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Nerves in cancer

Nature Reviews Cancer volume 20, pages 143–157 (2020)Cite this article

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Abstract

The contribution of nerves to the pathogenesis of malignancies has emerged as an important component of the tumour microenvironment. Recent studies have shown that peripheral nerves (sympathetic, parasympathetic and sensory) interact with tumour and stromal cells to promote the initiation and progression of a variety of solid and haematological malignancies. Furthermore, new evidence suggests that cancers may reactivate nerve-dependent developmental and regenerative processes to promote their growth and survival. Here we review emerging concepts and discuss the therapeutic implications of manipulating nerves and neural signalling for the prevention and treatment of cancer.

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Fig. 1: Autonomic innervation of major primary sites of cancer formation in the mouse: anatomical targets for preganglionic and postganglionic surgical denervation.
Fig. 2: Reactivation of nerve-mediated developmental and regenerative pathways in cancer.
Fig. 3: Neural regulation of the tumour microenvironment.

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References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  2. Zahalka, A. H. et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 358, 321–326 (2017). This article shows that adrenergic nerves regulate the vasculature in the TME to promote tumour growth and cancer progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhao, C. M. et al. Denervation suppresses gastric tumorigenesis. Sci. Transl Med. 6, 250ra115 (2014). This article shows that surgical transection of the vagus nerve inhibits development of gastric cancer.

    PubMed  PubMed Central  Google Scholar 

  4. Renz, B. W. et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell https://doi.org/10.1016/j.ccell.2017.11.007 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013). This paper showed a role for adrenergic and cholinergic nerves in prostate tumour growth and metastasis.

    PubMed  Google Scholar 

  6. Langley, J. in The autonomic nervous system, Part 1 (ed. Heffer, W.) (Simpkin, Marshall, Hamilton, Kent & Co. Ltd., 1921).

  7. Erin, N., Zhao, W., Bylander, J., Chase, G. & Clawson, G. Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells. Breast Cancer Res. Treat. 99, 351–364 (2006).

    CAS  PubMed  Google Scholar 

  8. Kappos, E. A. et al. Denervation leads to volume regression in breast cancer. J. Plast. Reconstr. Aesthet. Surg. 71, 833–839 (2018).

    PubMed  Google Scholar 

  9. Peterson, S. C. et al. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell Stem Cell 16, 400–412 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sinha, S. et al. PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk. Cancer Res. 77, 1868–1879 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Saloman, J. L. et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc. Natl Acad. Sci. USA 113, 3078–3083 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Vesalius, A. De Humani Corporis Fabrica (The Fabric of the Human Body) (Johannes Oporinus, 1543).

  13. Jobert, M. New treatment of cancer. Lancet 34, 112 (1840).

    Google Scholar 

  14. Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008). This study provides evidence for an increase in adrenergic nerve density in human cancer.

    CAS  PubMed  Google Scholar 

  15. Albo, D. et al. Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes. Cancer 117, 4834–4845 (2011).

    CAS  PubMed  Google Scholar 

  16. Raju, B., Haug, S. R., Ibrahim, S. O. & Heyeraas, K. J. Sympathectomy decreases size and invasiveness of tongue cancer in rats. Neuroscience 149, 715–725 (2007).

    CAS  PubMed  Google Scholar 

  17. Huang, D. et al. Nerve fibers in breast cancer tissues indicate aggressive tumor progression. Medicine 93, e172 (2014).

    PubMed  PubMed Central  Google Scholar 

  18. Partecke, L. I. et al. Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade. Pancreatology 16, 423–433 (2016).

    CAS  PubMed  Google Scholar 

  19. Shao, J. X. et al. Autonomic nervous infiltration positively correlates with pathological risk grading and poor prognosis in patients with lung adenocarcinoma. Thorac. Cancer 7, 588–598 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zoucas, E., Nilsson, C., Alm, P. & Ihse, I. Selective microsurgical sympathetic denervation of the rat pancreas. Eur. Surg. Res. 28, 367–373 (1996).

    CAS  PubMed  Google Scholar 

  21. Hayashi, A. et al. Retrograde labeling in peripheral nerve research: it is not all black and white. J. Reconstr. Microsurg. 23, 381–389 (2007).

    PubMed  Google Scholar 

  22. Huang, Z. J. & Zeng, H. Genetic approaches to neural circuits in the mouse. Annu. Rev. Neurosci. 36, 183–215 (2013).

    CAS  PubMed  Google Scholar 

  23. Tabatai, M., Booth, A. M. & de Groat, W. C. Morphological and electrophysiological properties of pelvic ganglion cells in the rat. Brain Res. 382, 61–70 (1986).

    CAS  PubMed  Google Scholar 

  24. McVary, K. T. et al. Growth of the rat prostate gland is facilitated by the autonomic nervous system. Biol. Reprod. 51, 99–107 (1994).

    CAS  PubMed  Google Scholar 

  25. Diaz, R. et al. Histological modifications of the rat prostate following transection of somatic and autonomic nerves. An. Acad. Bras. Cienc. 82, 397–404 (2010).

    PubMed  Google Scholar 

  26. Kamiya, A. et al. Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression. Nat. Neurosci. 22, 1289–1305 (2019). This study develops novel tools for manipulating nerve activity in the TME.

    CAS  PubMed  Google Scholar 

  27. Thoenen, H. & Tranzer, J. P. Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn-Schmiedebergs Arch. für Pharmakologie und Experimentelle Pathologie 261, 271–288 (1968).

    CAS  Google Scholar 

  28. Krukoff, T. L., Fernandez, M. C. & Vincent, D. H. Effects of neonatal sympathectomy with 6-hydroxydopamine or guanethidine on survival of neurons in the intermediolateral cell column of rat spinal cord. J. Auton. Nerv. Syst. 31, 119–126 (1990).

    CAS  PubMed  Google Scholar 

  29. de Champlain, J. Degeneration and regrowth of adrenergic nerve fibers in the rat peripheral tissues after 6-hydroxydopamine. Can. J. Physiol. Pharmacol. 49, 345–355 (1971).

    PubMed  Google Scholar 

  30. Szpunar, M. J., Belcher, E. K., Dawes, R. P. & Madden, K. S. Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer. Brain Behav. Immun. 53, 223–233 (2016).

    CAS  PubMed  Google Scholar 

  31. Horvathova, L. et al. Sympathectomy reduces tumor weight and affects expression of tumor-related genes in melanoma tissue in the mouse. Stress 19, 528–534 (2016).

    CAS  PubMed  Google Scholar 

  32. Coarfa, C. et al. Influence of the neural microenvironment on prostate cancer. Prostate 78, 128–139 (2018).

    CAS  PubMed  Google Scholar 

  33. Johnson, E. M., Jr., Cantor, E. & Douglas, J. R., Jr. Biochemical and functional evaluation of the sympathectomy produced by the administration of guanethidine to newborn rats. J. Pharmacol. Exp. Ther. 193, 503–512 (1975).

    PubMed  Google Scholar 

  34. Madden, M. E. & Sarras, M. P., Jr. The pancreatic ductal system of the rat: cell diversity, ultrastructure, and innervation. Pancreas 4, 472–485 (1989).

    CAS  PubMed  Google Scholar 

  35. Lindsay, T. H. et al. A quantitative analysis of the sensory and sympathetic innervation of the mouse pancreas. Neuroscience 137, 1417–1426 (2006).

    CAS  PubMed  Google Scholar 

  36. Fasanella, K. E., Christianson, J. A., Chanthaphavong, R. S. & Davis, B. M. Distribution and neurochemical identification of pancreatic afferents in the mouse. J. Comp. Neurol. 509, 42–52 (2008).

    PubMed  PubMed Central  Google Scholar 

  37. Lau, M. K., Davila, J. A. & Shaib, Y. H. Incidence and survival of pancreatic head and body and tail cancers: a population-based study in the United States. Pancreas 39, 458–462 (2010).

    PubMed  Google Scholar 

  38. Bai, H. et al. Inhibition of chronic pancreatitis and pancreatic intraepithelial neoplasia (PanIN) by capsaicin in LSL-KrasG12D/Pdx1-Cre mice. Carcinogenesis 32, 1689–1696 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Makki, J. Diversity of breast carcinoma: histological subtypes and clinical relevance. Clin. Med. Insights Pathol. 8, 23–31 (2015).

    PubMed  PubMed Central  Google Scholar 

  40. Berthoud, H. R. & Neuhuber, W. L. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 85, 1–17 (2000).

    CAS  PubMed  Google Scholar 

  41. Alm, P., Liedberg, G. & Owman, C. Gastric and pancreatic sympathetic denervation in the rat. Scand. J. Gastroenterol. 6, 307–312 (1971).

    CAS  PubMed  Google Scholar 

  42. Partecke, L. I. et al. Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFalpha in a murine pancreatic cancer model. Oncotarget 8, 22501–22512 (2017).

    PubMed  PubMed Central  Google Scholar 

  43. Renz, B. W. et al. Cholinergic signaling via muscarinic receptors directly and indirectly suppresses pancreatic tumorigenesis and cancer stemness. Cancer Discov. 8, 1458–1473 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338 e326 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Partecke, L. I. et al. Induction of M2-macrophages by tumour cells and tumour growth promotion by M2-macrophages: a quid pro quo in pancreatic cancer. Pancreatology 13, 508–516 (2013).

    CAS  PubMed  Google Scholar 

  46. Dicken, B. J. et al. Gastric adenocarcinoma: review and considerations for future directions. Ann. Surg. 241, 27–39 (2005).

    PubMed  PubMed Central  Google Scholar 

  47. Polli-Lopes, A. C., Zucoloto, S., de Queirós Cunha, F., da Silva Figueiredo, L. A. & Garcia, S. B. Myenteric denervation reduces the incidence of gastric tumors in rats. Cancer Lett. 190, 45–50 (2003).

    CAS  PubMed  Google Scholar 

  48. Muir, T. C., Pollock, D. & Turner, C. J. The effects of electrical stimulation of the autonomic nerves and of drugs on the size of salivary glands and their rate of cell division. J. Pharmacol. Exp. Ther. 195, 372–381 (1975).

    CAS  PubMed  Google Scholar 

  49. Srinivasan, R. & Chang, W. W. Effect of neonatal sympathectomy on the postnatal differentiation of the submandibular gland of the rat. Cell Tissue Res. 180, 99–109 (1977).

    CAS  PubMed  Google Scholar 

  50. Lillberg, K. et al. Stressful life events and risk of breast cancer in 10,808 women: a cohort study. Am. J. Epidemiol. 157, 415–423 (2003).

    PubMed  Google Scholar 

  51. Chida, Y., Hamer, M., Wardle, J. & Steptoe, A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat. Clin. Pract. Oncol. 5, 466–475 (2008).

    PubMed  Google Scholar 

  52. Antoni, M. H. et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat. Rev. Cancer 6, 240–248 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939–944 (2006). This study finds that elevated noradrenaline levels in the TME accelerate tumour growth.

    CAS  PubMed  Google Scholar 

  54. Hassan, S. et al. Behavioral stress accelerates prostate cancer development in mice. J. Clin. Invest. 123, 874–886 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Schuller, H. M., Al-Wadei, H. A., Ullah, M. F. & Plummer, H. K., 3rd. Regulation of pancreatic cancer by neuropsychological stress responses: a novel target for intervention. Carcinogenesis 33, 191–196 (2012).

    CAS  PubMed  Google Scholar 

  56. Le, C. P. et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat. Commun. 7, 10634 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sloan, E. K. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042–7052 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Westphalen, C. B. et al. Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J. Clin. Invest. 124, 1283–1295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hayakawa, Y. et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 31, 21–34 (2017).

    CAS  PubMed  Google Scholar 

  60. Hebb, C. & Linzell, J. L. Innervation of the mammary gland. A histochemical study in the rabbit. Histochem. J. 2, 491–505 (1970).

    CAS  PubMed  Google Scholar 

  61. Köves, K., Györgyi, Z., Szabó, F. & Boldogkői, Z. Characterization of the autonomic innervation of mammary gland in lactating rats studied by retrograde transynaptic virus labeling and immunohistochemistry. Acta Physiol. Hung. 99, 148–158 (2012).

    PubMed  Google Scholar 

  62. Gerendai, I. et al. Transneuronal labelling of nerve cells in the CNS of female rat from the mammary gland by viral tracing technique. Neuroscience 108, 103–118 (2001).

    CAS  PubMed  Google Scholar 

  63. Stanke, M. et al. Target-dependent specification of the neurotransmitter phenotype: cholinergic differentiation of sympathetic neurons is mediated in vivo by gp130 signaling. Development 133, 383–383 (2005).

    Google Scholar 

  64. Cole, S. W. & Sood, A. K. Molecular pathways: beta-adrenergic signaling in cancer. Clin. Cancer Res. 18, 1201–1206 (2012).

    CAS  PubMed  Google Scholar 

  65. Pinho, S. et al. Lineage-biased hematopoietic stem cells are regulated by distinct niches. Dev. Cell 44, 634–641 e634 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Maryanovich, M. et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat. Med. 24, 782–791 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20, 303–320 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Hanoun, M. et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15, 365–375 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Arranz, L. et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512, 78–81 (2014).

    CAS  PubMed  Google Scholar 

  70. von Bartheld, C. S., Bahney, J. & Herculano-Houzel, S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J. Comp. Neurol. 524, 3865–3895 (2016).

    Google Scholar 

  71. Azevedo, F. A. et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513, 532–541 (2009).

    PubMed  Google Scholar 

  72. Venkataramani, V. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019).

    CAS  PubMed  Google Scholar 

  73. Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Zeng, Q. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–531 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Li, L. & Hanahan, D. Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell 153, 86–100 (2013).

    CAS  PubMed  Google Scholar 

  76. Fernandez-Montoya, J., Avendano, C. & Negredo, P. The glutamatergic system in primary somatosensory neurons and its involvement in sensory input-dependent plasticity. Int. J. Mol. Sci. 19, 69 (2017).

    PubMed Central  Google Scholar 

  77. Knox, S. M. et al. Parasympathetic stimulation improves epithelial organ regeneration. Nat. Commun. 4, 1494 (2013).

    PubMed  Google Scholar 

  78. Nedvetsky, P. I. et al. Parasympathetic innervation regulates tubulogenesis in the developing salivary gland. Dev. Cell 30, 449–462 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Emmerson, E. et al. SOX2 regulates acinar cell development in the salivary gland. Elife https://doi.org/10.7554/eLife.26620 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  80. De Champlain, J., Malmfors, T., Olson, L. & Sachs, C. Ontogenesis of peripheral adrenergic neurons in the rat: pre- and postnatal observations. Acta Physiol. Scand. 80, 276–288 (1970).

    PubMed  Google Scholar 

  81. Borden, P., Houtz, J., Leach, S. D. & Kuruvilla, R. Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation. Cell Rep. 4, 287–301 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu, Y. et al. Sexually dimorphic BDNF signaling directs sensory innervation of the mammary gland. Science 338, 1357–1360 (2012). This study shows that gland-derived neurotrophins are necessary for nerve recruitment and organogenesis.

    CAS  PubMed  Google Scholar 

  83. Mattingly, A., Finley, J. K. & Knox, S. M. Salivary gland development and disease. Wiley Interdiscip. Rev. Dev. Biol. 4, 573–590 (2015).

    PubMed  Google Scholar 

  84. Levi-Montalcini, R. & Booker, B. Excessive growth of the sympathetic ganglia evoked by a protein isolated from mouse salivary glands. Proc. Natl Acad. Sci. USA 46, 373–384 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Knox, S. M. et al. Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science 329, 1645–1647 (2010). This study shows that parasympathetic nerves pattern gland growth and development.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Bloom, G. D., Carlsoo, B., Danielsson, A., Hellstrom, S. & Henriksson, R. Trophic effect of the sympathetic nervous system on the early development of the rat parotid gland: a quantitative ultrastructural study. Anat. Rec. 201, 645–654 (1981).

    CAS  PubMed  Google Scholar 

  87. Glebova, N. O. & Ginty, D. D. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J. Neurosci. 24, 743–751 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wheeler, E. F. & Bothwell, M. Spatiotemporal patterns of expression of NGF and the low-affinity NGF receptor in rat embryos suggest functional roles in tissue morphogenesis and myogenesis. J. Neurosci. 12, 930–945 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Riccio, A., Pierchala, B. A., Ciarallo, C. L. & Ginty, D. D. An NGF-TrkA-mediated retrograde signal to transcription factor CREB in sympathetic neurons. Science 277, 1097–1100 (1997).

    CAS  PubMed  Google Scholar 

  90. Lehigh, K. M., West, K. M. & Ginty, D. D. Retrogradely transported TrkA endosomes signal locally within dendrites to maintain sympathetic neuron synapses. Cell Rep. 19, 86–100 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Burris, R. E. & Hebrok, M. Pancreatic innervation in mouse development and beta-cell regeneration. Neuroscience 150, 592–602 (2007).

    CAS  PubMed  Google Scholar 

  92. McCredie, J., Cameron, J. & Shoobridge, R. Congenital malformations and the neural crest. Lancet 312, 761–763 (1978).

    Google Scholar 

  93. Cameron, J. & McCredie, J. Innervation of the undifferentiated limb bud in rabbit embryo. J. Anat. 134, 795–808 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Taylor, A. C. Development of the innervation pattern in the limb bud of the frog. Anat. Rec. 87, 379–413 (1943).

    Google Scholar 

  95. Kumar, A., Godwin, J. W., Gates, P. B., Garza-Garcia, A. A. & Brockes, J. P. Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science 318, 772–777 (2007). This study identifies neurotrophins in the regenerating limb mesenchyme that mediate axonogenesis and nerve-regulated limb patterning.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Boilly, B., Faulkner, S., Jobling, P. & Hondermarck, H. Nerve dependence: from regeneration to cancer. Cancer Cell 31, 342–354 (2017).

    CAS  PubMed  Google Scholar 

  97. Properzi, G., Cordeschi, G. & Francavilla, S. Postnatal development and distribution of peptide-containing nerves in the genital system of the male rat. An immunohistochemical study. Histochemistry 97, 61–68 (1992).

    CAS  PubMed  Google Scholar 

  98. James, J. M. & Mukouyama, Y. S. Neuronal action on the developing blood vessel pattern. Semin. Cell Dev. Biol. 22, 1019–1027 (2011).

    PubMed  PubMed Central  Google Scholar 

  99. Rageh, M. A. et al. Vasculature in pre-blastema and nerve-dependent blastema stages of regenerating forelimbs of the adult newt, Notophthalmus viridescens. J. Exp. Zool. 292, 255–266 (2002).

    PubMed  Google Scholar 

  100. Mitogawa, K., Makanae, A. & Satoh, A. Hyperinnervation improves Xenopus laevis limb regeneration. Dev. Biol. 433, 276–286 (2018).

    CAS  PubMed  Google Scholar 

  101. Grassme, K. S. et al. Mechanism of action of secreted newt anterior gradient protein. PLoS One 11, e0154176 (2016).

    PubMed  PubMed Central  Google Scholar 

  102. Miller, T. J., Deptula, P. L., Buncke, G. M. & Maan, Z. N. Digit tip injuries: current treatment and future regenerative paradigms. Stem Cell Int. 2019, 9619080 (2019).

    Google Scholar 

  103. Takeo, M. et al. Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499, 228–232 (2013). This study discovers a potential mechanism for nerve-mediated regeneration in mammals.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang, Y. et al. Activation of beta-catenin signaling programs embryonic epidermis to hair follicle fate. Development 135, 2161–2172 (2008).

    CAS  PubMed  Google Scholar 

  105. Knosp, W. M. et al. Submandibular parasympathetic gangliogenesis requires sprouty-dependent Wnt signals from epithelial progenitors. Dev. Cell 32, 667–677 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lucas, D. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19, 695–703 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Rinkevich, Y. et al. Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration. Proc. Natl Acad. Sci. USA 111, 9846–9851 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ekstrand, A. J. et al. Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc. Natl Acad. Sci. USA 100, 6033–6038 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Martin, P. Wound healing–aiming for perfect skin regeneration. Science 276, 75–81 (1997).

    CAS  PubMed  Google Scholar 

  110. Griffin, N., Faulkner, S., Jobling, P. & Hondermarck, H. Targeting neurotrophin signaling in cancer: The renaissance. Pharmacol. Res. 135, 12–17 (2018).

    CAS  PubMed  Google Scholar 

  111. Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Lei, Y. et al. Gold nanoclusters-assisted delivery of NGF siRNA for effective treatment of pancreatic cancer. Nat. Commun. 8, 15130 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. Saloman, J. L. et al. Systemic depletion of nerve growth factor inhibits disease progression in a genetically engineered model of pancreatic ductal adenocarcinoma. Pancreas 47, 856–863 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Miknyoczki, S. J. et al. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int. J. Cancer 81, 417–427 (1999).

    CAS  PubMed  Google Scholar 

  115. Pundavela, J. et al. ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer. Am. J. Pathol. 184, 3156–3162 (2014).

    CAS  PubMed  Google Scholar 

  116. Weeraratna, A. T., Arnold, J. T., George, D. J., DeMarzo, A. & Isaacs, J. T. Rational basis for Trk inhibition therapy for prostate cancer. Prostate 45, 140–148 (2000).

    CAS  PubMed  Google Scholar 

  117. Pundavela, J. et al. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. Mol. Oncol. 9, 1626–1635 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Allen, J. K. et al. Sustained adrenergic signaling promotes intratumoral innervation through BDNF induction. Cancer Res. 78, 3233–3242 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Francis, F. et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23, 247–256 (1999).

    CAS  PubMed  Google Scholar 

  121. Schaar, B. T., Kinoshita, K. & McConnell, S. K. Doublecortin microtubule affinity is regulated by a balance of kinase and phosphatase activity at the leading edge of migrating neurons. Neuron 41, 203–213 (2004).

    CAS  PubMed  Google Scholar 

  122. Mauffrey, P. et al. Progenitors from the central nervous system drive neurogenesis in cancer. Nature 569, 672–678 (2019).

    CAS  PubMed  Google Scholar 

  123. Ayanlaja, A. A. et al. Distinct features of doublecortin as a marker of neuronal migration and its implications in cancer cell mobility. Front. Mol. Neurosci. 10, 199 (2017).

    PubMed  PubMed Central  Google Scholar 

  124. Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A. & Sood, A. K. Sympathetic nervous system regulation of the tumour microenvironment. Nat. Rev. Cancer 15, 563–572 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fujiwara, T. & Uehara, Y. The cytoarchitecture of the wall and the innervation pattern of the microvessels in the rat mammary gland: a scanning electron microscopic observation. Am. J. Anat. 170, 39–54 (1984).

    CAS  PubMed  Google Scholar 

  126. Kepper, M. & Keast, J. Immunohistochemical properties and spinal connections of pelvic autonomic neurons that innervate the rat prostate-gland. Cell Tissue Res. 281, 533–542 (1995).

    CAS  PubMed  Google Scholar 

  127. Folkman, J., Watson, K., Ingber, D. & Hanahan, D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58–61 (1989).

    CAS  PubMed  Google Scholar 

  128. Eichmann, A. & Brunet, I. Arterial innervation in development and disease. Sci. Transl Med. 6, 252ps259 (2014).

    Google Scholar 

  129. Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

    CAS  PubMed  Google Scholar 

  130. De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013).

    PubMed  Google Scholar 

  131. Schoors, S. et al. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab. 19, 37–48 (2014).

    CAS  PubMed  Google Scholar 

  132. Felten, D. L. & Felten, S. Y. Sympathetic noradrenergic innervation of immune organs. Brain Behav. Immun. 2, 293–300 (1988).

    CAS  PubMed  Google Scholar 

  133. McHale, N. G. & Thornbury, K. D. Sympathetic stimulation causes increased output of lymphocytes from the popliteal node in anaesthetized sheep. Exp. Physiol. 75, 847–850 (1990).

    CAS  PubMed  Google Scholar 

  134. Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011). This study shows that the autonomic nervous system can directly regulate the immune system.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Wang, H. et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    CAS  PubMed  Google Scholar 

  136. Salmon, H., Remark, R., Gnjatic, S. & Merad, M. Host tissue determinants of tumour immunity. Nat. Rev. Cancer 19, 215–227 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Maes, M. et al. The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 10, 313–318 (1998).

    CAS  PubMed  Google Scholar 

  138. Cole, S. W. et al. Computational identification of gene-social environment interaction at the human IL6 locus. Proc. Natl Acad. Sci. USA 107, 5681–5686 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Shahzad, M. M. et al. Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis. J. Biol. Chem. 285, 35462–35470 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Miller, A. M. et al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J. Immunol. 177, 7398–7405 (2006).

    CAS  PubMed  Google Scholar 

  142. Bronte, V. et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 201, 1257–1268 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Nakai, A., Hayano, Y., Furuta, F., Noda, M. & Suzuki, K. Control of lymphocyte egress from lymph nodes through beta2-adrenergic receptors. J. Exp. Med. 211, 2583–2598 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Qiao, G. et al. β-adrenergic signaling blocks murine CD8+ T-cell metabolic reprogramming during activation: a mechanism for immunosuppression by adrenergic stress. Cancer Immunol. Immunother. 68, 11–22 (2019).

    CAS  PubMed  Google Scholar 

  145. Wong, C. H. Y., Jenne, C. N., Lee, W. Y., Leger, C. & Kubes, P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334, 101–105 (2011).

    CAS  PubMed  Google Scholar 

  146. Mohammadpour, H. et al. β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J. Clin. Invest. https://doi.org/10.1172/JCI129502 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Bucsek, M. J. et al. β-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy. Cancer Res. 77, 5639–5651 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    CAS  PubMed  Google Scholar 

  149. Cheng, Y. et al. Depression-induced neuropeptide Y secretion promotes prostate cancer growth by recruiting myeloid cells. Clin. Cancer Res. 25, 2621–2632 (2019).

    PubMed  Google Scholar 

  150. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    CAS  PubMed  Google Scholar 

  151. Hisasue, S. et al. Cavernous nerve reconstruction with a biodegradable conduit graft and collagen sponge in the rat. J. Urol. 173, 286–291 (2005).

    PubMed  Google Scholar 

  152. Twardowski, T., Fertala, A., Orgel, J. & San Antonio, J. Type I. Collagen and collagen mimetics as angiogenesis promoting superpolymers. Curr. Pharm. Des. 13, 3608–3621 (2007).

    CAS  PubMed  Google Scholar 

  153. Tuxhorn, J. A. et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin. Cancer Res. 8, 2912–2923 (2002).

    CAS  PubMed  Google Scholar 

  154. Burns-Cox, N., Avery, N. C., Gingell, J. C. & Bailey, A. J. Changes in collagen metabolism in prostate cancer: a host response that may alter progression. J. Urol. 166, 1698–1701 (2001).

    CAS  PubMed  Google Scholar 

  155. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174 (2002).

    CAS  PubMed  Google Scholar 

  156. Henriksen, J. H., Christensen, N. J. & Ring-Larsen, H. Noradrenaline and adrenaline concentrations in various vascular beds in patients with cirrhosis relation to haemodynamics. Clin. Physiol. 1, 293–304 (1981).

    CAS  PubMed  Google Scholar 

  157. Oben, J. A., Yang, S., Lin, H., Ono, M. & Diehl, A. M. Norepinephrine and neuropeptide Y promote proliferation and collagen gene expression of hepatic myofibroblastic stellate cells. Biochem. Biophys. Res. Commun. 302, 685–690 (2003).

    CAS  PubMed  Google Scholar 

  158. Kim-Fuchs, C. et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 40–47 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Szpunar, M. J., Burke, K. A., Dawes, R. P., Brown, E. B. & Madden, K. S. The antidepressant desipramine and alpha2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev. Res. 6, 1262–1272 (2013).

    CAS  Google Scholar 

  160. Chen, D. & Ayala, G. E. Innervating prostate cancer. N. Engl. J. Med. 378, 675–677 (2018).

    PubMed  Google Scholar 

  161. Lillemoe, K. D. et al. Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann. Surg. 217, 447–455; discussion 456–447 (1993). This randomized placebo-controlled trial shows that denervation increased survival in patients with cancer and elevated sensory nerve activity.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. US National Library of Medicine. ClinicalTrials.gov, http://www.clinicaltrials.gov/ct2/show/NCT01520441 (2015).

  163. Al-Wadei, H. A., Al-Wadei, M. H. & Schuller, H. M. Prevention of pancreatic cancer by the beta-blocker propranolol. Anticancer Drugs 20, 477–482 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Powe, D. G. et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1, 628–638 (2010).

    PubMed  PubMed Central  Google Scholar 

  165. De Giorgi, V. et al. Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch. Intern. Med. 171, 779–781 (2011).

    PubMed  Google Scholar 

  166. Diaz, E. S., Karlan, B. Y. & Li, A. J. Impact of beta blockers on epithelial ovarian cancer survival. Gynecol. Oncol. 127, 375–378 (2012).

    CAS  PubMed  Google Scholar 

  167. Grytli, H. H., Fagerland, M. W., Fossa, S. D., Tasken, K. A. & Haheim, L. L. Use of beta-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 73, 250–260 (2013).

    CAS  PubMed  Google Scholar 

  168. Wang, H. M. et al. Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann. Oncol. 24, 1312–1319 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Neeman, E., Zmora, O. & Ben-Eliyahu, S. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin. Cancer Res. 18, 4895–4902 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Bahnson, R. R., Andriole, G. L., Clayman, R. V. & Catalona, W. J. Catecholamine excess: probable cause of postoperative tachycardia following retroperitoneal lymph node dissection (RPLND) for testicular carcinoma. J. Surg. Oncol. 42, 132–135 (1989).

    CAS  PubMed  Google Scholar 

  171. Halme, A., Pekkarinen, A. & Turunen, M. On the excretion of noradrenaline, adrenaline, 17-hydroxycorticosteroids and 17-ketosteroids during the postoperative stage. Acta Endocrinol. 24, 1–52 (1957).

    CAS  Google Scholar 

  172. Lindenauer, P. K. et al. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N. Engl. J. Med. 353, 349–361 (2005).

    CAS  PubMed  Google Scholar 

  173. Blessberger, H. et al. Perioperative beta-blockers for preventing surgery-related mortality and morbidity. Cochrane Database Syst. Rev. 3, CD004476 (2018).

    PubMed  Google Scholar 

  174. Al-Niaimi, A. et al. The impact of perioperative beta blocker use on patient outcomes after primary cytoreductive surgery in high-grade epithelial ovarian carcinoma. Gynecol. Oncol. 143, 521–525 (2016).

    CAS  PubMed  Google Scholar 

  175. Yap, A. et al. Effect of beta-blockers on cancer recurrence and survival: a meta-analysis of epidemiological and perioperative studies. Br. J. Anaesth. 121, 45–57 (2018).

    CAS  PubMed  Google Scholar 

  176. Musselman, R. P. et al. Association between perioperative beta blocker use and cancer survival following surgical resection. Eur. J. Surg. Oncol. 44, 1164–1169 (2018).

    PubMed  Google Scholar 

  177. Cata, J. P. et al. Perioperative beta-blocker use and survival in lung cancer patients. J. Clin. Anesth. 26, 106–117 (2014).

    CAS  PubMed  Google Scholar 

  178. Horowitz, M., Neeman, E., Sharon, E. & Ben-Eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213–226 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Denk, F., Bennett, D. L. & McMahon, S. B. Nerve Growth Factor and Pain Mechanisms. Annu. Rev. Neurosci. 40, 307–325 (2017).

    CAS  PubMed  Google Scholar 

  180. Smith, M. et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J. Clin. Oncol. 34, 3005–3013 (2016).

    CAS  PubMed  Google Scholar 

  181. Collins, C. et al. Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint. Cancer Biol. Ther. 6, 1360–1367 (2007).

    CAS  PubMed  Google Scholar 

  182. Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Chan, E. et al. A phase I trial of CEP-701 + gemcitabine in patients with advanced adenocarcinoma of the pancreas. Invest. N. Drugs 26, 241–247 (2008).

    CAS  Google Scholar 

  184. Shabbir, M. & Stuart, R. Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside. Expert. Opin. Investig. Drugs 19, 427–436 (2010).

    CAS  PubMed  Google Scholar 

  185. US National Library of Medicine. ClinicalTrials.gov, http://www.clinicaltrials.gov/ct2/show/NCT00830180 (2014).

  186. Sopata, M. et al. Efficacy and safety of tanezumab in the treatment of pain from bone metastases. Pain 156, 1703–1713 (2015).

    CAS  PubMed  Google Scholar 

  187. Barford, K., Keeler, A., Deppmann, C. & Winckler, B. TrkA bumps into its future self. Dev. Cell 42, 557–558 (2017).

    CAS  PubMed  Google Scholar 

  188. Spitzer, N. C. Neurotransmitter Switching? No Surprise. Neuron 86, 1131–1144 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Habecker, B. A. & Landis, S. C. Noradrenergic regulation of cholinergic differentiation. Science 264, 1602–1604 (1994). This study shows that the sympathetic neurotransmitter phenotype is plastic and mediated by the tissue-specific microenvironment.

    CAS  PubMed  Google Scholar 

  190. Yang, B., Slonimsky, J. D. & Birren, S. J. A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor. Nat. Neurosci. 5, 539–545 (2002).

    CAS  PubMed  Google Scholar 

  191. Yamamori, T. et al. The cholinergic neuronal differentiation factor from heart-cells is identical to leukemia inhibitory factor. Science 246, 1412–1416 (1989).

    CAS  PubMed  Google Scholar 

  192. Amit, M., Na’ara, S. & Gil, Z. Mechanisms of cancer dissemination along nerves. Nat. Rev. Cancer 16, 399–408 (2016).

    CAS  PubMed  Google Scholar 

  193. Taylor, H. B. & Norris, H. J. Epithelial invasion of nerves in benign diseases of the breast. Cancer 20, 2245–2249 (1967).

    CAS  PubMed  Google Scholar 

  194. Ali, T. Z. & Epstein, J. I. Perineural involvement by benign prostatic glands on needle biopsy. Am. J. Surg. Pathol. 29, 1159–1163 (2005).

    PubMed  Google Scholar 

  195. Cracchiolo, J. R. et al. Patterns of recurrence in oral tongue cancer with perineural invasion. Head. Neck. 40, 1287–1295 (2018).

    PubMed  PubMed Central  Google Scholar 

  196. Fagan, J. J. et al. Perineural invasion in squamous cell carcinoma of the head and neck. Arch. Otolaryngol. Head Neck Surg. 124, 637–640 (1998).

    CAS  PubMed  Google Scholar 

  197. Al-Hussain, T., Carter, H. B. & Epstein, J. I. Significance of prostate adenocarcinoma perineural invasion on biopsy in patients who are otherwise candidates for active surveillance. J. Urol. 186, 470–473 (2011).

    PubMed  Google Scholar 

  198. Beard, C. J. et al. Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer. Int. J. Radiat. Oncol. Biol. Phys. 58, 19–24 (2004).

    CAS  PubMed  Google Scholar 

  199. Kraus, R. D. et al. The perineural invasion paradox: is perineural invasion an independent prognostic indicator of biochemical recurrence risk in patients with pT2N0R0 prostate cancer? A multi-institutional study. Adv. Radiat. Oncol. 4, 96–102 (2019).

    PubMed  Google Scholar 

  200. Zurborg, S. et al. Generation and characterization of an Advillin-Cre driver mouse line. Mol. Pain. 7, 66 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Lau, J. et al. Temporal control of gene deletion in sensory ganglia using a tamoxifen-inducible Advillin-Cre-ERT2 recombinase mouse. Mol. Pain. 7, 100 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Nassar, M. A. et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl Acad. Sci. USA 101, 12706–12711 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Chen, X. et al. A chemical-genetic approach to studying neurotrophin signaling. Neuron 46, 13–21 (2005).

    PubMed  Google Scholar 

  204. Karai, L. et al. Deletion of vanilloid receptor 1_expressing primary afferent neurons for pain control. J. Clin. Investigation 113, 1344–1352 (2004).

    CAS  Google Scholar 

  205. Erin, N., Boyer, P. J., Bonneau, R. H., Clawson, G. A. & Welch, D. R. Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart. Anticancer. Res. 24, 1003–1009 (2004).

    PubMed  Google Scholar 

  206. Vincenzi, F. F. Effect of botulinum toxin on autonomic nerves in a dually innervated tissue. Nature 213, 394–395 (1967).

    CAS  PubMed  Google Scholar 

  207. Ben-Shaanan, T. L. et al. Modulation of anti-tumor immunity by the brain’s reward system. Nat. Commun. 9, 2723 (2018).

    PubMed  PubMed Central  Google Scholar 

  208. Montgomery, K. L., Iyer, S. M., Christensen, A. J., Deisseroth, K. & Delp, S. L. Beyond the brain: optogenetic control in the spinal cord and peripheral nervous system. Sci. Transl Med. 8, 337rv335 (2016).

    Google Scholar 

  209. Sternson, S. M. & Roth, B. L. Chemogenetic tools to interrogate brain functions. Annu. Rev. Neurosci. 37, 387–407 (2014).

    CAS  PubMed  Google Scholar 

  210. Lin, C. W. et al. Genetically increased cell-intrinsic excitability enhances neuronal integration into adult brain circuits. Neuron 65, 32–39 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank S. Pinho for helpful discussions and advice on the drawing of figures. They are grateful to the National Institutes of Health for support (training grant T32 NS007098 and GM007288) and the National Cancer Institute Ruth L. Kirschstein National Research Service Award predoctoral M.D./Ph.D. fellowship (F30 CA203446) (to A.H.Z.) and R01 grant funding (HL097700, DK056638, HL069438, and U01 DK116312) (to P.S.F.). Their laboratory and institute have been supported the New York State Department of Health (NYSTEM Program, C029154; Prostate Cancer Hypothesis Development Research C030318GG).

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  1. Ali H. Zahalka

    Present address: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

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  1. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY, USA

    Ali H. Zahalka & Paul S. Frenette

  2. Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA

    Ali H. Zahalka & Paul S. Frenette

  3. Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA

    Paul S. Frenette

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A.H.Z. researched the data for the article. A.H.Z. and P.S.F. contributed equally to discussion of the content, writing, and editing the manuscript before submission.

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P.S.F. serves as consultant for Pfizer, has received research funding from Ironwood Pharmaceuticals and is shareholder and member of the scientific advisory board of Cygnal Therapeutics. A.H.Z declares no competing interests.

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Glossary

Innervation

Receiving neural input or synapse from a nerve or cluster of nerves.

Sympathetic nervous system

(SNS). A division of the autonomic nervous system that originates in the thoracic and lumbar portions of the spinal cord and travels to a paravertebral, intra-abdominal or intrapelvic ganglion, where it synapses with a postganglionic nerve that commonly uses noradrenaline as its main neurotransmitter.

Parasympathetic nervous system

(PSNS). A division of the autonomic nervous system that originates in the brainstem and sacral portions of the spinal cord and travels to ganglia located close to the organ that it will innervate, where it synapses with a postganglionic nerve that commonly uses acetylcholine as its main neurotransmitter.

Ganglion

A cluster of nerve cell bodies found in the autonomic and sensory nervous systems.

Sympathectomy

The removal of sympathetic innervation to a target organ by mechanical, chemical, genetic or other means.

Ganglionectomy

A form of denervation in which a cluster of nerve cell bodies known as a ganglion is removed.

Adrenergic nerve

A postganglionic sympathetic nerve that produces the neurotransmitter noradrenaline.

Noradrenaline

Also known as norepinephrine. A neurotransmitter of the catecholamine family often released by sympathetic nerves.

Exocrine

Referring to a family of glands that release their contents onto an epithelial surface (for example, sweat glands, salivary glands and glands of the gastrointestinal and genitourinary tracts).

Pyloroplasty

A surgical procedure to widen the lower part of the stomach to facilitate the emptying of gastric contents into the duodenum.

Botulinum neurotoxin

A neurotoxic protease that cleaves synaptic proteins, preventing acetylcholine release from nerve terminals.

Catecholamine

A monoamine neurotransmitter derived from tyrosine (includes noradrenaline).

Physical restraint stress model

A commonly used laboratory model to induce stress, involving immobilizing an animal in a small space such as a plastic tube.

Adrenergic receptors

G protein-coupled transmembrane receptors for noradrenaline and adrenaline.

Lymphangiogenesis

The formation of new lymphatic vessels from pre-existing lymphatic vessels.

Nicotinic receptors

Ion channel transmembrane receptors that allow cation diffusion on acetylcholine binding.

Muscarinic receptors

G protein-coupled transmembrane receptors for acetylcholine.

Neuropathy

Nerve damage or dysfunction usually resulting from an underlying disease process.

Schwann cells

Cells that ensheath axons of peripheral nerves, helping protect axons and forming the myelin sheath in myelinated axons.

Peptidergic

Pertaining to a neuron that expresses short peptide chain neurotransmitters (neuropeptides).

Acinar bud

An epithelial budding during organogenesis that will later form a functional secretory unit in the mature organ known as an acinus.

Arterioles

Small-diameter branches of an artery in tissue microcirculation that further segment to form capillaries.

Gastrectomy

Surgical removal of part or the entirety of the stomach, often performed to treat cancer.

Electroceuticals

A class of therapeutic agents that target nerve signalling by altering their firing patterns, such as with the use of implantable electrodes.

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Zahalka, A.H., Frenette, P.S. Nerves in cancer. Nat Rev Cancer 20, 143–157 (2020). https://doi.org/10.1038/s41568-019-0237-2

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