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 Monitoring the heart's mitochondria to predict cardiac arrest?
21.09.2017 | Boston Children's Hospital

nachricht Highly precise wiring in the Cerebral Cortex
21.09.2017 | Max-Planck-Institut für Hirnforschung

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: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Comet or asteroid? Hubble discovers that a unique object is a binary

21.09.2017 | Physics and Astronomy

Cnidarians remotely control bacteria

21.09.2017 | Life Sciences

Monitoring the heart's mitochondria to predict cardiac arrest?

21.09.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>