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Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 21 of 31

and other organs) that may further potentiate dysregulation of metabolism and enhance peripheral, pro-
inflammatory reactions [205] . Hypothalamus appears to be an important contributor in the development and
maintenance of the cachectic state [202] . Lower hypothalamic activity has been demonstrated by functional
magnetic resonance imaging scans in patients with cachexia associated with advanced lung cancer [206] .

A unique crosstalk between the central nervous system and prostate tumours was recently revealed. In a
striking experiment [207] , using a mouse model of prostate cancer, a French group demonstrated a process of
tumour-associated neo-neurogenesis, in which neural progenitors leave the brain of the mouse and reach,
through the systemic circulation, the primary tumour or the metastatic tissues. Once arrived there, they
differentiated into new adrenergic neurons that are known to support the early stages of the development
of cancer. The authors suggested the possibility that the tumour itself might deplete neurogenic niches in
the brain by attracting neural progenitors to support its own development [207] .

Recent experiments suggest a direct relationship between the neurovegetative nervous system and
certain tumors. As reviewed by Cole [208] , SNS activation modulates gene expression programs that
promote metastasis of solid tumours by stimulating macrophage infiltration, inflammation, angiogenesis,
epithelial-mesenchymal transition, and tumour invasion, and by inhibiting cellular immune responses and
programmed cell death. SNS activation may also influence cancer progression via indirect pathways in
which SNS innervation of distant tissues triggers secondary hormonal or cellular effects that subsequently
affect the tumour microenvironment. For example, sympathetic innervation of bone marrow can stimulate
the production of myeloid lineage immune cells which may infiltrate the tumoral microenvironment and
promote metastasis [209-211] . In prostate cancer, sympathetic nerve fibers may help tumors grow by interacting
with beta-adrenergic receptors on stromal cells [212] . Epidemiological studies showed that men with prostate
adenocarcinoma who take non-selective beta-blockers have lower prostate cancer-specific mortality
rates [213] . A similar activity of beta-blockers has been described in melanoma or breast cancer patients
indicating that adrenergic signaling might be involved in various types of cancer [214,215] .

If the role of the sympathetic system in cancer has been well documented, the contribution of the
parasympathetic division of the autonomic nervous system is less clear. As shown by Kevin Tracey and his
collaborators from the Feinstein Institute on Long Island, New York, the efferent vagus nerve-mediated
cholinergic signaling controls immune function and pro-inflammatory responses via the inflammatory
reflex [216] . T and B cells express most cholinergic system components - e.g., acetylcholine, choline
acetyltransferase, acetylcholinesterase, and, both muscarinic and nicotinic acethycholine (Ach) receptors
and the cholinergic signals generated by immune cells appear to be triggers of both the initiation and
termination of cytokine synthesis (e.g., IL-2 in T cells and TNF-α in macrophages) [217] . A recent study from
the University of Sichuan, China, suggested that parasympathetic innervation may contribute to stomach
cancer development via acetylcholine-mediated activation of muscarinic acetylcholine receptors [218] . In a
mouse model of stomach cancer, vagotomy suppressed gastric tumorigenesis [219] . Also in a prostate cancer
mouse model cholinergic-induced tumor invasion and metastasis were inhibited by pharmacological
blockade of the stromal type 1 muscarinic receptor, leading to improved survival of the mice [212] . However,
as discussed by Cole et al. [208] , cholinergic blockade may stimulate indirectly the SNS promotion of cancer.
An alternative strategy would be to target neurotrophic growth factors in cancer as many cancers are
associated with nerve infiltration. An antineurotrophic antibody (tanezumab) has been developed by Pfizer
and is currently used as an analgesic [220] .

As many as 8% of cancers might be associated with endocrine paraneoplastic syndromes [221] , but, a detailed
discussion on these syndromes, is beyond the scope of this article. In the context of our discussion on
the systemic hallmarks of cancer, it is clear, however, that production of specific hormones by tumors
of particular types is not a random event [222] . For example, squamous cell carcinomas typically produce