Editors' ChoiceCancer

Neurons promote glioma growth

Sci. Signal.  19 May 2015:
Vol. 8, Issue 377, pp. ec128
DOI: 10.1126/scisignal.aac5827

Neuronal activity promotes proliferation of neuronal precursors and oligodendrocytes, which are cells that can give rise to deadly brain cancers called gliomas (see Lehrman and Stevens). Venkatesh et al. used optogenetics to enhance neuronal activity and found that increased neuronal activity promoted the proliferation of a patient-derived high grade glioma (HGG) xenografted into mouse brains. Compared with control mice with the xenografted HGG (exposed to the same handling and light), mice with both xenografted HGG and light-activated channel rhodopsin to stimulate neuronal activity had increased proliferating tumor cells in response to either a single or repetitive light stimulation. Conditioned medium from light-exposed slice preparations from the channel rhodopsin-expressing mice increased proliferation and the number of viable cells in cultures of HGGs isolated from various patients. Conditioned medium from slice preparations from wild-type control mice also stimulated proliferation and enhanced viability in a manner dependent on neuronal activity, but these slices requires a longer incubation to produce active conditioned medium, consistent with spontaneous activity producing the necessary factor(s). Biochemical analysis followed by mass spectrometric analysis identified 11 candidates for the activity-released mitogen with the extracellular domain of neuroligin-3 (Nlgn3) as the top candidate. Indeed, recombinant human NLGN3 added at the concentration present in the conditioned medium exhibited a mitogenic effect on HGG cells in culture, and addition of the Nlgn3-binding protein neurexin-1β to the conditioned medium reduced the mitogenic effect. Transcriptome analysis of HGG cells identified genes activated in response to either the MAPK (mitogen-activated protein kinase) pathway or PI3K-Akt-mTOR (phosphoinositide 3-kinase to the kinase Akt to the kinase complex containing mechanistic target of rapamycin) pathway, but Western blot analysis for active proteins in these pathways indicated that recombinant NLGN3 stimulated the PI3K-Akt-mTOR pathway. Furthermore, pharmacological inhibition or knockdown of components of this pathway blocked the mitogenic effect of NLGN3. NLGN3 was increased at both transcript and endogenous protein levels in HGG cells exposed to recombinant Flag-tagged NLGN3, suggesting a positive feedback loop. The abundance of NLGN3 transcript inversely correlated with patient survival. Because Nlgn3 is a transmembrane protein, the mechanism of its cleavage and release of the extracellular domain remains an open question. However, this study not only demonstrated that neuronal activity promotes glioma growth but also identified Nlgn3 as a cleaved mitogenic factor produced in response to spontaneous or evoked neuronal activity.

H. S. Venkatesh, T. B. Johung, V. Caretti, A. Noll, Y. Tang, S. Nagaraja, E. M. Gibson, C. W. Mount, J. Polepalli, S. S. Mitra, P. J. Woo, R. C. Malenka, H. Vogel, M. Bredel, P. Mallick, M. Monje, Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015). [PubMed]

E. K. Lehrman, B. Stevens, Shedding light on glioma growth. Cell 161, 704–706 (2015). [PubMed]