Brain tumour cells interconnect to a functional and resistant network

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytoma / metabolism
  • Astrocytoma / pathology*
  • Astrocytoma / radiotherapy
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / radiotherapy
  • Cell Communication / radiation effects
  • Cell Death / radiation effects
  • Cell Proliferation / radiation effects
  • Cell Surface Extensions / metabolism
  • Cell Surface Extensions / radiation effects
  • Cell Survival / radiation effects
  • Connexin 43 / metabolism
  • Disease Progression
  • GAP-43 Protein / metabolism
  • Gap Junctions / metabolism*
  • Gap Junctions / radiation effects
  • Glioma / metabolism
  • Glioma / pathology
  • Glioma / radiotherapy
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Radiation Tolerance / drug effects

Substances

  • Connexin 43
  • GAP-43 Protein