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  • Perspective
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The neural addiction of cancer

Nature Reviews Cancer volume 23, pages 317–334 (2023)Cite this article

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Abstract

The recently uncovered key role of the peripheral and central nervous systems in controlling tumorigenesis and metastasis has opened a new area of research to identify innovative approaches against cancer. Although the 'neural addiction' of cancer is only partially understood, in this Perspective we discuss the current knowledge and perspectives on peripheral and central nerve circuitries and brain areas that can support tumorigenesis and metastasis and the possible reciprocal influence that the brain and peripheral tumours exert on one another. Tumours can build up local autonomic and sensory nerve networks and are able to develop a long-distance relationship with the brain through circulating adipokines, inflammatory cytokines, neurotrophic factors or afferent nerve inputs, to promote cancer initiation, growth and dissemination. In turn, the central nervous system can affect tumour development and metastasis through the activation or dysregulation of specific central neural areas or circuits, as well as neuroendocrine, neuroimmune or neurovascular systems. Studying neural circuitries in the brain and tumours, as well as understanding how the brain communicates with the tumour or how intratumour nerves interplay with the tumour microenvironment, can reveal unrecognized mechanisms that promote cancer development and progression and open up opportunities for the development of novel therapeutic strategies. Targeting the dysregulated peripheral and central nervous systems might represent a novel strategy for next-generation cancer treatment that could, in part, be achieved through the repurposing of neuropsychiatric drugs in oncology.

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Fig. 1: Bidirectional crosstalk between the nervous system and solid tumours.
Fig. 2: Efferent central neuroendocrine pathways controlling tumour development and progression.
Fig. 3: Brain areas and circuits participating in tumour development and progression.
Fig. 4: Afferent tumour-to-brain connections.

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Acknowledgements

The authors thank P. Jobling, University of Newcastle, Australia, for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Cancer and Microenvironment-National Institute of Health and Medical Research (INSERM), Institute of Biology François Jacob-Atomic Energy Commission (CEA), University of Paris Cité, University of Paris-Saclay, Paris, France

    Claire Magnon

  2. School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia

    Hubert Hondermarck

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C.M. conceived and researched data for the article and wrote, reviewed and edited the manuscript before submission. H.H. wrote, reviewed and edited the manuscript before submission.

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Correspondence to Claire Magnon.

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C.M. National Institute of Health and Medical Research (INSERM), National Institute of Cancer (INCA- PLBIO), Cancéropôle Ile-de-France, Foundation for cancer Research (ARC), University of Paris-Cité, University of Paris-Saclay, Atomic Energy Commission (CEA), Sanofi iAward Europe, France. H.H. National Health and Medical Research Council (NHMRC) and the Mark Hughes Foundation, Australia.

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Glossary

β-Adrenergic pathway

Intracellular signalling activated by the stimulation of G protein-coupled, β-adrenergic receptors by epinephrine or norepinephrine.

Adipokines

Cytokines secreted by adipose tissue that can function in a paracrine and endocrine manner.

Adrenergic nerves

Nerves for which the neurotransmitter is either epinephrine, norepinephrine, or dopamine.

Adrenergic splanchnic division

Paired autonomic nerves that carry both visceral sympathetic and sensory fibres.

Afferent signals

Neuronal signals carried from the peripheral nervous system to the central nervous system.

Amygdala

Brain area considered as the integrative centre for emotions, emotional behaviour and motivation.

Angiogenesis inhibitors

Compounds that inhibit the growth of new blood vessels.

Astrocytes

Star-shaped and supportive glial cells of the central nervous system.

Autonomic nervous system

Part of the nervous system responsible for the control of bodily functions that are not consciously directed, such as breathing, heartbeat and digestion.

Axonogenesis

Process by which neural extensions, known as axons, are generated. In cancer, tumours build up their own autonomic nerve network through a dynamic axonal outgrowth of pre-existing autonomic nerve fibres in the organ where the tumour initiates.

Calcitonin gene-related peptide

CGRP. Peptide produced by sensory neurons in both the central and peripheral nervous systems that induces dilatation of blood vessels.

Catecholamines

Neurotransmitters produced in the adrenal medulla and the postganglionic fibres of the sympathetic nervous system; the main catecholamines are epinephrine (also known as adrenaline), norepinephrine (also known as noradrenaline) and dopamine.

Cholinergic nerve fibres

Nerve fibres that mainly use acetylcholine as a neurotransmitter.

Efferent neural signals

Neuronal signals carried from the central nervous system to the peripheral nervous system.

Episodic autobiographical memory retrieval

Remembering or re-experiencing a specific personal event from the past.

Field potentials

Transient electrical signals generated in the nervous system.

Glutamatergic neurotransmission

Transmission of information between neurons using glutamate as a neurotransmitter.

Hippocampus

Central brain area that is essential for learning, emotions and memory.

Hypothalamic–pituitary–adrenal (HPA) axis

A neuroendocrine system that mediates glucocorticoid release through molecular interactions among the hypothalamus (a region of the brain located below the thalamus), the pituitary gland (a pea-shaped structure located below the hypothalamus) and the adrenal glands (small conical organs on top of the kidneys).

Immune-checkpoint inhibitors

Drugs used in immunotherapy of cancer to restore the function of the immune system.

Immunotherapies

The treatment of disease by activating or suppressing the immune system.

Lateral hypothalamus

LH. Brain area mainly involved in the regulation of feeding behaviour.

Leptomeningeal microenvironment

Refers to leptomeninges, the two innermost layers of tissue that cover the brain and spinal cord.

Locus coeruleus–noradrenergic system

Cluster of cells in the brainstem that is the main source of the neurotransmitter norepinephrine in the brain.

Mesencephalic periaqueductal grey region

Interface between the forebrain and the lower brainstem that has a role in integrated behavioural responses to internal or external stressors such as pain or threat.

Microglia

A specialized population of phagocytic cells, located in the central nervous system.

Mindfulness-based therapy

A psychotherapeutic approach that uses meditative practices based on awareness of internal thoughts, feelings and emotions.

Muscarinic cholinergic receptors

Membrane protein receptors involved in the transmission of nervous signals in the parasympathetic cholinergic nervous system.

Myelination

Formation of a myelin sheath, which is made of proteins and lipids, around certain nerves, and allows nerve impulses to travel faster.

Nerve fibres

Individual neural extensions also known as axons.

Nerve sheath tumours

Tumours from the cells that form the sheath covering certain peripheral nerves.

Neural cells

Differentiated cells of the nervous system, also called neurons.

Neural projections

Processes extending from a neural cell, such as axons or dendrites, that are collectively called neurites.

Neuroendocrine neurons

Neurons that can release neurohormones following neuronal stimulation.

Neurogenic area

An area in the brain where neurogenesis, the process by which new neurons are formed, occurs.

Neurotrophic growth factors

Peptides primarily involved in the regulation of survival, growth and differentiation of neurons.

Neurotropism

Ability to invade or attract neural tissues.

Nociception

Perception or sensation of pain.

Noradrenergic neurons

Neurons that use norepinephrine (also known as noradrenaline) as a neurotransmitter.

Nucleus of the solitary tract

Group of sensory neurons that are located in the dorsomedial medulla of the brain.

Oligodendrocytes

Category of glial cells producing the myelin in the central nervous system.

Orexinergic neurons

Neurons that release orexin, a peptide that regulates arousal, wakefulness and appetite.

Parabrachial nucleus

Area located in the dorsolateral pons of the brain and working as a sensory relay that receives visceral, nociceptive and thermoreceptive inputs from the periphery and transfers the information to the hypothalamus and amygdala.

Parasympathetic nerve fibres

Nerve fibres from the parasympathetic division of the autonomic nervous system, which is responsible for the rest and digestion response of the body.

Peptidergic

Describing neurons that secrete peptides as their neurotransmitters.

Phase shifts

Deregulation of circadian rhythms that originate in the suprachiasmatic nucleus of the brain, leading to a shift in the sleep or awake time.

Prefrontal cortex

PFC. Region of the brain that makes up the frontal area of the frontal lobe and is mainly involved in mediating complex cognitive processes.

Purinergic signalling

Extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine or adenosine triphosphate (ATP).

Retinohypothalamic tract

Light-initiated signalling pathway that signals from the retina to the suprachiasmatic nuclei of the hypothalamus in the brain.

Schwann cells

Glial cells of the peripheral nervous system that help separate and insulate nerve cells.

Seed and soil theory

A hypothesis that states that metastatic tumour cells can only grow at a site with a favourable local tissue microenvironment, just like a seed will only grow if it lands on fertile soil.

Stereotactic activation

Electronically guided activation.

Substantia nigra

Brain region that is part of the basal ganglia and is involved in the production of the neurotransmitter dopamine.

Suprachiasmatic nucleus

SCN. Bilateral brain area located in the anterior part of the hypothalamus that is involved in the control of circadian rhythms.

Sympathectomy

Surgical procedure during which at least one sympathetic nerve or sympathetic ganglion is removed.

Sympathetic nervous system

Part of the autonomic nervous system that is best known for its role in responding to dangerous or stressful situations.

Sympatho–adrenal system

SAS. Physiological connection between the sympathetic nervous system and the adrenal medulla that regulates the release of catecholamines in response to environmental stimuli.

Thymic involution

Shrinking of the thymus that can occur naturally with age or acutely, as a consequence of stress, chemotherapy or other factors.

Tumour neo-angiogenesis

Formation of new blood vessels in the tumour microenvironment.

Viscero-sensory relays

Direct and indirect connections between sensory nerves of the autonomic nervous system and an organ.

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Magnon, C., Hondermarck, H. The neural addiction of cancer. Nat Rev Cancer 23, 317–334 (2023). https://doi.org/10.1038/s41568-023-00556-8

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