Neural Signaling in Cancer

Abstract

Nervous system activity regulates development, homeostasis, and plasticity of the brain as well as other organs in the body. These mechanisms are subverted in cancer to propel malignant growth. In turn, cancers modulate neural structure and function to augment growth-promoting neural signaling in the tumor microenvironment. Approaching cancer biology from a neuroscience perspective will elucidate new therapeutic strategies for presently lethal forms of cancer. In this review, we highlight the neural signaling mechanisms recapitulated in primary brain tumors, brain metastases, and solid tumors throughout the body that regulate cancer progression.

Keywords: brain metastases; cancer neuroscience; glioma; neurotrophins; solid tumors; synaptic signaling.

Figure 1

Neural signaling in gliomas. Neuronal activity results in paracrine and synaptic signaling to glioma cells. Activity-regulated shedding of neuroligin-3 (NLGN3, orange) from synapses in the tumor microenvironment results in NLGN3 binding to an as-of-yet unknown binding partner (dark purple) on glioma cells, which stimulates oncogenic signaling pathways, including focal adhesion kinase (FAK) and downstream SRC, RAS, and PI3K-mTOR pathways. This results in cell proliferation and leads to expression of NLGN3 and other synaptic genes in the glioma cell. NLGN3 promotes synaptogenesis and is also shed from the glioma cell surface by the sheddase ADAM10 (scissors). AMPA receptor (AMPAR, magenta)-mediated electrochemical synapses form between neurons and glioma cells. AMPAR-mediated depolarization in glioma cells drives tumor growth through voltage-sensitive mechanisms. Neuronal activity-regulated BDNF (yellow triangles) signaling to the BDNF receptor TrkB (blue) on glioma cells, with consequent stimulation of the MAPK/ERK pathway, is an additional paracrine factor promoting glioma proliferation. Glutamate is shown as red circles. Figure adapted from image created with BioRender.com.

Figure 2

Examples of nervous system–cancer crosstalk in the brain and body. (a) Neurons (blue) form AMPA receptor (AMPAR, magenta)-dependent glutamatergic synapses with glioma cells ( green), and glioma cells are coupled to each other through connexin-43-mediated gap junctions (dark purple) and tumor microtube networks. (b) Glioma cells secrete synaptogenic factors and glutamate, which causes neuronal hyperexcitability, resulting in a feed-forward malignant loop driving paracrine and synaptic neuron-glioma interactions. (c) Breast cancer cells (yellow) metastatic to brain express NMDA receptors (NMDARs, red) and integrate perisynaptically in pseudotripartite synapses to exploit synaptic glutamatergic (red circles) transmission between neurons. Currently unknown NMDA-mediated signaling mechanisms drive breast cancer metastasis growth in the brain. (d) Many solid organ tumors (pink) of the body secrete neurotrophins, such as nerve growth factor (NGF), to increase peripheral nerve (magenta) branching into the tumor microenvironment, while nerve-derived neurotransmitter signaling regulates tumor growth. Figure adapted from image created with BioRender.com.