Hijacking of the nervous system in cancer: mechanism and therapeutic targets

Abstract

The activity of neurons in the vicinity of tumors is linked to a spectrum of cellular mechanisms, including the facilitation of tumor cell proliferation, synapse formation, angiogenesis, and macrophage polarization. This review consolidates the current understanding of neuro-oncological regulation, underscoring the nuanced interplay between neurological and oncological processes (termed as Cancer-Neuroscience). First, we elucidated how the nervous system accelerates tumor growth, metastasis, and the tumor microenvironment both directly and indirectly through the action of signaling molecules. Importantly, neural activity is also implicated in modulating the efficacy of therapeutic interventions, including immunotherapy. On the contrary, the nervous system potentially has a suppressive effect on tumorigenesis, further underscoring a dual-edged role of neurons in cancer progression. Consequently, targeting specific signaling molecules within neuro-oncological regulatory pathways could potentially suppress tumor development. Future research is poised to explore the intricate mechanisms governing neuro-tumor interactions more deeply, while concurrently refining treatment strategies for tumors by targeting the crosstalk between cancer and neurons.

Keywords: Cancer; Nervous system; Neurotransmitters; Neurotrophic factors; Therapeutic implications; Tumor microenvironment.

Fig. 1

Specific aspects of neuro-oncology regulation: A Neural activity regulates the differentiation direction of neural stem cells and promotes the proliferation of cancer cells by non-synaptically secreting neurotransmitters such as glutamate. B Neural activity can facilitate the metastasis of cancer cells. Breast cancer cells that have metastasized to the brain can replace astrocytes and surround normal nerve synapses, receive glutamate released from the presynaptic membrane, and activate the NMDAR signaling to promote the growth of tumors at the metastatic sites. C Interaction between nerves and tumors: Tumor cells can secrete signals such as BDNF and NGF to promote nerve growth into the microenvironment. Meanwhile, nerves can secrete neurotransmitters to promote tumor growth. D Anti-tumor effect of nerves: Nerves can inhibit tumors by reducing tumor growth and neovascularization. E Immunological remodeling of the tumor microenvironment by nerves: Nerves can regulate the differentiation of macrophages into the M2 type and have a pro-inflammatory effect. It increases the exhaustion of CD8 + T cells and creates an immunosuppressive microenvironment. F Nerves promote angiogenesis in the tumor microenvironment. Catecholamine stimulation can regulate vascular endothelial growth factor (VEGF) gene expression through β-adrenergic receptors. Original figure created with BioRender.com

Fig. 2

Innervation in gliomas promotes tumor growth. Neurons secrete brain-derived neurotrophic factor (BDNF), which binds to TrKB receptor and promotes the transfer of AMPA receptor in tumor cytoplasm to cell membrane. The amplitude of glutamate-induced current increased, and the larger depolarization amplitude promoted the proliferation of glioma cells. Neuroligin −3 (NLGN3) secreted in an activity-dependent manner activates a variety of carcinogenic pathways in glioma cells, including the PI3K-mTOR cascade, SRC kinase cascade, and SHC-RAS-RAF-MEK-ERK cascade. Original figure created with BioRender.com

Fig. 3

Several example mechanisms of therapeutic avenues of cancer neuroscience: A Inhibit of ADAM10/NLGN3 can suppress glioma growth by targeting its downstream PI3K-mTOR signaling pathway. B Neurosecretion-derived BDNF promotes tumor metastasis by binding to the TrkB receptor. Inhibition of BDNF-TrkB binding can suppress tumor metastasis. C Blocking the NGF-mediated neuro-tumor positive feedback loop. D Inhibiting sympathetic nerve signaling can mitigate the immunosuppressive microenvironment of the tumor. E The combination of β-blockers and immunosuppressants can augment the anti-tumor efficacy of anti-PD-L1 therapy. NLGN3 = Neuroligin-3. BDNF = brain derived neurotrophic factor. NGF = nerve growth factor. Original figure created with BioRender.com