Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Precisely Off The Mark: Possible Cause Discovered For Failure of Targeted Liver Cancer Therapies

24.11.2014

Targeted therapy against liver cancer: Cause of failure discovered

The failure of experimental liver cancer therapies directed specifically against the EGFR protein is presumably the result of insufficiently specific patient selection. This is the conclusion that can be drawn from data that were obtained within the framework of a project carried out by an Austrian Science Fund FWF doctoral programme, and that have now been published in NATURE Cell Biology.


Targeted therapies against liver cancer require a detailed picture of the liver. A FWF doctoral programme offers new insights.

© Nicole Amberg & Karin Komposch

The data prove that the tumour-promoting effect of EGFR originates, not directly from its expression in the tumour cells, but rather from its presence in the surrounding cells (macrophages) of the immune system. This predicts that experimental anti-EGFR therapeutic agents will prove effective only in patients who exhibit EGFR in the immune cells. This expanded understanding of the occurrence of EGFR in macrophages now offers, however, potential new approaches for the treatment of liver cancer.

Liver cancer is one of the most common malignant tumours. As treatment options are limited, the prognosis is very poor. Hopes were therefore high when, a few years ago, it was shown that a special protein – the epidermal growth factor receptor (EGFR) – accumulates in up to 70 percent of all liver tumours and promotes tumour development. It was believed that a target had been found for targeted therapies. However, the use of therapeutic agents to inhibit EGFR proved unsuccessful and the expected effect remained largely absent. Too little was known about the function of EGFR in liver cancer development. This is precisely what a research project at the Medical University of Vienna has now clarified.

SURPRISING FINDING

At the core of the work carried out at the Institute of Cancer Research were mouse models in which the presence of EGFR was suppressed in various different cell types of the liver. This made it possible to also grow liver tumours whose tumour cells were completely lacking EGFR. According to the previous knowledge, this would have been expected to result in decreased tumour growth. However, during the analysis a surprise emerged, as Prof. Maria Sibilia, coordinator of the FWF doctoral programme "Inflammation and Immunity", explains: "We found just the opposite – tumour growth increased. This was not the case for tumours in which EGFR was lacking only in the surrounding macrophages. There, tumour growth was considerably decreased." In fact, until now, it wasn't known that EGFR is even expressed in these immune cells. These liver macrophages, or Kupffer cells, become active particularly when inflammations and infections occur as a means to protect the body – the fact that EGFR has a tumour-promoting effect in these cells was not known.

To gain a better understanding of how the activity of EGFR on the Kupffer cells influences tumour growth, the team headed by Prof. Sibilia further analysed its functional mechanism. The group thereby succeeded in decoding a complex chain of cellular signalling pathways that actually leads to increased growth of liver cells. According to project team member Karin Komposch, "We were able to show that injuries to hepatocytes trigger the release of the messenger substance, interleukin-1beta. This, via diverse intermediate stages, causes EGFR in Kupffer cells to stimulate the production of interleukin-6 (IL-6), which causes liver cells to proliferate. In principle, the release of IL-6 should stimulate the proliferation of hepatocytes thus aiding in the repair of damaged tissue – but can also lead to uncontrolled hepatocyte proliferation, and thus to tumour formation."

TREATMENT & DIAGNOSIS

In the team's view, this fresh understanding now offers a new opportunity to use EGFR inhibitors in the treatment of liver cancer. These inhibitors would actually have to be used only in patients with EGFR expression in the Kupffer cells, and not in patients with EGFR expression exclusively in the tumour cells/hepatocytes. If these inhibitors were to act only in Kupffer cells, maximum reduction of tumour growth could be achieved. However, Ms. Komposch believes this work also offers another key finding for cancer diagnosis: "The presence of EGFR in the Kupffer cells could provide crucial information on the future course of tumour development, making it an important prognostic marker."

On the whole, the FWF doctoral programme findings thus provide both fundamental insight into complex cellular signalling pathways and concrete starting points for new developments in treatment and diagnosis.


Original publication: EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. H. Lanaya, A. Natarajan, K. Komposch, L. Li, N. Amberg, L. Chen, S. K.Wculek, M. Hammer, R. Zenz, M. Peck-Radosavljevic, W. Sieghart, M. Trauner, H. Wang und M. Sibilia. Nature Cell Biology 16, 972–981 (2014) doi:10.1038/ncb3031

Image and text available from Monday, 24 November 2014, from 10:00 a.m. CET, at:
http://www.fwf.ac.at/en/research-in-practice/project-presentations/2014/pv201411/


Scientific Contact:
Prof. Maria Sibilia
Medical University of Vienna
Institute of Cancer Research
Borschkegasse 8a
1090 Vienna, Austria
T +43 / 1 / 40160 - 57502
E sibilia-office@meduniwien.ac.at

Austrian Science Fund FWF:
Marc Seumenicht
Haus der Forschung
Sensengasse 1
1090 Vienna, Austria
T +43 / 1 / 505 67 40 - 8111
E marc.seumenicht@fwf.ac.at
W http://www.fwf.ac.at

Copy Editing & Distribution:
PR&D – Public Relations for Research & Education Mariannengasse 8
1090 Vienna, Austria
T +43 / 1 / 505 70 44
E contact@prd.at
W http://www.prd.at

Dr. Katharina Schnell | PR&D - Public Relations für Forschung & Bildung

Further reports about: EGFR Kupffer cells immune liver liver cancer macrophages tumour tumour cells tumour growth tumours

More articles from Health and Medicine:

nachricht Finnish research group discovers a new immune system regulator
23.02.2018 | University of Turku

nachricht Minimising risks of transplants
22.02.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>