Skip to main content
SpringerLink
Log in

Systemic Interactions Between Cancer and the Nervous System

  • Chapter
  • First Online:
Cancer Neuroscience

  • 454 Accesses

Abstract

Nervous systems were not classically considered to be actively involved in the process of tumorigenesis and cancer metastasis. However, studies over the last decade have demonstrated the presence of neurons and glial cells in the peritumoral regions of many human tumors, and the density of tumor-associated nerves is often correlated with cancer progression and metastatic spread. In general, it has been demonstrated that neuronal activity is widely pro-cancer in the brain, and blocking neural activity usually confers anticancer benefits [1]. For example, increased neuronal excitability has been observed in preclinical models of both pediatric and adult gliomas [2,3,4], and nerve ablation can suppress tumor development in various other malignancies [5]. With the growing global cancer burden, research in the nascent field of cancer neuroscience is quickly becoming intense, attracting interdisciplinary efforts from all over the world. This chapter will focus on the reciprocal cross talk between cancer and the nervous system via direct and indirect pathways. Subsequent influences on host behavior and cancer therapeutic resistance will also be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

Ach:

Acetylcholine

ACTH:

Adrenocorticotropic hormone

AGM:

Axon guidance molecule

β2-AR:

β2-Adrenergic receptor

B2BM:

Breast-to-brain metastases

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

CAF:

Cancer-associated fibroblast

CAM:

Cell adhesion molecule

CNS :

Central nervous system

CRF:

Corticotropin-releasing factor

CRP:

C-reactive protein

DeepISTI:

Deep intravital subcellular time-lapse imaging

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

EV:

Extracellular vesicle

GABA:

Gamma-aminobutyric acid

GPC3:

Glypican 3

HO neuron:

Hypocretin/orexin neuron

HPA:

Hypothalamic-pituitary-adrenal

LC:

Locus coeruleus

MMP:

Matrix metalloproteinase

MNT:

Macrophage to neuron-like cell transition

NCAM1:

Neural cell adhesion molecule 1

NE:

Norepinephrine

NGF:

Nerve growth factor

NGLGN3:

Neuroligin 3

NSC:

Neural stem cell

NSCLC:

Non-small cell lung cancer

PD-1:

Programmed death receptor-1

PDAC:

Pancreatic ductal adenocarcinoma

PNI:

Perineural invasion

PSC:

Pancreatic stellate cell

S1P1:

Sphingosine-1-phosphate receptor 1

SNS :

Sympathetic nervous system

SVZ:

Subventricular zone

TAM:

Tumor-associated macrophage

TCGA:

The Cancer Genome Atlas

TM:

Tumor microtube

TME:

Tumor microenvironment

TNBC:

Triple-negative breast cancer

TNF-α:

Tumor necrosis factor-alpha

TNT:

Tunneling nanotube

TRPA1:

Transient receptor potential ankyrin 1

VEGF:

Vascular endothelial growth factor

VTA:

Ventral tegmental area

xCT:

Cystine-glutamate transporter

References

  1. Monje, M., et al., Roadmap for the Emerging Field of Cancer Neuroscience. Cell, 2020. 181(2): p. 219–222.

    Google Scholar 

  2. Venkatesh, H.S., et al., Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion. Cell, 2015. 161(4): p. 803–16.

    Google Scholar 

  3. Venkatesh, H.S., et al., Electrical and synaptic integration of glioma into neural circuits. Nature, 2019. 573(7775): p. 539–545.

    Google Scholar 

  4. Venkataramani, V., et al., Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature, 2019. 573(7775): p. 532–538.

    Google Scholar 

  5. Magnon, C., Role of the autonomic nervous system in tumorigenesis and metastasis. Mol Cell Oncol, 2015. 2(2): p. e975643.

    Google Scholar 

  6. Loewenstein, W.R. and Y. Kanno, Intercellular communication and the control of tissue growth: lack of communication between cancer cells. Nature, 1966. 209(5029): p. 1248–9.

    Google Scholar 

  7. Mehta, P.P., et al., Incorporation of the gene for a cell-cell channel protein into transformed cells leads to normalization of growth. J Membr Biol, 1991. 124(3): p. 207–25.

    Google Scholar 

  8. Zhu, D., et al., Transfection of C6 glioma cells with connexin 43 cDNA: analysis of expression, intercellular coupling, and cell proliferation. Proc Natl Acad Sci U S A, 1991. 88(5): p. 1883–7.

    Google Scholar 

  9. Temme, A., et al., High incidence of spontaneous and chemically induced liver tumors in mice deficient for connexin32. Curr Biol, 1997. 7(9): p. 713–6.

    Google Scholar 

  10. Hitomi, M., et al., Differential connexin function enhances self-renewal in glioblastoma. Cell Rep, 2015. 11(7): p. 1031–42.

    Google Scholar 

  11. Osswald, M., et al., Brain tumour cells interconnect to a functional and resistant network. Nature, 2015. 528(7580): p. 93–8.

    Google Scholar 

  12. Alonso, F., et al., Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion. Oncotarget, 2016. 7(12): p. 14015–28.

    Google Scholar 

  13. Chen, Q., et al., Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature, 2016. 533(7604): p. 493–498.

    Google Scholar 

  14. Payne, S.L., et al., Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer. EBioMedicine, 2021. 75: p. 103767.

    Google Scholar 

  15. Zeng, Q., et al., Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature, 2019. 573(7775): p. 526–531.

    Google Scholar 

  16. Winkler, F. and W. Wick, Harmful networks in the brain and beyond. Science, 2018. 359(6380): p. 1100–1101.

    Google Scholar 

  17. Latario, C.J., et al., Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner. Molecular Biology of the Cell, 2020. 31(12): p. 1259–1272.

    Google Scholar 

  18. Pan, C. and F. Winkler, Insights and opportunities at the crossroads of cancer and neuroscience. Nature Cell Biology, 2022.

    Google Scholar 

  19. Jiang, S.H., et al., Neurotransmitters: emerging targets in cancer. Oncogene, 2020. 39(3): p. 503–515.

    Google Scholar 

  20. Platel, J.C., et al., NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network. Neuron, 2010. 65(6): p. 859–72.

    Google Scholar 

  21. Paez-Gonzalez, P., et al., Identification of distinct ChAT(+) neurons and activity-dependent control of postnatal SVZ neurogenesis. Nat Neurosci, 2014. 17(7): p. 934–42.

    Google Scholar 

  22. Liu, X., et al., Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors. Nat Neurosci, 2005. 8(9): p. 1179–87.

    Google Scholar 

  23. Zahalka, A.H. and P.S. Frenette, Nerves in cancer. Nat Rev Cancer, 2020. 20(3): p. 143–157.

    Google Scholar 

  24. Shurin, M.R., et al., The Neuroimmune Axis in the Tumor Microenvironment. J Immunol, 2020. 204(2): p. 280–285.

    Google Scholar 

  25. Nagaraja, A.S., et al., Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. Oncogene, 2016. 35(18): p. 2390–7.

    Google Scholar 

  26. Kang, Y., et al., Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer. Clin Cancer Res, 2016. 22(7): p. 1713–24.

    Google Scholar 

  27. Peixoto, R., M.L. Pereira, and M. Oliveira, Beta-Blockers and Cancer: Where Are We? Pharmaceuticals (Basel), 2020. 13(6).

    Google Scholar 

  28. Udumyan, R., et al., Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma. Cancer Research, 2017. 77(13): p. 3700–3707.

    Google Scholar 

  29. Le, C.P., et al., Lymphovascular and neural regulation of metastasis: shared tumour signalling pathways and novel therapeutic approaches. Best Pract Res Clin Anaesthesiol, 2013. 27(4): p. 409–25.

    Google Scholar 

  30. Zhao, C.M., et al., Denervation suppresses gastric tumorigenesis. Sci Transl Med, 2014. 6(250): p. 250ra115.

    Google Scholar 

  31. Hayakawa, Y., et al., Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell, 2017. 31(1): p. 21–34.

    Google Scholar 

  32. Magnon, C., et al., Autonomic nerve development contributes to prostate cancer progression. Science, 2013. 341(6142): p. 1236361.

    Google Scholar 

  33. Renz, B.W., et al., Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. Cancer Discov, 2018. 8(11): p. 1458–1473.

    Google Scholar 

  34. Kamiya, A., et al., Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression. Nat Neurosci, 2019. 22(8): p. 1289–1305.

    Google Scholar 

  35. Fernández-Montoya, J., C. Avendaño, and P. Negredo, The Glutamatergic System in Primary Somatosensory Neurons and Its Involvement in Sensory Input-Dependent Plasticity. International Journal of Molecular Sciences, 2018. 19(1): p. 69.

    Google Scholar 

  36. Li, L. and D. Hanahan, Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell, 2013. 153(1): p. 86–100.

    Google Scholar 

  37. Wu, Y., A. Berisha, and J.C. Borniger, Neuropeptides in Cancer: Friend and Foe? Advanced Biology, 2022. 6(9): p. 2200111.

    Google Scholar 

  38. Tan, F., C.J. Thiele, and Z. Li, Neurotrophin Signaling in Cancer, in Handbook of Neurotoxicity, R.M. Kostrzewa, Editor. 2014, Springer New York: New York, NY. p. 1825–1847.

    Google Scholar 

  39. Griffin, N., et al., Targeting neurotrophin signaling in cancer: The renaissance. Pharmacol Res, 2018. 135: p. 12–17.

    Google Scholar 

  40. Di Donato, M., et al., Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells. Front Cell Dev Biol, 2021. 9: p. 676568.

    Google Scholar 

  41. Forsyth, P.A., et al., p75 neurotrophin receptor cleavage by alpha- and gamma-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells. J Biol Chem, 2014. 289(12): p. 8067–85.

    Google Scholar 

  42. Mirakaj, V. and P. Rosenberger, Immunomodulatory Functions of Neuronal Guidance Proteins. Trends Immunol, 2017. 38(6): p. 444–456.

    Google Scholar 

  43. Chedotal, A., G. Kerjan, and C. Moreau-Fauvarque, The brain within the tumor: new roles for axon guidance molecules in cancers. Cell Death Differ, 2005. 12(8): p. 1044–56.

    Google Scholar 

  44. Biankin, A.V., et al., Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature, 2012. 491(7424): p. 399–405.

    Google Scholar 

  45. Mehlen, P., C. Delloye-Bourgeois, and A. Chedotal, Novel roles for Slits and netrins: axon guidance cues as anticancer targets? Nat Rev Cancer, 2011. 11(3): p. 188–97.

    Google Scholar 

  46. Gohrig, A., et al., Axon guidance factor SLIT2 inhibits neural invasion and metastasis in pancreatic cancer. Cancer Res, 2014. 74(5): p. 1529–40.

    Google Scholar 

  47. Pasquale, E.B., Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer, 2010. 10(3): p. 165-80.

    Google Scholar 

  48. Freemont, A.J. and J.A. Hoyland, Cell adhesion molecules. Clin Mol Pathol, 1996. 49(6): p. M321–30.

    Google Scholar 

  49. Windisch, R., et al., Oncogenic Deregulation of Cell Adhesion Molecules in Leukemia. Cancers (Basel), 2019. 11(3).

    Google Scholar 

  50. Deborde, S., et al., Schwann cells induce cancer cell dispersion and invasion. J Clin Invest, 2016. 126(4): p. 1538–54.

    Google Scholar 

  51. Jahanban-Esfahlan, R., et al., Combination of nanotechnology with vascular targeting agents for effective cancer therapy. J Cell Physiol, 2018. 233(4): p. 2982–2992.

    Google Scholar 

  52. Baghban, R., et al., Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal, 2020. 18(1): p. 59.

    Google Scholar 

  53. Wang, W., et al., Nerves in the Tumor Microenvironment: Origin and Effects. Front Cell Dev Biol, 2020. 8: p. 601738.

    Google Scholar 

  54. Gysler, S.M. and R. Drapkin, Tumor innervation: peripheral nerves take control of the tumor microenvironment. J Clin Invest, 2021. 131(11).

    Google Scholar 

  55. Zahalka, A.H., et al., Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science, 2017. 358(6361): p. 321–326.

    Google Scholar 

  56. Kuol, N., et al., Role of the Nervous System in Tumor Angiogenesis. Cancer Microenviron, 2018. 11(1): p. 1–11.

    Google Scholar 

  57. Wang, H., et al., Role of the nervous system in cancers: a review. Cell Death Discov, 2021. 7(1): p. 76.

    Google Scholar 

  58. Devi, S., et al., Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses. Immunity, 2021. 54(6): p. 1219–1230 e7.

    Google Scholar 

  59. Cole, S.W. and A.K. Sood, Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res, 2012. 18(5): p. 1201–6.

    Google Scholar 

  60. Partecke, L.I., et al., Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade. Pancreatology, 2016. 16(3): p. 423–33.

    Google Scholar 

  61. Sloan, E.K., et al., The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res, 2010. 70(18): p. 7042–52.

    Google Scholar 

  62. Reijmen, E., et al., Therapeutic potential of the vagus nerve in cancer. Immunology Letters, 2018. 202: p. 38–43.

    Google Scholar 

  63. Zhu, P., et al., Alpha5 nicotinic acetylcholine receptor mediated immune escape of lung adenocarcinoma via STAT3/Jab1-PD-L1 signalling. Cell Commun Signal, 2022. 20(1): p. 121.

    Google Scholar 

  64. Gonzalez, H., C. Hagerling, and Z. Werb, Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev, 2018. 32(19–20): p. 1267–1284.

    Google Scholar 

  65. Biffi, G. and D.A. Tuveson, Deciphering cancer fibroblasts. J Exp Med, 2018. 215(12): p. 2967–2968.

    Google Scholar 

  66. Secq, V., et al., Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling. Cell Death Dis, 2015. 6: p. e1592.

    Google Scholar 

  67. Karakasheva, T.A., et al., IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment. Cancer Research, 2018. 78(17): p. 4957–4970.

    Google Scholar 

  68. Rothaug, M., C. Becker-Pauly, and S. Rose-John, The role of interleukin-6 signaling in nervous tissue. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 2016. 1863(6, Part A): p. 1218–1227.

    Google Scholar 

  69. Qing, H., et al., Origin and Function of Stress-Induced IL-6 in Murine Models. Cell, 2020. 182(2): p. 372–387.e14.

    Google Scholar 

  70. Tokumaru, Y., et al., Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation. Int J Mol Sci, 2020. 21(16).

    Google Scholar 

  71. Santos, G.S.P., et al., Sympathetic nerve-adipocyte interactions in response to acute stress. Journal of Molecular Medicine, 2022. 100(2): p. 151–165.

    Google Scholar 

  72. Thomas, D. and P. Radhakrishnan, Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol Cancer, 2019. 18(1): p. 14.

    Google Scholar 

  73. Tomaselli, K.J., L.F. Reichardt, and J.L. Bixby, Distinct molecular interactions mediate neuronal process outgrowth on non-neuronal cell surfaces and extracellular matrices. J Cell Biol, 1986. 103(6 Pt 2): p. 2659–72.

    Google Scholar 

  74. Najafi, M.F., et al., Which form of collagen is suitable for nerve cell culture? Neural Regeneration Research, 2013. 8(23): p. 2165–2170.

    Google Scholar 

  75. Reinhard, J., et al., The extracellular matrix niche microenvironment of neural and cancer stem cells in the brain. The International Journal of Biochemistry & Cell Biology, 2016. 81: p. 174–183.

    Google Scholar 

  76. Sood, D., et al., 3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors. Nat Commun, 2019. 10(1): p. 4529.

    Google Scholar 

  77. Norouzi, M., Recent advances in brain tumor therapy: application of electrospun nanofibers. Drug Discov Today, 2018. 23(4): p. 912–919.

    Google Scholar 

  78. Granato, A.E.C., et al., A novel decellularization method to produce brain scaffolds. Tissue Cell, 2020. 67: p. 101412.

    Google Scholar 

  79. Simsa, R., et al., Brain organoid formation on decellularized porcine brain ECM hydrogels. PLoS One, 2021. 16(1): p. e0245685.

    Google Scholar 

  80. Chen, S.H., et al., Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche. Am J Cancer Res, 2019. 9(1): p. 1–21.

    Google Scholar 

  81. Entschladen, F., et al., Neoneurogenesis: Tumors may initiate their own innervation by the release of neurotrophic factors in analogy to lymphangiogenesis and neoangiogenesis. Medical Hypotheses, 2006. 67(1): p. 33–35.

    Google Scholar 

  82. Mauffrey, P., et al., Progenitors from the central nervous system drive neurogenesis in cancer. Nature, 2019. 569(7758): p. 672–678.

    Google Scholar 

  83. Dobrenis, K., et al., Granulocyte colony-stimulating factor off-target effect on nerve outgrowth promotes prostate cancer development. Int J Cancer, 2015. 136(4): p. 982–8.

    Google Scholar 

  84. Liebig, C., et al., Perineural invasion in cancer: a review of the literature. Cancer, 2009. 115(15): p. 3379–91.

    Google Scholar 

  85. Bapat, A.A., et al., Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer, 2011. 11(10): p. 695–707.

    Google Scholar 

  86. Arese, M., et al., Tumor progression: the neuronal input. Ann Transl Med, 2018. 6(5): p. 89.

    Google Scholar 

  87. Amit, M., S. Na’ara, and Z. Gil, Mechanisms of cancer dissemination along nerves. Nat Rev Cancer, 2016. 16(6): p. 399–408.

    Google Scholar 

  88. Zhang, Y., et al., Pim-1 kinase as activator of the cell cycle pathway in neuronal death induced by DNA damage. Journal of Neurochemistry, 2010. 112(2): p. 497–510.

    Google Scholar 

  89. Gasparini, G., et al., Nerves and Pancreatic Cancer: New Insights into A Dangerous Relationship. Cancers, 2019. 11(7): p. 893.

    Google Scholar 

  90. Demir, I.E., et al., Perineural Mast Cells Are Specifically Enriched in Pancreatic Neuritis and Neuropathic Pain in Pancreatic Cancer and Chronic Pancreatitis. Plos One, 2013. 8(3).

    Google Scholar 

  91. Cavel, O., et al., Endoneurial Macrophages Induce Perineural Invasion of Pancreatic Cancer Cells by Secretion of GDNF and Activation of RET Tyrosine Kinase Receptor. Cancer Research, 2012. 72(22): p. 5733–5743.

    Google Scholar 

  92. Shan, C., et al., Schwann cells promote EMT and the Schwann-like differentiation of salivary adenoid cystic carcinoma cells via the BDNF/TrkB axis. Oncol Rep, 2016. 35(1): p. 427–435.

    Google Scholar 

  93. Xiang, T., X. Xia, and W. Yan, Expression of Matrix Metalloproteinases-2/-9 is Associated With Microvessel Density in Pancreatic Cancer. American Journal of Therapeutics, 2017. 24(4): p. e431–e434.

    Google Scholar 

  94. Klupp, F., et al., Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients. BMC Cancer, 2016. 16(1): p. 494.

    Google Scholar 

  95. Liu, Y., W. Zhou, and D.-W. Zhong, Meta-analyses of the associations between four common TGF-β1 genetic polymorphisms and risk of colorectal tumor. Tumor Biology, 2012. 33(4): p. 1191–1199.

    Google Scholar 

  96. Huberfeld, G. and C.J. Vecht, Seizures and gliomas — towards a single therapeutic approach. Nature Reviews Neurology, 2016. 12(4): p. 204–216.

    Google Scholar 

  97. Yu, K., et al., PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature, 2020. 578(7793): p. 166–171.

    Google Scholar 

  98. Amit, M., et al., Loss of p53 drives neuron reprogramming in head and neck cancer. Nature, 2020. 578(7795): p. 449–454.

    Google Scholar 

  99. Tang, P.C.-T., et al., Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain. Science Advances, 2022. 8(40): p. eabn5535.

    Google Scholar 

  100. Davidson, J.R., et al., Sleep disturbance in cancer patients. Soc Sci Med, 2002. 54(9): p. 1309–21.

    Google Scholar 

  101. Berisha, A., K. Shutkind, and J.C. Borniger, Sleep Disruption and Cancer: Chicken or the Egg? Front Neurosci, 2022. 16: p. 856235.

    Google Scholar 

  102. Walker, W.H., 2nd and J.C. Borniger, Molecular Mechanisms of Cancer-Induced Sleep Disruption. Int J Mol Sci, 2019. 20(11).

    Google Scholar 

  103. Kubota, T., et al., Tumor necrosis factor receptor fragment attenuates interferon-gamma-induced non-REM sleep in rabbits. J Neuroimmunol, 2001. 119(2): p. 192–8.

    Google Scholar 

  104. Greenberg, D.B., et al., Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer. J Pain Symptom Manage, 1993. 8(4): p. 196–200.

    Google Scholar 

  105. Spath-Schwalbe, E., et al., Interferon-alpha acutely impairs sleep in healthy humans. Cytokine, 2000. 12(5): p. 518–21.

    Google Scholar 

  106. Imeri, L. and M.R. Opp, How (and why) the immune system makes us sleep. Nature Reviews Neuroscience, 2009. 10(3): p. 199–210.

    Google Scholar 

  107. Alam, M.N., et al., Interleukin-1beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation. Eur J Neurosci, 2004. 20(1): p. 207–16.

    Google Scholar 

  108. Manfridi, A., et al., Interleukin-1beta enhances non-rapid eye movement sleep when microinjected into the dorsal raphe nucleus and inhibits serotonergic neurons in vitro. Eur J Neurosci, 2003. 18(5): p. 1041–9.

    Google Scholar 

  109. Brambilla, D., et al., Interleukin-1 inhibits firing of serotonergic neurons in the dorsal raphe nucleus and enhances GABAergic inhibitory post-synaptic potentials. Eur J Neurosci, 2007. 26(7): p. 1862–9.

    Google Scholar 

  110. Francis, N. and J.C. Borniger, Cancer as a homeostatic challenge: the role of the hypothalamus. Trends Neurosci, 2021. 44(11): p. 903–914.

    Google Scholar 

  111. Alexandre, C., et al., Decreased alertness due to sleep loss increases pain sensitivity in mice. Nat Med, 2017. 23(6): p. 768–774.

    Google Scholar 

  112. Au, C.C., J.B. Furness, and K.A. Brown, Ghrelin and Breast Cancer: Emerging Roles in Obesity, Estrogen Regulation, and Cancer. Front Oncol, 2016. 6: p. 265.

    Google Scholar 

  113. Garofalo, C. and E. Surmacz, Leptin and cancer. J Cell Physiol, 2006. 207(1): p. 12–22.

    Google Scholar 

  114. Borniger, J.C., et al., A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non-metastatic Breast Cancer. Cell Metab, 2018. 28(1): p. 118–129 e5.

    Google Scholar 

  115. Yehuda, S., et al., REM sleep deprivation in rats results in inflammation and interleukin-17 elevation. J Interferon Cytokine Res, 2009. 29(7): p. 393–8.

    Google Scholar 

  116. Karin, M. and F.R. Greten, NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol, 2005. 5(10): p. 749–59.

    Google Scholar 

  117. De Lorenzo, B.H.P., et al., Chronic Sleep Restriction Impairs the Antitumor Immune Response in Mice. Neuroimmunomodulation, 2018. 25(2): p. 59–67.

    Google Scholar 

  118. Huang, J., et al., Sleep Deprivation Disturbs Immune Surveillance and Promotes the Progression of Hepatocellular Carcinoma. Front Immunol, 2021. 12: p. 727959.

    Google Scholar 

  119. Li, S.-B., et al., Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression. Science Advances, 2020. 6(37): p. eabc2590.

    Google Scholar 

  120. He, J., et al., Sleep restriction impairs blood-brain barrier function. J Neurosci, 2014. 34(44): p. 14697–706.

    Google Scholar 

  121. Medina-Flores, F., et al., Sleep loss disrupts pericyte-brain endothelial cell interactions impairing blood-brain barrier function. Brain Behav Immun, 2020. 89: p. 118–132.

    Google Scholar 

  122. Bellesi, M., et al., Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex. J Neurosci, 2017. 37(21): p. 5263–5273.

    Google Scholar 

  123. Dlamini, Z., et al., Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination. Cancers (Basel), 2021. 13(9).

    Google Scholar 

  124. Reiche, E.M., S.O. Nunes, and H.K. Morimoto, Stress, depression, the immune system, and cancer. Lancet Oncol, 2004. 5(10): p. 617–25.

    Google Scholar 

  125. Powell, N.D., A.J. Tarr, and J.F. Sheridan, Psychosocial stress and inflammation in cancer. Brain Behav Immun, 2013. 30 Suppl: p. S41–7.

    Google Scholar 

  126. Miller, A.H., V. Maletic, and C.L. Raison, Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry, 2009. 65(9): p. 732–41.

    Google Scholar 

  127. Dai, S., et al., Chronic Stress Promotes Cancer Development. Front Oncol, 2020. 10: p. 1492.

    Google Scholar 

  128. Smith, S.M. and W.W. Vale, The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci, 2006. 8(4): p. 383–95.

    Google Scholar 

  129. Renz, B.W., et al., beta2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell, 2018. 34(5): p. 863–867.

    Google Scholar 

  130. Lutgendorf, S.K., et al., Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun, 2011. 25(2): p. 250–5.

    Google Scholar 

  131. Thaker, P.H., et al., Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med, 2006. 12(8): p. 939–44.

    Google Scholar 

  132. Janelsins, M.C., et al., Prevalence, mechanisms, and management of cancer-related cognitive impairment. Int Rev Psychiatry, 2014. 26(1): p. 102–13.

    Google Scholar 

  133. Pendergrass, J.C., S.D. Targum, and J.E. Harrison, Cognitive Impairment Associated with Cancer: A Brief Review. Innov Clin Neurosci, 2018. 15(1–2): p. 36–44.

    Google Scholar 

  134. Olson, B. and D.L. Marks, Pretreatment Cancer-Related Cognitive Impairment-Mechanisms and Outlook. Cancers (Basel), 2019. 11(5).

    Google Scholar 

  135. Mampay, M., M.S. Flint, and G.K. Sheridan, Tumour brain: Pretreatment cognitive and affective disorders caused by peripheral cancers. Br J Pharmacol, 2021. 178(19): p. 3977–3996.

    Google Scholar 

  136. Kim, J., et al., Tumor-induced disruption of the blood-brain barrier promotes host death. Dev Cell, 2021. 56(19): p. 2712–2721 e4.

    Google Scholar 

  137. Kadry, H., B. Noorani, and L. Cucullo, A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS, 2020. 17(1): p. 69.

    Google Scholar 

  138. Morad, G., et al., Tumor-Derived Extracellular Vesicles Breach the Intact Blood-Brain Barrier via Transcytosis. ACS Nano, 2019. 13(12): p. 13853–13865.

    Google Scholar 

  139. Morad, G., et al., Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood-Brain Barrier. Int J Mol Sci, 2020. 21(11).

    Google Scholar 

  140. Eng, J.W., et al., Housing temperature-induced stress drives therapeutic resistance in murine tumour models through beta2-adrenergic receptor activation. Nat Commun, 2015. 6: p. 6426.

    Google Scholar 

  141. Chen, H., et al., beta2-AR activation induces chemoresistance by modulating p53 acetylation through upregulating Sirt1 in cervical cancer cells. Cancer Sci, 2017. 108(7): p. 1310–1317.

    Google Scholar 

  142. Takahashi, N., et al., Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance. Cancer Cell, 2018. 33(6): p. 985–1003 e7.

    Google Scholar 

  143. Feng, Z., et al., Chronic restraint stress attenuates p53 function and promotes tumorigenesis. Proc Natl Acad Sci U S A, 2012. 109(18): p. 7013–8.

    Google Scholar 

  144. Liu, D., et al., Neural regulation of drug resistance in cancer treatment. Biochim Biophys Acta Rev Cancer, 2019. 1871(1): p. 20–28.

    Google Scholar 

  145. Gridelli, C., et al., Erlotinib in the treatment of non-small cell lung cancer: current status and future developments. Anticancer Res, 2010. 30(4): p. 1301–10.

    Google Scholar 

  146. Nilsson, M.B., et al., Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with beta-blockers. Sci Transl Med, 2017. 9(415).

    Google Scholar 

  147. Renz, B.W., et al., beta2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell, 2018. 33(1): p. 75–90 e7.

    Google Scholar 

  148. Chakravarthy, R., K. Mnich, and A.M. Gorman, Nerve growth factor (NGF)-mediated regulation of p75(NTR) expression contributes to chemotherapeutic resistance in triple negative breast cancer cells. Biochem Biophys Res Commun, 2016. 478(4): p. 1541–7.

    Google Scholar 

  149. Jaboin, J., et al., Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3’-kinase pathway. Cancer Res, 2002. 62(22): p. 6756–63.

    Google Scholar 

  150. Li, Z., et al., Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death. Cell Death Differ, 2007. 14(2): p. 318–26.

    Google Scholar 

  151. Demir, I.E., et al., Nerve growth factor & TrkA as novel therapeutic targets in cancer. Biochim Biophys Acta, 2016. 1866(1): p. 37–50.

    Google Scholar 

  152. O’Donnell, J.S., et al., Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev, 2017. 52: p. 71–81.

    Google Scholar 

  153. Xia, A., et al., T Cell Dysfunction in Cancer Immunity and Immunotherapy. Front Immunol, 2019. 10: p. 1719.

    Google Scholar 

  154. Barrueto, L., et al., Resistance to Checkpoint Inhibition in Cancer Immunotherapy. Transl Oncol, 2020. 13(3): p. 100738.

    Google Scholar 

  155. Zhou, L., et al., Propranolol Attenuates Surgical Stress-Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy. J Immunol, 2016. 196(8): p. 3460–9.

    Google Scholar 

  156. Chongsathidkiet, P., et al., Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med, 2018. 24(9): p. 1459–1468.

    Google Scholar 

  157. Zappasodi, R., T. Merghoub, and J.D. Wolchok, Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies. Cancer Cell, 2018. 34(4): p. 690.

    Google Scholar 

  158. Robert, C., A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun, 2020. 11(1): p. 3801.

    Google Scholar 

  159. Bucsek, M.J., et al., beta-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8(+) T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Research, 2017. 77(20): p. 5639–5651.

    Google Scholar 

  160. Cohen, P.S., et al., Neuropeptide-Y expression in the developing adrenal-gland and in childhood neuroblastoma tumors. Cancer Research, 1990. 50(18): p. 6055–6061.

    Google Scholar 

  161. Servick, K., War of nerves. Science, 2019. 365(6458): p. 1071–1073.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Yue Wu & Jeremy C. Borniger

Authors
  1. Yue Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremy C. Borniger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy C. Borniger .

Editor information

Editors and Affiliations

  1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Moran Amit

  2. Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Nicole N. Scheff

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wu, Y., Borniger, J.C. (2023). Systemic Interactions Between Cancer and the Nervous System. In: Amit, M., Scheff, N.N. (eds) Cancer Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-031-32429-1_10

Download citation

Publish with us

Policies and ethics

Search

Navigation