Neural Influences on Tumor Progression Within the Central Nervous System

Abstract

For decades, researchers have studied how brain tumors, the immune system, and drugs interact. With the advances in cancer neuroscience, which centers on defining and therapeutically targeting nervous system-cancer interactions, both within the local tumor microenvironment (TME) and on a systemic level, the subtle relationship between neurons and tumors in the central nervous system (CNS) has been deeply studied. Neurons, as the executors of brain functional activities, have been shown to significantly influence the emergence and development of brain tumors, including both primary and metastatic tumors. They engage with tumor cells via chemical or electrical synapses, directly regulating tumors or via intricate coupling networks, and also contribute to the TME through paracrine signaling, secreting proteins that exert regulatory effects. For instance, in a study involving a mouse model of glioblastoma, the authors observed a 42% increase in tumor volume when neuronal activity was stimulated, compared to controls (p < 0.01), indicating a direct correlation between neural activity and tumor growth. These thought-provoking results offer promising new strategies for brain tumor therapies, highlighting the potential of neuronal modulation to curb tumor progression. Future strategies may focus on developing drugs to inhibit or neutralize proteins and other bioactive substances secreted by neurons, break synaptic connections and interactions between infiltrating cells and tumor cells, as well as disrupt electrical coupling within glioma cell networks. By harnessing the insights gained from this research, we aspire to usher in a new era of brain tumor therapies that are both more potent and precise.

Keywords: central nervous system tumors; neuron; oligodendrocyte precursor cell; paracrine signal; synapse.

FIGURE 1

Synaptic connections between neurons and brain tumor cells and their implications in tumor progression. (A) The involvement of AMPA receptors in glioma biology is depicted. Neuronal activity initiates the opening of calcium‐permeable AMPA receptors, which are essential for mediating the electrophysiological functions of neurons. The activation of these receptors allows for the transmission of signals to synapses with glioma cells, leading to the depolarization of the glioma cell membranes. This depolarization is a critical event that promotes the proliferation of tumor cells. The diagram illustrates the process where the presynaptic neuron releases glutamate, which then binds to the AMPA receptors on the postsynaptic glioma cell, initiating a series of intracellular signaling events that result in tumor growth. (B) The formation of aberrant synaptic connections between neurons and breast cancer cells in the brain is shown. These “triple synapses” involve presynaptic neurons, postsynaptic tumor cells, and the release of neurotransmitters like glutamate. The interaction between glutamate and NMDA receptors on the cancer cells' membrane triggers a cascade of events that intensify the metastasis and proliferation of breast cancer cells within the brain. The diagram highlights the unique synaptic structure where the breast cancer cells release glutamate, which in turn activates NMDA receptors, fostering continuous synaptic transmission and contributing to tumor progression. (C) The role of gap junctions in the intercellular communication between glioma cells is detailed. Glioma cells establish extensive networks primarily through the formation of gap junctions, which are conduits for the exchange of signaling molecules, including calcium ions, between adjacent glioma cells. This exchange is instrumental in influencing the migration and proliferation of tumor cells, indicating the significance of gap junctions in the collective behavior of glioma cell populations. The diagram illustrates how these gap junctions extend into the surrounding tissues, enhancing the invasiveness and proliferation of brain tumors and facilitating the communication that drives tumor growth. These synaptic connections and networks represent potential therapeutic targets for disrupting the supportive role of neurons in brain tumor progression, offering new avenues for the development of treatments aimed at modulating these interactions to inhibit tumor growth and spread.

FIGURE 2

Paracrine signals from neurons in the occurrence and growth of brain tumors. (A) The role of the synaptic protein neuroligin‐3 (NLGN3) in the tumor microenvironment (TME) is illustrated. The secretory form of NLGN3, generated by the action of the protease ADAM10, is depicted as a key factor that stimulates the proliferation of glioma cells. This process underscores the contribution of synaptic proteins to the complex interactions within the TME that can promote glioma growth. The diagram shows how NLGN3, once cleaved and released, can bind to its receptors on glioma cells, initiating downstream signaling pathways that enhance cell survival and proliferation. (B) The BDNF/TrkB signaling pathway and its implications for synaptic plasticity and tumor malignancy are detailed. When dysregulated, this pathway can augment the complexity and strength of the tumor's synaptic network, thus fostering further tumor progression. The diagram illustrates the mechanism by which BDNF, secreted by neurons, interacts with the TrkB receptor on tumor cells, initiating a cascade of intracellular signaling events that can lead to increased tumor cell survival, growth, and potentially the formation of stronger synaptic connections with neurons. (C) The influence of olfactory neurons on the proliferation of oligodendrocyte precursor cells (OPCs) through the release of insulin‐like growth factor 1 (IGF1) is shown. Specifically, the mitral and tufted (M/T) cells in the olfactory bulb are highlighted as the primary source of IGF1, which can accelerate the proliferation of OPCs that have undergone pro‐oncogenic mutations. The diagram depicts the process where sensory input, such as the presence of certain gases, stimulates olfactory neurons, leading to the release of IGF1 and the subsequent promotion of gliomagenesis in the olfactory bulb. These paracrine signals represent critical mechanisms by which neurons can modulate the behavior of tumor cells in the brain. Understanding these pathways is essential for developing targeted therapies that may disrupt the supportive role of the neuronal environment in brain tumor growth and spread.

FIGURE 3

The role of neurons in the transformation of oligodendrocyte precursor cells (OPCs) into tumorigenic cells. The pivotal role of brain‐derived neurotrophic factor (BDNF) and insulin‐like growth factor 1 (IGF‐1) in the transformation of OPCs into glioma cells is highlighted. These factors exert their influence through paracrine signaling pathways, which allow for the modulation of neighboring cells, including OPCs, in a manner that promotes their differentiation into tumorigenic cells. The diagram illustrates how BDNF and IGF‐1, secreted by neurons, bind to their respective receptors on OPCs, triggering intracellular signaling cascades that enhance the survival, proliferation, and potentially the malignant transformation of these cells. The direct synaptic communication between glutamatergic and GABAergic neurons and OPCs is detailed as a crucial aspect of this process. These synaptic interactions facilitate the transmission of electrical and chemical signals that promote the differentiation of OPCs into glioma cells, thereby contributing to the complex interplay between the nervous system and the development of brain tumors. The diagram shows the synaptic connections between neurons and OPCs, indicating the flow of signals that can drive the transformation of OPCs. The potential dysregulation of myelin plasticity that may promote the proliferation of malignant cells within the primary brain cancer group is suggested as an area of future investigation. The diagram represents the hypothesis that the mechanisms involved in myelin development and plasticity could be exploited by malignant counterparts of activity‐responsive neural precursor cells to foster growth. This figure emphasizes the multifaceted communication between neurons and OPCs and how these interactions can lead to the initiation and progression of brain tumors. Understanding these neuronal influences on OPCs is essential for uncovering new therapeutic targets and developing strategies to prevent or treat gliomagenesis.