Perspectives of cellular communication through tunneling nanotubes in cancer cells and the connection to radiation effects

Abstract

Direct cell-to-cell communication is crucial for the survival of cells in stressful situations such as during or after radiation exposure. This communication can lead to non-targeted effects, where non-treated or non-infected cells show effects induced by signal transduction from non-healthy cells or vice versa. In the last 15 years, tunneling nanotubes (TNTs) were identified as membrane connections between cells which facilitate the transfer of several cargoes and signals. TNTs were identified in various cell types and serve as promoter of treatment resistance e.g. in chemotherapy treatment of cancer. Here, we discuss our current understanding of how to differentiate tunneling nanotubes from other direct cellular connections and their role in the stress reaction of cellular networks. We also provide a perspective on how the capability of cells to form such networks is related to the ability to surpass stress and how this can be used to study radioresistance of cancer cells.

Keywords: Cancer; Cellular communication; Radioresistance; Tunneling nanotubes.

Fig. 1

Confocal microscopy image of membrane labelled (CellMask© Orange) U87 glioblastoma cells. TNTs are the fine straight structures which interconnect cells, clear TNTs are marked by yellow arrows. Other fine structures which do not have cell-to-cell contact are filopodia (blue arrows). Magenta arrows point to structures which are not distinguishable between not yet fused TNTs and filopodia. U87 glioblastoma cells have a high frequency of TNTs. Scale bar 50 μm

Fig. 2

3D rendering of membrane labelled (PKH26) U87 glioblastoma cells interconnected by a special shaped TNT which has kinks and its middle section lies on the substrate. Filopodia can be clearly distinguished as they have no connections

Fig. 3

Schematic representation of the two reported kinds of TNT connection to the cell body. On the left side a close-ended TNT is illustrated. Instead of membrane continuity there is a distinct junction between the connected cells recognizable. Such a junction is mostly found at one end of the nanotube as drawn here, but it has been also observed that these junctions can dynamically shift along the membrane tunnel. On the right side an open-ended nanotube is drawn, there the membrane of the tunnel has been fused with the plasma membrane of the connected cell and thus a membrane continuity was generated

Fig. 4

Illustrations of TNT formation models. On the left side, the formation of a nanotube by the actin-driven growth of membrane protrusions is shown. a) The protrusion from one cell elongates until it reaches the target cell, where physical contact will be established by adhesion followed by a membrane fusion of tunnel and target cell. An open-ended nanotube connection will be generated. b) It might also be possible that two different membrane protrusions meet each other and establish a connection by adhesion and fusion. c) On the right side, the second formation model is illustrated, the TNT formation by cell dislodgement. Here, the cells migrate apart from each other after physical contact and during their migration the nanotunnel will be pulled out of the cells. At the end of the migration, the cells are still connected via the generated TNT

Fig. 5

Mind map summarizing the complex interactions of TNTs related to radiotherapy