Tumor innervation: peripheral nerves take control of the tumor microenvironment

Abstract

In recent decades, cancer research has expanded exponentially beyond the study of abnormally dividing cells to include complex and extensive heterotypic interactions between cancer and noncancer cells that constitute the tumor microenvironment (TME). Modulation of stromal, immune, and endothelial cells by cancer cells promotes proliferation, survival, and metabolic changes that support tumor growth and metastasis. Recent evidence demonstrates that tumors can recruit peripheral nerves to the TME, leading to enhanced tumor growth in a range of cancer models through distinct mechanisms. This process, termed tumor innervation, is associated with an aggressive tumor phenotype and correlates with poor prognosis in clinical studies. Therefore, the peripheral nervous system may play an underrecognized role in cancer development, harboring targetable pathways that warrant investigation. To date, nerves have been implicated in driving proliferation, invasion, metastasis, and immune evasion through locally delivered neurotransmitters. However, emerging evidence suggests that cell-cell communication via exosomes induces tumor innervation, and thus exosomes may also mediate neural regulation of the TME. In this Review, seminal studies establishing tumor innervation are discussed, and known and putative signaling mechanisms between peripheral nerves and components of the TME are explored as a means to identify potential opportunities for therapeutic intervention.

Figure 1. Tumor innervation.

Local sympathetic, parasympathetic, and sensory nerves act on incipient cancer cells and the microenvironment to regulate proliferation and enhance metastasis. As tumors progress, new axons are recruited to the tumor microenvironment to further potentiate growth, via exosomes and other mechanisms. Tumor-nerve interactions are tissue specific; thus, interactions depicted are representative of observations in several cancer types.

Figure 2. Neural communication in the TME.

Neurotrophins (NGF, BDNF), neurotransmitters (norepinephrine [NE], acetylcholine [ACh]), neuropeptides (SP, CGRP), and their cognate receptors modulate activity of cancer cells and components of the TME. Norepinephrine induces cancer cell proliferation and production of neurotrophins, while also inducing angiogenesis in endothelial cells and alternative (M₂) activation of macrophages. Neurotrophins further induce axonogenesis through activation of TrkA/B expressed on nerve cells. T cell activity and expression of cell death receptors (FAS/PD-1) on T cells and cancer cells (PD-L1) are modulated by neurotransmitters, altering tumor immunity within the TME. Stromal cells also respond to neuropeptides to alter ECM composition via expression of MMPs, which regulate invasion and metastasis.

Figure 3. Exosomes as intercellular messengers between nerves and the TME.

Exosomes are capable of local and distant signaling. They can induce axonogenesis of nerve fibers into the TME and modulate tumor growth. Tumor-derived exosomes (TEX) also influence T cell function within the TME, leading to an immune-suppressive environment. Nerves are also capable of both exosome release and internalization, and thus may also participate in exosome-mediated communication within the TME. TEX have been implicated in developing the metastatic niche; however, it is not yet known whether altered neural signaling, either locally or via the central nervous system, is in part responsible for promoting the growth of seeded cells into metastatic tumors. Identification of exosome-mediated signaling may lead to novel treatments to limit angiogenesis, tumor immunity, metastasis, and cancer pain.