Researchers show that brain cancer proliferation is stimulated by nerve activity in the cortex.


Deadly brain tumours called high-grade gliomas grow with the help of nerve activity in the cerebral cortex, according to a new study by researchers at the Stanford University School of Medicine.  The current study, conducted in mice with an aggressive human brain cancer implanted in their brains, is the first to demonstrate stimulation of tumour growth by brain activity. The opensource study is published in the journal Cell.

It is rare for an organ’s primary function to drive the growth of tumours within it, state the team, adding that they don’t think about bile production promoting liver cancer growth, or breathing promoting the growth of lung cancer.  However, the team state that they have shown that brain function is driving these brain cancers.

The team explain that high-grade gliomas are the leading cause of brain-tumour death in children and adults with survival rates scarcely improving in the last 30 years.  Clinically, the team liken fighting high-grade gliomas to fighting a forest fire and state that the new findings indicate that this metaphorical forest fire has been difficult to extinguish because there is something akin to gasoline seeping up from the soil.

The tumours studied fell into the broad category of high-grade gliomas.  The following type of gliomas were studied in the current study, diffuse intrinsic pontine glioma, which strikes school-aged children; pediatric cortical glioblastoma, which affects primarily teens and young adults; anaplastic oligodendroglioma, which affects young adults; and glioblastoma multiforme, which affects older adults. Although these tumours originate in different regions of the brain, all of them originate near or can spread to the cerebral cortex explain the team, which is the brain’s highly folded outer layer that helps humans perceive the world, form conscious thoughts and use language.

The current study identified a specific protein, called neuroligin-3, which is largely responsible for the increase in tumour growth associated with neuronal activity in the cerebral cortex. The results showed that neuroligin-3 had similar effects across the different types of high-grade gliomas, in spite of the fact that the four cancers have different molecular and genetic characteristics.  To see a microenvironmental factor that affects all of these very distinct classes of high-grade gliomas was a big surprise, state the team.

The identity of the factor was also unexpected. The team explain that in healthy tissue, neuroligin-3 helps to direct the formation and activity of synapses, playing an important role in the brain’s ability to remodel itself. The new study showed that a secreted form of neuroligin-3 promotes tumour growth.  This group of tumours hijacks a basic mechanism of neuroplasticity.

To conduct the current study the team employed optogenetics, a Stanford-developed technique that uses genetic manipulation to insert light-sensitive proteins into specific neurons, allowing the neurons to be activated with the flip of a light switch. Into the cerebral cortex of mice with these light-sensitive proteins, the team implanted cancer cells from a human pediatric cortical glioblastoma. After the tumours became established, neurons near the tumours were activated with light. The team then compared tumour growth between these mice and a control group with implanted tumours but without the nerve activation. Increased tumour proliferation and growth in the mice that received neurostimulation via optogenetics were the first indications that neuronal activity fed the brain tumours.

The team performed follow-up experiments on slices of mouse brain to identify secreted factors that made the tumour cells proliferate. They then conducted biochemical analyses to identify neuroligin-3, confirm that the protein could stimulate tumour growth in cultured samples of several kinds of human high-grade gliomas and study which signals the protein uses within glioma cells to promote their growth.

In addition, the researchers also examined neuroligin-3 data from The Cancer Genome Atlas, a large public database of human cancer genetics. More activity of the neuroligin-3 gene in high-grade gliomas was linked to shorter survival among patients with these tumours.

The team state that the current study’s findings may open doors to new high-grade glioma treatments. Although, in theory, the results indicate that sedating patients to reduce neural activity could reduce brain tumour growth, this is unlikely to be accepted as an ethical or practical cancer therapy.

A better approach, surmise the team, would be to develop drugs that specifically block the tumour-stimulating activities of neuroligin-3, such as a drug that stops the protein from being secreted into the area around the cancer cells.

Source:  Stanford Medicine

Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.  Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.   Monje et al 2015.

Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth. Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion. Monje et al 2015.

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  • Pingback: Researchers Show That Brain Cancer Proliferation Is Stimulated By Nerve Activity in the Cortex | Little Fighters Cancer Trust

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