Neurons occur even within the tumor microenvironment - and contribute to the development of cancer. These nerve cells originate from progenitors deriving from the brain and transported via the bloodstream. An astonishing discovery that opens up a whole new field of research relating to both the role of the nervous system in cancer development and the interactions between the vascular-, immune- and nervous systems in tumorigenesis.
The production of new neurons is a rather rare event in adults and is limited to two specific brain regions: the dentate gyrus in the hippocampus and the sub-ventricular zone. But an Inserm Atip-Avenir team led by Claire Magnon* at the Institute of Cellular and Molecular Radiobiology directed by Paul-Henri Roméo (French Alternative Energies and Atomic Energy Commission (CEA), Fontenay-aux-Roses), has recently shown that this phenomenon also occurs outside of the central nervous system: in tumors!
In her 2013 research involving prostate tumors, Magnon had already revealed that the infiltration by nerve fibers - derived from the prolongations of the axons of existing neurons - was linked to the onset and progression of this form of cancer. Since then, other studies have confirmed the unexpected, but seemingly important, role of nerve fibers in the microenvironment of many solid tumors.
Keen to understand the origin of the neuronal network in tumors, Magnon had a surprising idea: what if the nervous network involved in tumor development came from new neurons forming in situ? And if so, how could this tumor neurogenesis be initiated?
Neural stem cells in tumors
To test this hypothesis, Magnon studied the tumors of 52 prostate cancer patients. There she discovered cells that express a protein called doublecortin (DCX), known for being expressed by the neural progenitor cells, during embryonic development and in adults in the two brain regions where neurons are renewed. Furthermore, in the tumors studied, the quantity of DCX+ cells correlates perfectly with the severity of the cancer. "This astonishing discovery confirms the presence of DCX+ neuronal progenitors outside the brain in adults. And our research shows that they indeed contribute to the formation of new neurons in tumors," she clarifies.
Migration from brain to tumor
To determine the origin of these neuronal progenitors, Magnon used transgenic mice - carriers of tumors. She quantified the DCX+ cells present in the two brain regions in which they usually reside and observed, during the establishment of a tumor, decreased levels in one of them: the subventricular zone. "There were two possible explanations: either the DCX+ cells die in this region - of unknown cause, or they leave this region - which could explain their appearance at tumor level." Various experiments confirmed the second hypothesis with the demonstrated passage of the DCX+ cells from the sub-ventricular zone of the brain into the bloodstream and the extreme similarity of the central cells and those found in the tumor. "In practice, we observe abnormalities in the permeability of the sub-ventricular zone blood-brain barrier in cancerous mice, promoting the passage of DCX+ cells into the blood. It is not possible right now to know whether this permeability issue precedes the onset of cancer under the influence of other factors, or whether it is caused by the cancer itself, via signals sent out by the tumor in formation. Regardless of the cause, the DCX+ cells migrate into the blood to the tumor, including the metastatic nodules, where they integrate the microenvironment. There they differentiate into neuroblasts, followed by adrenaline-producing adrenergic neurons. However, adrenaline regulates the vascular system, and it is probably this mechanism that in turn favors tumor development. But these hypotheses remain to be verified".
A therapeutic avenue
In the meantime, this research paves the way for a new therapeutic avenue. In fact, clinical findings show that patients with prostate cancer who use beta blockers (that block the adrenergic receptors) for cardiovascular purposes, present better survival rates. "It would be pertinent to test these drugs as a cancer treatment," considers the researcher. Two clinical trials along these lines commenced recently in the USA**. More generally, "the study of this nervous network in the tumor microenvironment could provide responses as to why there is resistance to some treatments and promote the development of new drugs," she concludes.
* Cancer and Microenvironment Laboratory, Atip-Avenir team, JRU967 Inserm/IBFJ-iRCM-CEA/Université Paris 11/Université Paris Diderot, Fontenay-aux-Roses
** Beta Adrenergic Receptor Blockade as a Novel Therapy for Patients With Adenocarcinoma of the Prostate and Propranolol Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery