Neurons as stromal drivers of nervous system cancer formation and progression

Abstract

Similar to their pivotal roles in nervous system development, neurons have emerged as critical regulators of cancer initiation, maintenance, and progression. Focusing on nervous system tumors, we describe the normal relationships between neurons and other cell types relevant to normal nerve function, and discuss how disruptions of these interactions promote tumor evolution, focusing on electrical (gap junctions) and chemical (synaptic) coupling, as well as the establishment of new paracrine relationships. We also review how neuron-tumor communication contributes to some of the complications of cancer, including neuropathy, chemobrain, seizures, and pain. Finally, we consider the implications of cancer neuroscience in establishing risk for tumor penetrance and in the design of future anti-tumoral treatments.

Keywords: T cells; brain tumors; glioma; microglia; nerves; neuronal activity; neurotransmitter; synapse.

Figure 1.. Neurons interact with numerous cell types during nervous system development and maintenance.

Neurons in the central nervous system interact with microglia through chemokine attraction (chemoattraction) to enable synaptic pruning and induce neuroplasticity, but can also communicate with T cells in the meningeal spaces to modify neuronal function and behavior. In addition, neurons form cooperative relationships with astroglial cells (neurotransmitters), neural progenitors (gap junctions), and oligodendrocyte precursors (OPCs, direct synapses, neurotransmitters) to regulate neuroglial function, neurogenesis, and adaptive myelination. Similar interactions also occur in the peripheral nervous system between immune system cells, Schwann cells, and neurons.

Figure 2.. Neurons interact with tumor cells through the elaboration of paracrine factors.

Neurons can increase tumor cell growth through activity-regulated cleavage (ADAM10-mediated) of membrane-bound Nlgn3 (m-Nlgn3) to generate a bioavailable soluble Nlgn3 molecule (s-Nlgn3) that increases tumor cell growth. Neurons can also control tumor cell growth either directly through secretion of other mitogens that bind mitogen receptors on tumor cells, or indirectly through immune cells (T cells and microglia) via the elaboration of paracrine factors (midkine, Mdk; Ccl4; Ccl5).

Figure 3.. Neurons directly and indirectly interact with tumor cells.

Neurons can form bona fide synapses or respond to local neurotransmitters to regulate tumor cell growth, which can be propagated between adjacent tumor cells through tumor microtubes, thus creating interconnected electrically coupled syncytia. Aberrant expression of ion channels on cancer cells can additionally modulate tumor expansion, and neurons can also directly synapse onto tumor microtubes.

Figure 4.. Tumors interact with non-neoplastic cells in the tumor microenvironment to influence their local milieu and create neuronal dysfunction.

Gliomas are functionally coupled with neurons in the brain to impair normal brain function, induce seizures, or cause pain. Additionally, nervous system tumors secrete paracrine factors that modify the tumor microenvironment to increase tumor growth or promote resistance to anti-neoplastic therapies, but also interrupt the normal relationships between glial cells and neurons relative to chemotherapy-related cognitive impairment (CRCI) and neuronal injury.

Figure 5.. Integrated hallmarks of cancer.

Modification of the hallmarks of cancer, now incorporating the relationships between cell (neuron and tumor cell) excitability and other properties, such as genetic mutation, cell invasion, cell metabolism, immune properties, mitogenic signaling, and cell death/senescence, as relevant to brain tumor (glioma) pathobiology.

Figure 6.. Risk factors operate at the level of the neuron to modulate cancer risk.

Operating at the transcriptional or epigenetic level, genetic mutations and genomic background can alter neuronal excitability in numerous ways, including ion channel and neurotransmitter receptor function, the formation of neuron-tumor synapses, and the elaboration of paracrine factors that act either directly on the cancer cells or indirectly through non-neoplastic cells in the tumor microenvironment. Environmental factors, nervous system injury, systemic diseases, and perinatal exposures (infection) can additionally operate to disrupt interactions between neurons and cancer cells, such that the combination of these factors establish a ground state of neuronal excitability that makes cancer development more or less likely to occur.