Nerves in cancer

Abstract

The contribution of nerves to the pathogenesis of malignancies has emerged as an important component of the tumour microenvironment. Recent studies have shown that peripheral nerves (sympathetic, parasympathetic and sensory) interact with tumour and stromal cells to promote the initiation and progression of a variety of solid and haematological malignancies. Furthermore, new evidence suggests that cancers may reactivate nerve-dependent developmental and regenerative processes to promote their growth and survival. Here we review emerging concepts and discuss the therapeutic implications of manipulating nerves and neural signalling for the prevention and treatment of cancer.

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Fig. 1: Autonomic innervation of major primary sites of cancer formation in the mouse: anatomical targets for preganglionic and postganglionic surgical denervation.
Fig. 2: Reactivation of nerve-mediated developmental and regenerative pathways in cancer.
Fig. 3: Neural regulation of the tumour microenvironment.

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Acknowledgements

The authors thank S. Pinho for helpful discussions and advice on the drawing of figures. They are grateful to the National Institutes of Health for support (training grant T32 NS007098 and GM007288) and the National Cancer Institute Ruth L. Kirschstein National Research Service Award predoctoral M.D./Ph.D. fellowship (F30 CA203446) (to A.H.Z.) and R01 grant funding (HL097700, DK056638, HL069438, and U01 DK116312) (to P.S.F.). Their laboratory and institute have been supported the New York State Department of Health (NYSTEM Program, C029154; Prostate Cancer Hypothesis Development Research C030318GG).

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A.H.Z. researched the data for the article. A.H.Z. and P.S.F. contributed equally to discussion of the content, writing, and editing the manuscript before submission.

Correspondence to Paul S. Frenette.

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Competing interests

P.S.F. serves as consultant for Pfizer, has received research funding from Ironwood Pharmaceuticals and is shareholder and member of the scientific advisory board of Cygnal Therapeutics. A.H.Z declares no competing interests.

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Nature Reviews Cancer thanks E. Repasky, S. Ben-Eliyahu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Innervation

Receiving neural input or synapse from a nerve or cluster of nerves.

Sympathetic nervous system

(SNS). A division of the autonomic nervous system that originates in the thoracic and lumbar portions of the spinal cord and travels to a paravertebral, intra-abdominal or intrapelvic ganglion, where it synapses with a postganglionic nerve that commonly uses noradrenaline as its main neurotransmitter.

Parasympathetic nervous system

(PSNS). A division of the autonomic nervous system that originates in the brainstem and sacral portions of the spinal cord and travels to ganglia located close to the organ that it will innervate, where it synapses with a postganglionic nerve that commonly uses acetylcholine as its main neurotransmitter.

Ganglion

A cluster of nerve cell bodies found in the autonomic and sensory nervous systems.

Sympathectomy

The removal of sympathetic innervation to a target organ by mechanical, chemical, genetic or other means.

Ganglionectomy

A form of denervation in which a cluster of nerve cell bodies known as a ganglion is removed.

Adrenergic nerve

A postganglionic sympathetic nerve that produces the neurotransmitter noradrenaline.

Noradrenaline

Also known as norepinephrine. A neurotransmitter of the catecholamine family often released by sympathetic nerves.

Exocrine

Referring to a family of glands that release their contents onto an epithelial surface (for example, sweat glands, salivary glands and glands of the gastrointestinal and genitourinary tracts).

Pyloroplasty

A surgical procedure to widen the lower part of the stomach to facilitate the emptying of gastric contents into the duodenum.

Botulinum neurotoxin

A neurotoxic protease that cleaves synaptic proteins, preventing acetylcholine release from nerve terminals.

Catecholamine

A monoamine neurotransmitter derived from tyrosine (includes noradrenaline).

Physical restraint stress model

A commonly used laboratory model to induce stress, involving immobilizing an animal in a small space such as a plastic tube.

Adrenergic receptors

G protein-coupled transmembrane receptors for noradrenaline and adrenaline.

Lymphangiogenesis

The formation of new lymphatic vessels from pre-existing lymphatic vessels.

Nicotinic receptors

Ion channel transmembrane receptors that allow cation diffusion on acetylcholine binding.

Muscarinic receptors

G protein-coupled transmembrane receptors for acetylcholine.

Neuropathy

Nerve damage or dysfunction usually resulting from an underlying disease process.

Schwann cells

Cells that ensheath axons of peripheral nerves, helping protect axons and forming the myelin sheath in myelinated axons.

Peptidergic

Pertaining to a neuron that expresses short peptide chain neurotransmitters (neuropeptides).

Acinar bud

An epithelial budding during organogenesis that will later form a functional secretory unit in the mature organ known as an acinus.

Arterioles

Small-diameter branches of an artery in tissue microcirculation that further segment to form capillaries.

Gastrectomy

Surgical removal of part or the entirety of the stomach, often performed to treat cancer.

Electroceuticals

A class of therapeutic agents that target nerve signalling by altering their firing patterns, such as with the use of implantable electrodes.

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Zahalka, A.H., Frenette, P.S. Nerves in cancer. Nat Rev Cancer 20, 143–157 (2020). https://doi.org/10.1038/s41568-019-0237-2

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