The production of new neurons is rather rare for an adult, and is confined to two particular areas of the brain: the dentate gyrus in the hippocampus, and the sub-ventricular zone. However, the Arip-Avenir team from the Inserm, under Claire Magnon’s leadership, at the Cellular and Molecular Radiobiology Institute led by Paul-Henri Roméo (CEA, Fontenay-aux-Roses), just proved that this phenomenon also occurs outside the central nervous system, i.e. in tumors!

This researcher had already showed in 2013 that the infiltration of nerve fibers, stemmed from the axon extensions of preexisting neurons, in prostate tumors was associated with the occurrence and evolution of the cancer. Since then, other studies have allowed us to confirm this unexpected, but apparently significant, role of nerve fibers in the tumor microenvironment of numerous solid cancers.

Claire Magnon, eager to understand the origins of this tumor neural network, has had a surprising idea: what if the nervous system involved in tumor development came from new neurons born in situ? And if that were true, how could the tumoral neurogenesis be initiated? 

To test this hypothesis, Claire Magnon studied the tumors of 52 patients with prostate cancer. In those, she found cells expressing a protein called Doublecortin (DCX), which we know is expressed by neural progenitor cells during the embryonic development, and in the two zones of the brain where neurons renew themselves, for adults. Moreover, the number of DCX+ cells in the tumors studied is in perfect correlation with the severity of the caner. “This surprising discovery is the proof of the presence of DCX+ neural progenitors outside of the adult brain. Our research shows that they indeed do take part in the formation of new neurons in the tumors,” she explains.

Claire Magnon used transgenic mouse bearing tumors to determine the origins of those neural progenitors. She quantified the DCX+ cells in the two areas of the brain they usually reside in. She then observed that, when a new tumor appears, that number decreases in one of those two areas: the sub-ventricular zone. “There were two possible explanations: either the DCX+ cells died in that area for unknown reasons, or they were leaving said area, which could explain their appearance around the tumor”. Several experiments showed that the second hypothesis was the correct one, with the identification of DCX+ cells passing from the sub-ventricular zone of the brain to the blood flow, and of the extreme similarity between the central cells and those found around the tumor. “In practice, we found anomalies in the permeability of the blood-brain barrier around the sub-ventricular zone in cancerous mouse, which encouraged the passing of DCX+ cells in the blood. As of now, we do not know if this permeability issue precedes the appearance of the cancer because of unrelated factors, or if the cancer itself, through signals send by the forming tumor, induces it. At any rate, DCX+ cells migrate in the blood to the tumor, including in the metastatic nodules, where they settle in the microenvironment. There, they differentiate first in neuroblasts, then in adrenergic neurons that produce adrenalin. However, since adrenalin regulates the vascular system, it is probably this mechanism that encourages the tumor’s development. We have yet to confirm those hypotheses, though”.

In the meantime, this research offers us a new therapeutic approach. Indeed, clinical observation shows that patients with prostate cancer that use beta-blockers (to stop adrenergic receptors) to cardiovascular purposes have better survival rates. “It would be interesting to test those medications as cancer drugs” the researcher believes. Two clinical trials recently opened in the United States with this goal in mind. More generally speaking, “studying this nervous system in the tumor microenvironment could give us answers about why cancers resist certain treatments, and encourage the development of new medications” she concludes.