Can Stopping Nerves, Stop Cancer?

Abstract

The nervous system is viewed as a tissue affected by cancer and as a conduit for the transmission of cancer pain and perineural invasion. Here, we review recent studies that indicate a more direct role. Several studies have shown that reducing stress or suppressing sympathetic drive correlates with improved outcomes and prolonged survival. Recent studies using animal models of visceral and somatic cancer further support a role for the nervous system in cancer progression. Specifically, nerve ablation had a profound impact on disease progression, including delayed development of precancerous lesions, and decreased tumor growth and metastasis. In this review, we summarize new evidence and discuss how future studies may address the role of neural signaling in the modulation of tumorigenesis.

Keywords: autonomic; peripheral nervous system; sensory neurons; tumorigenesis.

Figure 1

Peripheral tissues including skin, stomach, pancreas and prostate are innervated by sensory neurons of the dorsal root ganglia (DRG; solid black lines). Thoracic and abdominal organs also receive sensory input from primary afferents whose cells bodies are located in the nodose ganglion (NG; solid red lines) and travel in the vagus nerve (VN). Sensory innervation from DRG to the stomach and pancreas travels with sympathetic preganglionic axons (right side of diagram) in the greater splanchnic nerve (SN) and pass through the celiac ganglion (CG) before reaching their target organ. The VN also contains parasympathetic preganglionic axons (dashed red lines) whose cell bodies are located in the brainstem. These axons synapse on parasympathetic postganglionic neurons (not shown) in the organ wall. Sympathetic innervation arises from sympathetic preganglionic neurons (blue dashed lines, right side of diagram) whose cell bodies are in the spinal cord at T1-L2 vertebral levels. Axons from these neurons innervate sympathetic postganglionic neurons in paravertebral ganglia (PG) located alongside the vertebral column or prevertebral ganglia found near the organ. Prevertebral ganglia include the CG, that innervates the stomach and pancreas, and the inferior mesenteric ganglion (IMG) that innervates the prostate. Preganglionic parasympathetic axons innervating the prostate (dashed red lines) arise from neurons located at sacral spinal cord levels and travel via pelvic SN to synapse on postganglionic parasympathetic neurons near the base of the bladder (not shown). Skin receives both sensory and sympathetic postganglionic input from appropriate spinal levels, but no parasympathetic input.

Figure 2

Two-way chemical communication exists between cancer cells and the peripheral nervous system. Tumors release molecules that also are made by neurons including neurotransmitters and neurotrophic growth factors (e.g. Artn, NGF, GDNF, BDNF, Nrtn). Tumors also have receptors that respond to molecules released by nerves and, in an autocrine fashion, to molecules released by the tumor itself. Neurons have receptors that allow them to respond to molecules released by other neurons and glia and these interactions are likely amplified in the tumor environment. “Released Molecules” are color coded to match their respective “Receptor/Channel”. SP, substance P; NPY, neuropeptide Y; CGRP, calcitonin gene related peptide; Ach, acetylcholine; NE, norepinephrine, NGF, nerve growth factor, BDNF, brain-derived neurotrophic growth factor; GDNF, glial cell-line derived growth factor; Artn, artemin; Nrtn, neurturin; AA, arachidonic acid; TRP, transient receptor potential family (e.g. TRPV1, TRPA1); P2X, ionotropic purinergic receptor; NK-R, neurokinin receptor (for SP); NE-R, norepinephine receptor (e.g., beta 2/3 adrenergic receptor), nAchR, nicotinic acetylcholine receptor; TrkA, tropomyosin receptor kinase A; TrkB, tropomyosin receptor kinase B; GFRα1, GDNF receptor alpha 1 (binds GDNF and Nrtn); GFRα2, GDNF receptor alpha 2 (binds Nrtn and GDNF); GFRα3, GDNF receptor alpha 3 (binds Artn); P2Y, metabotropic purinergic receptor; mAchR, muscarinic acetylcholine receptor; PAR2, protease activated receptor 2; ET-R, endothelin receptor.