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Nature. 2015 Dec 3;528(7580):93-8. doi: 10.1038/nature16071. Epub 2015 Nov 4.

Brain tumour cells interconnect to a functional and resistant network.

Author information

1
Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
2
Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
3
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224, 69120 Heidelberg, Germany.
4
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), INF 224, 69120 Heidelberg, Germany.
5
Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, INF 307, 69120 Heidelberg, Germany.
6
Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar der Technischen Universität München, 81675 Munich, Germany.
7
Neurosurgery Clinic, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
8
Department of Neuroradiology, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
9
Department of Neurophysiology, Institute of Physiology, University of Würzburg, 97070 Würzburg, Germany.
10
Department of Medical Physics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
11
Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
12
Light Microscopy Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
13
Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
14
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
15
Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria.
16
Tools For Bio-Imaging, Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany.
17
Institute of Physiology II, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany.
18
Department of Medicine I, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria.
19
Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
20
Department of Cell Biology and Anatomy, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4Z6, Canada.
21
Clark Smith Brain Tumor Research Centre, Southern Alberta Cancer Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
22
Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany.
23
Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
24
CCU Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany.
25
Department of Radiation Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Abstract

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.

PMID:
26536111
DOI:
10.1038/nature16071
[Indexed for MEDLINE]

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