1. Introduction

Tumor-associated immune cells, fibroblasts, epithelial cells, pericytes, and adipocytes can enhance metastasis by regulating extracellular matrix remodeling and neovascularization, and by promoting the epithelial-mesenchymal transition of the malignant cells [22,59]. Recently, intratumoral neurofilaments have been recognized as important constituents of the tumor milieu [60–62], and the degree of tumor innervation has been correlated with metastases and patient survival [63–65], Although the involvement of neurotransmitters and neuropeptides in nerve-mediated metastases has been proposed, the role of the neuroglia of the peripheral nervous system (PNS) in promoting metastases of solid tumors remains unconsidered. With the exception of perineural invasion (i.e., locoregional invasion of cancer into the space surrounding a nerve), the extent to which the Schwann cells, the principal glia of the PNS, participate in the formation of metastases has not been elucidated. A recent surge in studies of Schwann cell biology has revealed their expansive functions in neurodegenerative diseases, pain syndrome, autoimmune and inflammatory neuropathies, nerve and tissue repair, tissue regeneration, and cell-based therapy for spinal cord injury and autoimmune neurological diseases. However, the pro-metastatic activity of Schwann cells during surgery/biopsy-associated wound healing has not yet been considered.

New data demonstrates that nerves/Schwann cells are present in human and animal tumor specimens, and that nerves/Schwann cells may accelerate tumor growth and progression in mouse tumor models [66–71]. It is conceivable to suggest that this effect is due to cancer cell-Schwann cell-nerve cell crosstalk, which induces the so-called “repair-like” phenotype of Schwann cells and results in: (i) attraction and activation of immune regulatory cells, (ii) reorganization of the extracellular matrix, and (iii) enhanced migratory and invasive potential of malignant cells. New in vivo data suggest that these consequences of tumor-nerve-Schwann cell interactions might increase cancer's metastatic potential. We can speculate that neuroglial failure occurs when adaptive strategies developed by tumor-activated Schwann cells fail, and, in some settings, when the program associated with Schwann cell-driven tissue repair culminates in a maladaptive response that contributes to metastatic disease. It is possible that tumor-associated “repair-like” Schwann cells promote metastasis during surgery/biopsy-associated wound healing even more strongly since surgical stress and wound healing pathways contribute to the higher level of Schwann cell activation, dedifferentiation, and proliferation in the regenerating tumor microenvironment. However, this has never been experimentally tested.

2. The Neuronal Regulation of Tumor Progression

The crosstalk between malignant cells and the stromal and infiltrating cells is fundamental in the tumorigenesis process. Nerve endings are also detected within solid tumors [72,73]. Their communication with tumor cells is believed to represent so-called “neuro-neoplastic synapses” or “tumor-nervous connections” [74,75]. The role of the nerve filaments seen within the tumor mass was first believed to be mechanical, providing “paths” for the migration of the perineural invading cells [76,77]. Perineural invasion, also called perineural spread or neurotropic carcinomatous spread, is malignant cell invasion in, around, and through nerves, which is histologically observed as cancer cells within the layers of the nerve sheath including epineurium, perineurium, and endoneurium. However, it is now clear that the PNS, as a functionally pertinent association of cells and factors at the tumor milieu, regulates tumor development, growth, and dissemination [75,78,79]. Neurons within and at the tumor periphery release neurotransmitters, neuropeptides, and other biologically active substances acting on specific receptors on cancerous cells, stromal elements, and infiltrating immune cells, and altering cell function and cellular interactions in the tumor milieu.

A growing body of evidence shows that cancerous cells can utilize the benefit of the factors released by the nerves to generate a positive environment for survival, proliferation, and spreading [64,80–82]. Neural-related factors can alter the progression of metastasis, affecting the base membranes’ degradation and cancerous cell invasiveness, motility, extravasation, and colonization. They also modulate angiogenesis, the tumor stroma, immune cell functions, bone marrow activity, and local and systemic inflammatory pathways to impact metastases [74,83]. These neurotransmitters, neurotrophins, and neuropeptides include acetylcholine, catecholamines, γ-aminobutyric acid, serotonin, substance P, neurokinin A, bombesin, neuropeptide Y, vasoactive intestinal polypeptide, opioids, neurotensin, and other neuromodulating molecules. For instance, activation of β-adrenoceptors on tumor cells and tumor-associated macrophages can promote metastasis in animal models of breast, pancreatic, colon, neuroblastoma, ovarian, and prostate cancers [64,65,84–87]. Interestingly, in the head and neck cancer model, the crosstalk between malignant cells and neurons represents a mechanism by which tumor-associated neurons can be reprogrammed towards an adrenergic phenotype that augments tumor progression [88]. Although impediment of signaling pathways of the sympathetic nervous system with β-blockers or genetic deletion of β-adrenergic receptors primarily terminates metastasis of different types of tumors, α-adrenergic receptors’ function in cancer metastasis is yet to be clarified [89]. Acetylcholine secreted by tumor-infiltrating nerves from the parasympathetic nervous system was reported to target stromal cells expressing muscarinic receptors and to play a role in modulating tumor cell invasion and migration [64]. Neuropeptide Y, which can be released from sympathetic neurons, is generally accepted to be a powerful angiogenic factor [90]. Substance P and its receptors, at least in breast cancer, have been implicated in bone marrow metastasis formation [91]. Methionine-enkephalin expression in colorectal carcinomas may be associated with nodal and liver metastasis [92], while expression of bombesin/gastrin-releasing peptide in prostate cancer may be related to the lymph node metastases [93].

Although a broad understanding of the complex and multifaceted tumor-regulating role of neuronal factors has been reached [75,94], little is known about the role of tumor innervation in metastasis development in response to surgery and therapy. This gap in our knowledge is important because understanding the role of the PNS in cancer progression and metastasis formation after surgical procedures (tumor biopsy or resection) has a high significance in the clinical management of patients with cancer. In spite of exciting evidence that the removal of nerves from the tumor microenvironment is sufficient to terminate or decelerate disease progression, chemical or surgical denervation is unlikely to be of clinical use [79]. On the other hand, novel clinical studies emphasize cancer patient vulnerability to disease recurrence and metastasis formation following diagnostic and surgical interventions: for instance, excisional or incisional biopsy. The potential magnitude of perioperative vulnerability is underscored by the fact that greater than 60% of nearly 18–20 million patients diagnosed with cancer each year worldwide will require surgical resection [95]. As such, any opportunity to abrogate the risk of cancer progression arising during or after the vulnerable perioperative period could provide substantial benefit to patients. Thus, understanding the role of the PNS in surgery-induced metastasis should support the development of novel clinical approaches to reduce or limit metastasis formation.

This entry is adapted from the peer-reviewed paper 10.3390/cells10020454