In aggressive glioblastoma, cancer cells plug into the brain’s neuronal network and receive impulses that appear to stimulate tumor growth. These impulses, which are transmitted via synaptic connections, may explain how brain tumors spread so quickly. They may also be subject to jamming—that is, to interference by drugs. If so, it may be possible to pull the plug on brain cancer.
The shocking discovery that cancer tissue, like brain tissue, may be electrically active was reported by scientists from Heidelberg University Hospital and the German Cancer Research Center. In a paper (“Glutamatergic synaptic input to glioma cells drives brain tumor progression”) that appeared in Nature, these scientists noted that previous research had already established that glioblastoma cells connect with one another rather like neurons. This finding has been extended in the new research, which argues that tumor cells not only interconnect like neurons, they also interconnect with neurons.
Even more intriguingly, the interconnections are active.
“We report a direct communication channel between neurons and glioma cells in different disease models and human tumors: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells,” the authors of the Nature article wrote. “These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumor microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype.”
In addition to studying cell cultures of tissue samples from patients, the researchers observed the growth of human glioblastomas that they had transferred to mice. To do so, obtained detailed three-dimensional images of the connections—only micrometers large—between neurons and tumor cells as well as showing their molecular structure and signals within the cells. Electrical recordings from tumor cells revealed electrical currents generating from the synaptic connections, which form the starting point for further processing of these signals in the tumor cells.
“We were able to show that signal transmission from neurons to tumor cells does, in fact, work like stimulating synapses between the neurons themselves,” noted Thomas Kuner, a corresponding author of the current study and director of the department of functional neuroanatomy at Heidelberg University’s Institute for Anatomy and Cell Biology.
The current study also explored the relationship between tumor-neuron signaling and tumor growth: “Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumor-microtube-positive tumor cells and glioma growth. Invasion and growth are also reduced by anesthesia and the AMPA receptor antagonist perampanel, respectively.”
Although it remains unclear how activation of the tumor cell leads to increased tumor growth, the current study indicates that the growth mechanism can be blocked in animals. Possible methods, as indicated above, include a significant reduction of brain activity (anesthesia) and pharmacological interventions that interrupt binding of the neurotransmitters on the AMPA receptor. Another possibility involves blocking the AMPA receptor using genetic engineering.
“This mechanism is, therefore, an extremely interesting approach for drug development and future drug treatments,” emphasized Frank Winkler, head of a neurooncology unit at the German Cancer Research Center, and another corresponding author. “Suitable substances have in fact already been approved that block the AMPA receptor and are used to treat other neurological diseases. These substances are promising candidates for clinical trials.”
The authors of the Nature paper concluded that their findings not only suggest how glioblastomas can be so aggressive, they also show how they might be stopped. Means of interfering with the newly discovered tumor activation mechanism could be explored in clinical trials.