The Nervous System: Orchestra Conductor in Cancer, Regeneration, Inflammation And Immunity

Abstract

Although the role of nerves in stimulating cellular growth and dissemination has long been described in tissue regeneration studies until recently a similar trophic function of nerves in disease was not well recognized. However, recent studies in oncology have demonstrated that the growth and dissemination of cancers also require the infiltration of nerves in the tumor microenvironment. Nerves generate various neuro signaling pathways, which orchestrate cancer initiation, progression, and metastases. 

Similarly, nerves are increasingly implicated in their regulatory functions in immunity and inflammation. This orchestrator role of nerves in cellular and molecular interactions during regeneration, cancer, immunity, and inflammation offers new possibilities for targeting or enhancing neuro signaling in human health and diseases.

The relationship between cell growth and immunity is very close. The immune response requires extensive cell proliferation and differentiation to generate immune cells that attack foreign invading pathogens. When the body receives an immune response from external stimuli, immune cells such as T cells, B cells, and macrophages need to multiply and expand rapidly to fight against pathogens in time. Cell growth is regulated by multiple factors, including nutrition, growth factors, signaling pathways, etc. These factors also have direct or indirect effects on the growth and proliferation of immune cells. For example, certain growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), etc., can promote cell growth and proliferation. In addition, some cytokines (such as interleukins, interferons, etc.) can also activate the growth and differentiation of immune cells. 

Therefore, cell growth and immunity affect each other, and the regulation of cell growth plays an important role in the success or failure of the immune response, the speed and efficiency of pathogen clearance, and so on. From this point of view, our human immunity is very important, so we must improve our immunity. Cistanche has a significant effect on improving immunity. Cistanche contains a variety of biologically active components, such as polysaccharides, two mushrooms, Huangli, etc., these ingredients can stimulate various cells of the immune system and increase their immune activity.

Click health benefits of cistanche

KEYWORDS

cancer, immunity, inflammation, nerves, nervous system, and regeneration.

1 | INTRODUCTION

The peripheral nervous system (PNS) comprises nerves outside the central nervous system (CNS), including selected cranial nerves, spinal roots, sensory and autonomic ganglia, somatic nerves, and neuromuscular junctions. The role of the PNS has been thought to be restricted to several essential functions, including control of voluntary striated muscles, conveyance of nonvisual sensory information to the CNS, and autonomic function regulation. Peripheral nerves have also been well characterized in injury and disease. Traditionally, peripheral nerve dysfunction includes peripheral neuropathies, peripheral nerve injuries, and neuromuscular disorders, such as amyotrophic lateral sclerosis, muscular dystrophy, myasthenia gravis, and spinal muscular atrophy.

In recent years, the field of cancer neuroscience has emerged and has highlighted the role of nerves beyond traditional peripheral nerve diseases and to a variety of other organsystems.1,2Nerves are emerging as promoters of cancer growth and dissemination and although their mechanisms of action need to be fully elucidated, nerves appear to stimulate various signaling pathways in cancer cells and other cellular components of the tumor microenvironment (TME).1,3 Apart from tumor cells and stromal cells, immune cells are a major component in the TME and also interact with nerves and tumor innervation, which should now be considered a hallmark of cancer.3 More broadly, nerves are increasingly described for their regulatory functions in immunity and inflammation. Diseases from inflammatory bowel disease4 to endometriosis5 have posited neural etiologies, at least in part. Interestingly, the role of nerves in stimulating cellular growth and dissemination has long been associated with animal regeneration, where nerves are necessary for the reconstitution of lost body parts,6 and the recent extension of the concept of nerve dependence from regeneration to cancer and immunity are an important milestone.7

In this review, we aim to offer a perspective on exonerate biology and the role of nerves outside the nervous system in health and disease. We will first highlight the current knowledge about nerve dependence in regeneration and the emerging role of nerves in both cancer and immunity. The striking similarities in nerve activities between cancer, regeneration, and immunity emphasize the trophic impact of nerves and suggest that targeting nerves and neuro signaling is a promising therapeutic approach for the treatment of various human diseases.

2 | DEPENDENCE OF REGENERATION ON NERVES

2.1 | The role of nerves in regeneration

Nerve involvement in limb regeneration was initially discovered in the salamander, which has the remarkable property to regenerate appendages (limbs and tail) after amputation. Starting with the formation of a cellular bud, called the blastema, regeneration of limb and tail occurs in only a few weeks and requires the infiltration of nerves into the blastema. Denervation of the stump prevents the formation and growth of the blastema, and in the absence of nerves, instead of regeneration, simple wound healing takes place. Nerve dependence in regeneration was first reported in the middle of the 19th century6 in the context of salamander limb regeneration and was later shown to also apply to tissues other than appendages and other species. In the regeneration of the amphibian lens, neural retina, and forebrain, regeneration can only occur in the presence of olfactory nerve projections.8 

In the fish, fin, and barbel regeneration also requires innervation for the creation of a regenerative blastema and the progressive reconstitution of a fully functional structure.8-10 In mammals, nerves are required for heart regeneration through the stimulation of stem cell growth,11 and in digit tip regeneration (the remnant of limb regeneration in amphibians), denervation also blocks regeneration.12,13

2.2 | The molecular bases for nerve dependence in regeneration

The understanding of nerve involvement in regeneration at the molecular level largely remains to be elucidated.

On the one hand, blastema cells produce neurotrophic factors that attract nerves in the regenerative structure, and on the other hand, nerves liberate various mitogenic factors and neurotransmitters that stimulate neuro signaling in blastema cells. Neuregulin and nerve growth factor (NGF) have been shown to facilitate innervation during heart regeneration11 and in digit tip regeneration, a Wntmediated mechanism, is necessary to attract nerves that promote blastema cell growth.13 Immune cells, and in particular macrophages, may also contribute to the attraction of nerves to the blastema. Macrophages secrete neurotrophic factors that can stimulate nerve outgrowth,14 and this mechanism seems to be at play in regeneration.15 

Importantly, growing nerves have been shown to secrete a series of growth factors and neurotransmitters through nerve endings. Transferrin,16 substance P,17 fibroblast growth factors (FGFs) and bone morphogenetic protein2 (BMP2),18 platelet-derived growth factor (PDGF) and oncostatin,19 as well as the morphogenetic factor nAG (a determinant of proximodistal position)20,21 have all been shown to be released by nerve endings during regeneration and actively stimulate the growth of the regenerate. Nerves also induce the overexpression of histone deacetylase 1 (HDAC1) which contributes to the proliferation of regenerative cells.22 Denervation causes the deprivation of the above-listed nerve-released molecules and that results in the impairment or strong reduction in regenerative capacities. Of note, likely, this list of trophic factors released by nerves is not exhaustive, with other molecular players likely yet to be discovered. 

Importantly, the cellular complexity of nerves should be taken into account in the molecular mechanisms of nerve dependence. Indeed, peripheral nerves are not only made of neurons but also include supportive Schwann cells, which are also involved in the stimulatory impact of nerves in regeneration by directly producing and releasing trophic factors such as PDGF.19-21

2.3 | Nerves as a source of stem/ progenitor cells

Aside from the release of molecules by nerve endings in the blastema cells, an important mechanism of nerve dependence in regeneration has recently been discovered. In digit tip regeneration and skin repair, peripheral nerves provide a reservoir of mesenchymal precursor cells that directly contribute to regeneration.23 Neural crest–derived mesenchymal precursor cells in the endoneurium can migrate to the blastema and later evolve into progenitors of nonneural cells, contributing to the growth and differentiation of the blastema, and in particular the formation of bones.23 

Similarly, neural crest–derived nerve mesenchymal cells contributed to the dermis during skin wound healing.23 These findings support a model where peripheral nerves directly contribute precursor cells to promote the repair and regeneration of injured tissues.

Together, not only nerves stimulate regeneration through paracrine-based molecular interactions but also they can provide a source of precursor cells that directly contribute to regeneration. This dual function of nerves places them in a central role as orchestrators for the cellular and molecular interactions played during regeneration and, as we will describe in the next section, there are strong similarities between the role and mechanism of action of nerves in regeneration and cancer (Figure 1).

3 | THE ROLE OF NERVES IN CANCER

3.1 | The importance of nerves in cancer

Previous studies have pointed to the expression and involvement of neurotrophic growth factors, such as NGF24 and other neurotrophins,25 as well as neurotransmitter signaling26 in tumor growth. Perineural invasion (the invasion of nerves by cancer cells) has been known for several years,27 but the role of nerves in tumorigenesis was not acknowledged until more recently. Nerve dependence in regeneration was ignored by the cancer community despite demonstrations, made as early as the 1950s, that denervation can lead to a slow down or even the arrest of tumor growth in cervical cancer,28 pheochromocytoma29, and transplanted tumors in the mouse.30 However, cancer research on the role of nerves accelerated in 2013 when the impact of denervation on the development of prostate cancer was reported.31 The authors found that denervation of sympathetic (adrenergic) and parasympathetic (cholinergic) nerves reduced both tumor progression and the formation of metastases in the mouse. Beta-adrenergic and cholinergic signaling in tumor cells, presumably activated by the liberation of noradrenaline and acetylcholine from sympathetic and parasympathetic nerves, respectively, resulted in the stimulation of beta-adrenergic and cholinergic receptors and ultimately led to prostate tumor growth and dissemination.31 In a separate study, sympathetic nerves were also shown to be the inducers of an angio-metabolic switch, through the release of noradrenaline, resulting in the vascularization of prostate tumors, thus promoting overall tumor growth and dissemination.32 

Interestingly, this nerve dependence in prostate cancer explained the long-observed fact that men with spinal cord injuries had a lower incidence of prostate cancer,33 as spinal cord injury induces functional denervation, and the crucial importance of neural signaling in prostate cancer is now acknowledged.34 Preventing the infiltration of sympathetic and parasympathetic nerves in the prostate, or targeting their respective signaling pathways, is now being evaluated in clinical trials with beta-blockers (antagonists of beta-adrenergic receptors).34 Existing epidemiological studies had suggested that the use of beta-blockers could reduce mortality in prostate cancer.35 Interestingly, the clinical ramifications of the role of nerves in cancer go beyond treatment, as nerves could also be used to identify life-threatening prostate cancers (that require aggressive therapeutic interventions) from indolent prostate cancers (that only require active surveillance). Nerve infiltration is indeed higher in high-risk prostate cancer compared with low-risk prostate cancer31 and perineural invasion, which is associated with nerve infiltration, has recently been shown to be an independent predictor of metastatic progression in prostate cancer.36 

In addition, as nerve trunks in the prostate can be observed by using magnetic resonance imaging (MRI), nerve density determined by MRI could be a noninvasive way to identify aggressive prostate cancers at the time of diagnosis.37 Thus, in clinical terms, nerve involvement could be used for the establishment of cancer prognosis, to predict patient outcome, and in the treatment for preventing or interfering with neuron signaling. As will be described below, it is also likely that these findings and clinical ramifications in prostate cancer can be extended to other, if not all, human tumors.

After prostate cancer, the stimulatory impact of nerves in tumorigenesis was reported in gastric cancer. In gastric cancer, based on surgical and chemical denervation, the vagal nerve was shown to be necessary for tumor initiation and progression.38 Denervation experiments, as well as the use of inhibitors or molecular targeting against cholinergic signaling, demonstrated the role of parasympathetic nerves in the promotion of gastric cancer.38,39 Interestingly, a feedforward loop has been demonstrated in which gastric tumor cells produce and release NGF to promote tumor innervation and in return, cholinergic signaling activates the proliferation and dissemination of gastric cancer stem cells through Yap- and Wnt-mediated pathways.39

In basal cell carcinoma of the skin, surgical ablation of sensory nerves in hair follicles suppresses tumor formation, and sensory nerves stimulate stem cell proliferation through a mechanism involving the activation of nerve-derived hedgehog signaling.40 Importantly, this demonstrated that the stimulatory role of nerves in cancer is not limited to autonomic nerves (sympathetic and parasympathetic) but that sensory nerves are also involved.

Pancreatic cancer development appears to be under a balanced neural influence where sensory41,42 and sympathetic nerves43 stimulate the growth of pancreatic cancer cells, through neurokinin receptor and beta-adrenergic signaling, respectively, whereas parasympathetic nerves suppress cancer growth through cholinergic signaling.44 In the regulation of cardiac activity, a positive versus the negative type of regulation by sympathetic versus parasympathetic nerves is well established,45 and the same principle of opposing neural effects may also be applicable in cancer progression. Of note, both nerve density and nerve size are increased in pancreatic cancer, and these changes may be of interest as prognostic biomarkers.46

In breast cancer, a differential impact of sympathetic versus parasympathetic innervation is also at play. Using genetic manipulation in the mouse, breast cancer growth and progression were accelerated following stimulation of sympathetic nerves in breast tumors but were reduced following stimulation of parasympathetic nerves.47 There was also an increased sympathetic and decreased parasympathetic nerve density in tumors associated with poor clinical outcomes and correlated with higher expression of immune checkpoint molecules.47 These data demonstrate that similarly to pancreatic cancer, different nerve types may have a differential, and possibly opposite, impact on breast tumor development; whether this applies to other cancer types will need to be clarified

Although brain cancer occurs in the CNS, the impact of neurons on brain cancer development has been shown. Neuronal cells have been shown to promote glioma growth through the liberation of synaptic protein neuroligin-3 (NLGN3) that stimulates glioma cell proliferation through a PI3K-mTOR signaling pathway.48

NLGN3 release is stimulated by neural activity48 and can be targeted in animal models to decrease the development of glioma cells.49 The release of other proteins, such as pleiotrophin from neural cells, can promote glioma cell invasion50 and in return, glioma cells can also impact neuron activity.51 One mechanism that ties brain cancer and synaptic signaling is dependent on the presence of driver mutations in the PI3K gene, drawing an important connection between the genomic instability of cancer and the activation of neural signals.52 These studies in brain cancer extend the demonstration that neuronal cells and macromolecules are essential in cancer and could be targeted in future treatments.

3.2 | The brain as a possible source of tumor progenitor cells

A recent study has identified that some neural progenitor cells produced in the subventricular zone—a neurogenic area of the brain—can cross the blood–brain barrier and egress into the circulation.53 These cells can then infiltrate and reside in the prostate tumor where they generate new adrenergic neurons that contribute to the stimulation of prostate cancer growth and dissemination.53 This new paradigm, by which the brain is a source of progenitor cells that participate in tumor progression, is similar to recent discoveries in the field of regeneration pointing to peripheral nerves as a source of mesenchymal stem and progenitor cells that participate in the outgrowth of the regenerate.23

3.3 | The Role of Nerves in cancer immunity and Inflammation

The cross-talk between nerves and immune cells is thought to be involved in cancer immunity and inflammation. Neuroimmune interactions, from the nervous to the immune systems and vice versa are well established,54 and their impact on cancer progression has been reviewed.55 Not only various neuro signaling, and in particular adrenergic signaling, are necessary for the generation of immune cells from the bone marrow,56 but also the infiltration and activation of immune cells in the TME can be driven by adrenergic signaling and contribute to metastasis.26 The interaction between innervation and inflammation is also illustrated by the fact that the vagus nerve modulates memory T cells, resulting in the inhibition of myeloid-derived suppressor cell growth in the spleen, and the promotion of cancer progression through suppression of cytotoxic T cells.57 Together, in terms of neuroimmune interactions in cancer, it seems that only the tip of the iceberg has been explored to date, and the coming years should see a considerable expansion of this field of research.

Overall, the role of nerves in cancer and the resulting therapeutic ramifications are emerging, with striking similarities between the regulatory impact of nerves in regeneration and cancer(Figure 1). It should be noted that there are also differences in the role of nerves in regeneration versus cancer, as a balance between stimulatory and inhibitory neural effects has never been described in regeneration. Whether the dual roles of nerves in regeneration have not been described because they do not exist or because it has been missed until now remains to be elucidated. In any case, the concept of nerve dependence in regeneration has now been extended to cancer, and beyond the cancers described above, innervation of the TME is reported in an increasing number of malignancies, such as in thyroid (58) and esophageal (59) cancer.

4 | THE ROLE OF NERVES IN INFLAMMATION AND IMMUNITY

4.1 | Neuroimmunology

Neuroimmunology has primarily focused on the CNS and associated neuroinflammatory disorders, such as multiple sclerosis, as well as the role of neuroimmune interactions in neurodegenerative and neuropsychiatric diseases.58 Neuroimmune interactions in the CNS can have both deleterious effects and a role in normal brain development and recovery from trauma. Multiple sclerosis is a classic example of the deleterious effects of aberrant immune activation, in which T lymphocytes and other inflammatory mediators attack the myelin sheath in the CNS.59 Neuroimmune interactions in the CNS extend to microglia and the complement system, with roles in neurodegenerative disorders, including Alzheimer's disease.60 More recently, the study of neuroimmune interactions related to the PNS has come to the fore.61

4.2 | Cross talk between peripheral neurons and immune cells

As opposed to oncology, research on the gastrointestinal (GI)tract has long acknowledged the role of neurons, including those of the enteric nervous system (ENS), in selected gastroenterological diseases, such as inflammatory bowel disease (IBD), and serves to illustrate general principles relevant to peripheral neuroimmunology.4 The GI tract is characterized by a dense, complex network of nerves and neurons that coordinate gut physiological functions.62 In addition, the GI tract is replete with a variety of immune cells that interact with nerves and neurons. Neuroimmune cross-talk in the gut is critical to the maintenance of normal physiology and homeostasis as well as being involved in a variety of gut perturbations including infection, food allergy, and IBD.63

In the gut, ENS neurons and neurites are entangled and communicate with immune cells including macrophages. One premise for gut physiology is that both immune cells and neurons sense danger and communicate with each other. The PNS and immune systems serve as sentinels for dangerous pathogens, noxious agents, and other stimuli. Figure 2 illustrates a simple, pragmatic view of homeostasis and disrupted biology. Figure 2A shows a homeostatic gut with tolerogenic communication between neurons and immune cells. We designate the tolerogenic state by notations, I0 or N0. When neurons and/or immune cells receive an inflammatory stimulus, they convert to an inflammatory state we depict as I1 or N1. If the inflammatory stimulus is brief or inconsequential, neurons and immune cells can revert to baseline and homeostasis. But otherwise, initial remodeling and disease initiation commences. 

As the disease progresses, immune cells have a large role in driving inflammation and disease progression and can recruit additional neurons into the disease state as in Figure  2B. As the disease progresses further and may be treated with, for example, anti-TNFα agents, immune cells are brought back to the I0 state, but if the enteric neuron aberration is not resolved, neurons could bring the immune cells back to the activated state I1 as shown in Figure 2C. Activation of neural anti-inflammatory pathways could have the potential for treating IBD that is refractory to other, primarily immune, treatments.

ENS neurons that influence gut immune cells include intrinsic primary afferent neurons, vasoactive intestinal peptide neurons that project to the mucosa, and cholinergic neurons that influence macrophages in the external muscle layers.62 Canonical enteric neuropeptides, such as calcitonin gene-related peptide, and neurotransmitter pathways, including cholinergic, influence immune cells with anti-inflammatory potential.61 Acetylcholine is an important neurotransmitter for communication between extrinsic/intrinsic neurons and ENS to immune cells. The muscarinic GPCRs and nicotinic ligand-gated ion channels are expressed in varying patterns across the subsets of neurons and immune cells enabling specific signaling. It is expressed on multiple neuronal types and particularly on peripheral nerves including the ENS. Several preclinical studies have confirmed the therapeutic potential of targeting alpha 7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through the modulation of proinflammatory cytokines.64 Alone or in combination, neuropeptide and/or neurotransmitter modulation may restore neuroimmune homeostasis with potential antiinflammatory benefits for IBD.

Outside of the GI system, neuroimmune cross talk has a wide-ranging role in the maintenance of the tolerogenic state, as well as a factor in a variety of diseases. The role of the PNS and immune systems as sentinels for dangerous signals is common with barrier tissues, including the skin, replete with immune cells, nociceptors, and sensory neurons that serve to detect a variety of danger alerts. Innate lymphoid cells and the PNS communicate and determine the state of resident immune cells, including macrophages, and fibroblasts.65 In fact, neuroimmune interactions appear to play a fundamental role in psoriasis, a chronic inflammatory skin disease, including dysfunction of nociceptive neurons.66 Neuroimmune interactions in disease are not limited to the skin and the GI system. For example, the PNS plays an important role in the pathophysiology of endometriosis, a chronic debilitating condition.67 Sensory nerves that surround and innervate endometriotic lesions not only drive the chronic and debilitating pain associated with endometriosis but also contribute to a pro-growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells.

5 | CONCLUSION: EMERGING CLINICAL TRANSLATION

The role of the nervous system in health and disease is expanding, and the emerging exploration of the neuroscience of human diseases opens a new frontier in biomedicine. From regeneration to cancer, immunity, and beyond, a better understanding of the role played by the nervous system as the orchestra conductor of cellular and tissular growth and differentiation should delineate new avenues for the management of human health and diseases.

Therapeutic translation of cancer neuroscience is already emerging with the targeting of adrenergic and cholinergic neuron signaling in the TME, proven to be effective in reducing tumor progression in vivo,31,38,43,44 but the existing experimental and clinical evidence now need to be tested in clinical trials. Some clinical trials have already been completed, and more are on the way about the use of beta-blockers to target adrenergic signaling in cancer. 

In breast cancer, β-blockers reduced the biomarkers of metastasis in phase II randomized trial68 and inhibited cancer progression with reduced patient mortality.69 It should also be noted that, at this stage, the reported neuro signaling activities in cancer are mostly adrenergic and cholinergic, but the potential role of other neuro signaling pathways should not be underestimated. For instance, dopamine receptor D2 is correlated with gastric cancer prognosis70, and repositioning dopamine D2 receptor agonists can enhance chemotherapy and treat bone metastatic tumors71; therefore, dopamine and its signaling also appear as valid targets in cancer. Aside from impairing neuron signaling, another promising approach is to target neurotrophic growth factors to prevent tumor innervation.72 Blocking antibodies against NGF24 and other neurotrophic growth factors,25 or pharmacological inhibitors of their tyrosine kinase receptors Trk39,43,44 have been demonstrated to inhibit tumor progression, and the effect of anti-neurotrophic growth factor strategies also extends to the inhibition of cancer-induced pain.73 Pain is a serious issue in oncology, and the perspective of targeting simultaneously cancer progression and cancer pain by targeting neurotrophic growth factors and their signaling pathways is particularly attractive.

Aside from therapeutics, the other promising area for cancer neuroscience is tumor prognosis. Determining the outcome of the tumor at the time of diagnosis is increasingly important for treatment choice and patient segmentation, and as nerve infiltration in the TME is associated with tumor aggressiveness,31,46,74,75 the assessment of nerve density may become part of routine clinicopathological analyses in oncology, as well as an increasing utility through imaging, particularly in prostate cancer.37 Similarly, neurotrophic growth factors and their receptors are overexpressed in human tumors,76-79 and they could also be of value in cancer clinicopathology. Of note, the expression of neurotrophic growth factors is associated with cancer prognosis in dogs and therefore the value of quantifying neurotrophic growth factors in clinicopathology may also apply to veterinary oncology.80

In conclusion, clinical translation currently emerging in the fields of cancer neuroscience and exonerate biology is likely to pave the way for further clinical developments in immunity, inflammation, cancer, and regenerative medicine. Moreover, the nervous system, particularly the brain, is the integration center of cognition, emotions, and social interactions. The deciphering of the psychological mechanisms involved in physical health has already been pioneered,81 and it can be anticipated that the recent developments of neuroscience that we have described here may also lead to a better understanding of the contribution of neurophysiological, cognitive, and social inputs in human health and diseases.

ACKNOWLEDGMENTS

We gratefully acknowledge robust discussions with Grazia Piizzi leading to the concepts shown in Figure 2.

CONFLICT OF INTEREST

Pearl S. Huang and John A. Wagner are employees of Cygnal Therapeutics and may own stock and/or stock options. Hubert Hondermarck is a member of the Scientific Advisory Board of Cygnal Therapeutics.

AUTHOR CONTRIBUTIONS

All authors collaborated on the paper and offered substantive revisions and approval of the final version.

REFERENCES

1. Faulkner S, Jobling P, March B, Jiang CC, Hondermarck H. Tumor neurobiology and the war of nerves in cancer. Cancer Discov. 2019;9(6):702-710. 

2. Monje M, BornigerJC, D'Silva NJ, et al. Roadmap for the emerging field of cancer neuroscience. Cell. 2020;181(2):219-222. 

3. Gillespie S, Monje M. The neural regulation of cancer. Ann Rev Cancer Biol. 2020;4:371-390. https://doi.org/10.1146/annurevcancerbio-030419-033349 

4. Stavely R, Abalo R, Nurgali K. Targeting enteric neurons and plexitis for the management of inflammatory bowel disease. Curr Drug Targets. 2020;21(14):1428-1439. 

5. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. 2005;308:1587-1589. 

6. Todd TJ. On the process of reproduction of the members of the aquatic salamander. Q J Sci Literature Arts. 1823;16:84-96. 

7. Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: from regeneration to cancer. Cancer Cell. 2017;31(3):342-354. 

8. Goss RJ. Principles of Regeneration. Academic Press; 1969. 

9. Geraudie J, Singer M. Necessity of an adequate nerve supply for regeneration of the amputated pectoral fin in the teleost Fundulus. J Exp Zool. 1985;234:367-374.

10. Simoes MG, Bensimon-Brito A, Fonseca M, et al. Denervation impairs the regeneration of amputated zebrafish fins. BMC Dev Biol. 2014;14:49. 

11. Mahmoud A, O’Meara C, Gemberling M, et al. Nerves regulate cardiomyocyte proliferation and heart regeneration. Dev Cell. 2015;34:387-399. 

12. Rinkevich Y, Montoro DT, Muhonen E, et al. Clonal analysis reveals nerve-dependent and independent roles in mammalian hind limb tissue maintenance and regeneration. Proc Natl Acad Sci USA. 2014;111:9846-9851. 

13. Takeo M, Chou WC, Sun Q, et al. Wnt activation in nail epithelium couples nail growth with digit regeneration. Nature. 2013;499:228-232. 

14. Yin Y, Cui Q, Li Y, et al. Macrophage-derived factors stimulate optic nerve regeneration. J Neurosci. 2003;23(6):2284-2293. 

15. Godwin JW, Pinto AR, Rosenthal NA. Macrophages are required for adult salamander limb regeneration. Proc Natl Acad Sci USA. 2013;110:9415-9420. 

16. Mescher AL, Connell E, Hsu C, Patel C, Overton B. Transferrin is necessary and sufficient for the neural effect on growth in amphibian limb regeneration blastemas. Dev Growth Differ. 1997;39:677-684. 

17. Smith MJ, Globus M, Vethamany-Globus S. Nerve extracts and substance P activate the phosphatidylinositol signaling pathway and mitogenesis in newt forelimb regenerates. Dev Biol. 1995;167:239-251. 

18. Satoh A, Makanae A, Nishimoto Y, Mitogawa K. FGF and BMP derived from dorsal root ganglia regulate blastema induction in limb regeneration in Ambystoma mexicanum. Dev Biol. 2016;417:114-125. 

19. Johnston AP, Yuzwa SA, Carr MJ, et al. Dedifferentiated Schwann cell precursors secreting paracrine factors are required for the regeneration of the mammalian digit tip. Cell Stem Cell. 2016;19(4):433-448. 

20. Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP. Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science. 2007;318:772-777. 

21. Grassme KS, Garza-Garcia A, Delgado JP, et al. Mechanism of action of secreted newt anterior gradient protein. PLoS One. 2016;11(4):e0154176. 

22. Wang MH, Wu CH, Huang TY, et al. Nerve-mediated expression of histone deacetylases regulates limb regeneration in axolotls. Dev Biol. 2019;449(2):122-131. 

23. Carr MJ, Toma JS, Johnston APW, et al. Mesenchymal precursor cells in adult nerves contribute to mammalian tissue repair and regeneration. Cell Stem Cell. 2019;24(2): 240-256.e9. 

24. Adriaenssens E, Vanhecke E, Saule P, et al. Nerve growth factor is a potential therapeutic target in breast cancer. Cancer Res. 2008;68(2):346-351. 

25. Vanhecke E, Adriaenssens E, Verbeke S, et al. Brain-derived neurotrophic factor and neurotrophin-4/5 are expressed in breast cancer and can be targeted to inhibit tumor cell survival. Clin Cancer Res. 2011;17(7):1741-1752. 

26. Sloan EK, Priceman SJ, Cox BF, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Can Res. 2010;70:7042-7052. 

27. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. 2009;115(15):3379-3391.

For more information:1950477648nn@gmail.com