Tumor Innervation: Cancer Has Some Nerve

Abstract

Over the past decade, several landmark reports have demonstrated that the nervous system plays an active role in cancer initiation and progression. These studies demonstrate that ablation of specific nerve types (parasympathetic, sympathetic, or sensory) abrogates tumor growth in a tissue-specific manner. Further, many tumor types are more densely innervated than their normal tissues of origin. These striking results raise fundamental questions regarding tumor innervation, how it is initiated, and how it molecularly contributes to disease. In this review, we aim to address what is currently known about the origin of tumor-infiltrating nerves, how they may be recruited to tumors, and how their presence may give rise to aggressive disease.

Figure 1.. Overview of the nervous system.

The central nervous system is comprised of the brain and the spinal cord (blue), that integrates afferent signals from the peripheral nervous system (orange) and consequently triggers a response by means of efferent signals to the body. Somatosensory nerves in the peripheral nervous system may be stimulated by activation of mechanoreceptors, proprioceptors, naturietic peptide B (NPPB+) itch, transient receptor potential cation channel, subfamily A member 1 (TRPA1+) chemical, transient receptor potential vanilloid (TRPV1+) heat, or transient receptor potential cation channel subfamily M member 8 (TRPM8+) cold receptors. Efferent signals consist of both motor and autonomic nerves. Autonomic nerves may either be tyrosine hydroxylase (TH+) sympathetic nerves that control ‘fight or flight’ responses, or vasoactive intestinal peptide/vesicular acetylcholine transporter (VAChT+/VIP+) parasympathetic nerves that maintain homeostasis of the body.

Figure 2.. Schematic of potential sources of tumor innervation.

Densely innervated tumors may be supported by neurons derived from many different origins. In addition to canonical locoregional innervation extending from spinal cord ganglia, neural progenitor cells from the subventricular zone may be able to migrate through the vasculature to peripheral tumor sites. Alternatively, plastic or stem-like cancer cells may transdifferentiate within the tumor microenvironment and support disease progression.

Figure 3.. Dense innervation influences immune cell populations and vasculature within the tumor microenvironment.

During early tumorigenesis, tumors are likely sparsely innervated and vascularized, with active immunosurveillance managed by pro-inflammatory macrophages and active cytotoxic T-cells. As the cancer progresses, dense innervation yields increased angiogenesis, and preferentially supports the survival of immunosuppressive cell populations (anti-inflammatory M2 macrophages, exhausted/PD-1 expressing T-cells, regulatory T-cells).