The neuroscience of cancer

Abstract

The nervous system regulates tissue stem and precursor populations throughout life. Parallel to roles in development, the nervous system is emerging as a critical regulator of cancer, from oncogenesis to malignant growth and metastatic spread. Various preclinical models in a range of malignancies have demonstrated that nervous system activity can control cancer initiation and powerfully influence cancer progression and metastasis. Just as the nervous system can regulate cancer progression, cancer also remodels and hijacks nervous system structure and function. Interactions between the nervous system and cancer occur both in the local tumour microenvironment and systemically. Neurons and glial cells communicate directly with malignant cells in the tumour microenvironment through paracrine factors and, in some cases, through neuron-to-cancer cell synapses. Additionally, indirect interactions occur at a distance through circulating signals and through influences on immune cell trafficking and function. Such cross-talk among the nervous system, immune system and cancer-both systemically and in the local tumour microenvironment-regulates pro-tumour inflammation and anti-cancer immunity. Elucidating the neuroscience of cancer, which calls for interdisciplinary collaboration among the fields of neuroscience, developmental biology, immunology and cancer biology, may advance effective therapies for many of the most difficult to treat malignancies.

Fig. 1 |. Neuron–glioma interactions in the CNS.

Neuronal activity promotes glioma progression that through activity-regulated secretion of paracrine growth factors, including NLGN3, IGF-1 and BDNF, and by electrochemical communication mediated by synapses between neurons and glioma cells, as well as through potassium-evoked glioma currents. Such electrochemical signals are amplified in a glioma-to-glioma gap junction-coupled network that serves–among other functions–to amplify and synchronize depolarizing currents in the tumour cell network. Membrane depolarization alone is sufficient to promote glioma cell proliferation through voltage-dependent mechanisms that remain to be fully elucidated. ‘Hub’ cells autonomously generate currents that spread through the gap junction-connected tumour network to drive a tumour-intrinsic rhythm of periodic depolarization and consequent calcium transients important for tumour growth. AMPA receptor-mediated synaptic signalling between neurons and glioma cells promotes both tumour cell proliferation and invasion. In turn, glioma cell secretion of factors such as glutamate and synaptogenic proteins (for example, glypican-3 and TSP-1) promotes neuronal hyperexcitability and functional remodelling of neural circuits, thereby increasing neuronal activity in the tumour microenvironment. Glioma-induced increases in excitatory neuronal activity enhance activity-regulated influences on glioma progression. Original figure created with BioRender.com.

Fig. 2 |. Sensory experience and cancers.

a, Visual experience, for example, light, induces activity in retinal ganglion cell (RGC) neurons, whose axons comprise the optic nerve. Optic nerve activity promotes shedding of NLGN3, thereby regulating the initiation, growth and maintenance of low-grade gliomas that occur in the optic pathway in association with the tumour predisposition syndrome NF1. b, Odorants stimulate olfactory receptor neurons to signal to mitral/tufted cells (a neuronal subtype) in the olfactory bulb, which secrete IGF-1 in an olfactory experience- and neuronal activity-dependent manner, contributing to olfactory bulb high-grade glioma initiation and growth in a mouse model. c, Pain mediated by cutaneous nociceptor nerves in the melanoma tumour microenvironment, stimulated by secretory leukocyte protease inhibitor (SLP1) secreted by cancer cells, results in nerve-derived release of the neuropeptide CGRP. CGRP acts on T lymphocytes to promote T cell exhaustion, thereby limiting anti-cancer immunity and permitting melanoma growth. d, Cutaneous mechanosensory nerves innervate the touch dome epithelium, providing Hedgehog (Hh) ligand to touch dome epithelial stem cells, which can give rise to basal cell carcinoma. Mechanosensory nerve-derived Hedgehog ligand induces Hedgehog pathway activity in basal cell carcinoma cells, promoting tumour initiation and growth. Original figure created with BioRender.com.

Fig. 3 |. Neuronal mechanisms regulating the tumour immune microenvironment.

a, Extensive cross-talk occurs between neurons/nerves, immune cells and cancer cells. These interactions can influence anti-cancer immunity and pro-cancer inflammation. b, B cell-derived GABA drives immunosuppression in colon adenocarcinoma. GABA secreted by B lymphocytes binds to GABA_A receptors on T cells to suppress cytotoxic T cell responses and promote an immune-suppressive state in tumour-associated macrophages. c, Serotonin produced by platelets in pancreatic and gastric cancer drives the upregulation of PD-L1 on cancer cells, suppressing cytotoxic T cell responses. Original figure created with BioRender.com.

Fig. 4 |. PNS interactions with cancer.

a, Local paracrine signalling from nerves to the tumour or to stromal cells in the tumour microenvironment regulates cancer growth and invasion, while tumour-derived factors remodel peripheral nerves, promoting further nerve ingrowth into the tumour microenvironment. b, Nerve-derived factors such as neurotransmitters and neuropeptides can modulate immune cell trafficking and function. Consequently, altered immune function can influence anti-cancer immunity and tumour growth-promoting inflammation. c, Systemic interactions between the nervous system and cancers can be mediated by systemic paracrine signalling, for example, circulating catecholamines (including adrenaline), signalling directly to tumour cells or to other cell types in the tumour microenvironment. Reciprocally, tumour cells can influence the nervous system through circulating factors that may in turn regulate such systemic nervous system–cancer interactions (for example, altering the function of the hypothalamic–pituitary–adrenal axis). Original figure created with BioRender.com.

Fig. 5 |. Autonomic nervous system regulation of cancer.

a, Nerve–cancer cross-talk in gastric and intestinal cancers. In gastric cancer, acetylcholine signals to tumour cell muscarinic acetylcholine receptors to promote tumour cell proliferation, while tumour cells secrete axonogenic factors such as NGF to increase nerve ingrowth in the tumour microenvironment. b, Nerve-cancer cross-talk in pancreatic cancer. In contrast to its role in gastric cancer, acetylcholine can suppress pancreatic tumorigenesis. By contrast, β-adrenergic signalling (noradrenaline) promotes pancreatic cancer growth, and pancreatic cancer cells secrete NGF to increase sympathetic innervation of the tumour microenvironment. Original figure created with BioRender.com.