Tumor Network in Brain Increases Treatment Resistance

Astrocytomas are special type of brain tumours that are difficult to treat, because they do not respond to standard forms of treatment. One reason for this resistance could be their ability to form a communication network. This was discovered by scientists taking part in an international study involving experts from the Comprehensive Cancer Center (CCC) of MedUni Vienna and Vienna General Hospital. The study has now been published in the renowned specialist journal “Nature” and is regarded as a milestone by the medical world.

Gliomas are tumours of the central nervous system (brain tumours) and are subdivided into astrocytomas and oligodendrogliomas. Whilst oligodendrogliomas are relatively rare, with only 40 new cases every year, and respond well to standard radiotherapy and chemotherapy treatments, astrocytomas are highly invasive and difficult to treat. For this reason they are also associated with a poor prognosis: sufferers usually only survive for a few years. In Austria around 400 people develop an astrocytoma every year.

Until now it has not been understood why astrocytomas respond so poorly to current treatments compared with other gliomas. In the present study, which was set up in collaboration with the University of Heidelberg, the study team successfully identified a starting point that opens up the possibility of treating astrocytomas more effectively in future. Matthias Preusser, specialist in brain tumours at the University Department of Internal Medicine I at MedUni Vienna and Vienna General Hospital, head of the CCC unit for tumours of the central nervous system (CCC-CNS) and co-author of the new study, in which the Clinical Institute for Neurology of MedUni Vienna and Vienna General Hospital also took part, says: “Astrocytomas form interconnecting communication networks. To do this, the tumour cells form long thin channels from their membranes, so-called tumour microtubules, that connect them to other tumour cells. They use these channels to exchange information and molecules in the form of electrical charges and calcium. This network favours the spread of tumour cells, cell division and makes astrocytomas more resistant to treatment.” Indeed, using this network, astrocytomas are able to initiate repair mechanisms and so eliminate any damage to individual tumour cells caused, for example, by radiotherapy treatment.

Outline of a head with the brain exposed in orange.
Until now it has not been understood why astrocytomas respond so poorly to current treatments compared with other gliomas. In the present study, which was set up in collaboration with the University of Heidelberg, the study team successfully identified a starting point that opens up the possibility of treating astrocytomas more effectively in future. Image is adapted from the MedUni Vienna press release.

New therapeutic approach: disrupting the network

One approach to achieving more therapeutic success in the future is to disrupt communication between the astrocytomas by blocking the channel system. Preusser: “It is conceivable that greater therapeutic success could be achieved by using drugs to disrupt the formation or function of the membrane channels.” The research team was able to show that the network interfaces are created by a certain molecule, connexin 43, that is able to form pores. On the other hand, the protein GAP 43 seems to play an important role in the formation of the microtubules. Preusser: “Potential treatment strategies could therefore be to chemically inhibit the tumour cell network using calcium blockers or substances that affect connexin 43 or GAP 43.”

About this brain cancer research

Source: MedUni Vienna
Image Source: The image is adapted from the MedUni Vienna press release
Original Research: Abstract for “Brain tumor cells interconnect to a functional and resistant network” by Matthias Osswald, Erik Jung, Felix Sahm, Gergely Solecki, Varun Venkataramani, Jonas Blaes, Sophie Weil, Heinz Horstmann, Benedikt Wiestler, Mustafa Syed, Lulu Huang, Miriam Ratliff, Kianush Karimian Jazi, Felix T. Kurz, Torsten Schmenger, Dieter Lemke, Miriam Gömmel, Martin Pauli, Yunxiang Liao, Peter Häring, Stefan Pusch, Verena Herl, Christian Steinhäuser, Damir Krunic, Mostafa Jarahian, Hrvoje Miletic, Anna S. Berghoff, Oliver Griesbeck, Georgios Kalamakis, Olga Garaschuk, Matthias Preusser, Samuel Weiss, Haikun Liu, Sabine Heiland, Michael Platten, Peter E. Huber, Thomas Kuner, Andreas von Deimling, Wolfgang Wick and Frank Winkler in Nature. Published online November 4 2015 doi:10.1038/nature16071


Abstract

Brain tumor cells interconnect to a functional and resistant network

Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.

“Brain tumor cells interconnect to a functional and resistant network” by Matthias Osswald, Erik Jung, Felix Sahm, Gergely Solecki, Varun Venkataramani, Jonas Blaes, Sophie Weil, Heinz Horstmann, Benedikt Wiestler, Mustafa Syed, Lulu Huang, Miriam Ratliff, Kianush Karimian Jazi, Felix T. Kurz, Torsten Schmenger, Dieter Lemke, Miriam Gömmel, Martin Pauli, Yunxiang Liao, Peter Häring, Stefan Pusch, Verena Herl, Christian Steinhäuser, Damir Krunic, Mostafa Jarahian, Hrvoje Miletic, Anna S. Berghoff, Oliver Griesbeck, Georgios Kalamakis, Olga Garaschuk, Matthias Preusser, Samuel Weiss, Haikun Liu, Sabine Heiland, Michael Platten, Peter E. Huber, Thomas Kuner, Andreas von Deimling, Wolfgang Wick and Frank Winkler in Nature. Published online November 4 2015 doi:10.1038/nature16071

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