers in men and about three percent in women are liver cell carcinomas. It is the second most frequent cause of death associated with cancer. Risk factors for HCC include liver diseases through Hepatitis B and C infections as well as alcohol abuse or the classic "fatty liver."
Up to now, the tumor-promoting role of EGFR has only been linked with its expression directly in the tumor cells. However, the study group of Maria Sibilia, Manager of the Institute for Cancer Research at the Medical University of Vienna and Deputy Manager of the Comprehensive Cancer Centre, in cooperation with the research groups of Michael Trauner and Markus Peck-Radosavljevic at the clinical division for gastroenterology and hepatology (Manager: Michael Trauner) as well as the Eastern Hepatobiliary Surgery Institute/Hospital in Shanghai discovered that EGFR plays a more decisive role in the macrophages of the liver (these are important cells of the immune system which are called Kupffer cells in the liver) with respect to the growth of the liver cell carcinoma than previously assumed.
"In this study we were able to prove that the inhibition of EGFR has a tumor inhibiting effect on the macrophages and not its inhibition on the tumor cell itself," explains Maria Sibilia. However, if the EGFR conversely exists on these macrophages in an excessive number, it can promote the growth of the tumor. Its existence on the macrophages reduces the chance of survival for HCC patients.
This could explain why EGFR inhibitors utilised for cancer treatment and aiming directly for the tumor cells have achieved clinically disappointing results in the fight against the liver cell carcinoma in the past. For the first time, this study proves the tumor-promoting mechanism for EGFR in non-tumor cells, which could lead to more effective and precise treatment strategies with macrophages as a point of approach in the future.
- Hanane Lanaya, Anuradha Natarajan, Karin Komposch, Liang Li, Nicole Amberg, Lei Chen, Stefanie K. Wculek, Martina Hammer, Rainer Zenz, Markus Peck-Radosavljevic, Wolfgang Sieghart, Michael Trauner, Hongyang Wang, Maria Sibilia. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nature Cell Biology, 2014; DOI: 10.1038/ncb3031
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