Skip to main content

Advertisement

SpringerLink
Log in

Schwann cells: a new player in the tumor microenvironment

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Cancerous cells must cooperate with the surrounding stroma and non-malignant cells within the microenvironment to support the growth and invasion of the tumor. The nervous system is a component of every organ system of the body, and therefore, is invariably at the front line of the tumor invasion. Due to the complexity of the nervous system physiology, this review separately discusses the contributions of the central and peripheral nervous systems to the tumorigenesis and tumor progression. We further focus the discussion on the evidence that Schwann cells aid in tumor growth and invasion. Schwann cells, a largely unexplored element of the tumor microenvironment, may participate in the creation of tumor-favorable conditions through both bi-directional interaction with cancer cells and the facilitation of the immune-suppressive microenvironment through the mechanism of neural repair and immunomodulation.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

BDNF:

Brain-derived neurotrophic factor

CCR1:

C-C chemokine receptor type 1

CNS:

Central nervous system

CXCR4:

C-X-C chemokine receptor type 4

DRG:

Dorsal root ganglia

ERK:

Extracellular signal-regulated kinase

GDNF:

Glial cell-derived neurotrophic factor

HER2:

Human epidermal growth factor receptor 2

IFN-α:

Interferon alpha

IL:

Interleukin

IP-10:

Interferon gamma-induced protein 10

JNK c-Jun:

N-terminal kinase

MAG:

Myelin-associated glycoprotein

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemoattractant protein 1

MDSC:

Myeloid-derived suppressor cell

NCAM:

Neural cell adhesion molecule

NF-κB:

Nuclear factor of kappa light polypeptide gene enhancer in B-cells

NGF:

Nerve growth factor

NRG1:

Neuregulin 1

NTRK1:

Neurotrophic receptor tyrosine kinase type 1

P75NTR:

p75 neurotrophin receptor

PNS:

Peripheral nervous system

SNS:

Sympathetic nervous system

STAT1:

Signal transducer and activator of transcription 1

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor alpha

References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21(3):309–322. doi:10.1016/j.ccr.2012.02.022

    Article  CAS  PubMed  Google Scholar 

  3. Gidron Y, Perry H, Glennie M (2005) Does the vagus nerve inform the brain about preclinical tumours and modulate them? Lancet Oncol 6(4):245–248. doi:10.1016/S1470-2045(05)70096-6

    Article  PubMed  Google Scholar 

  4. Green McDonald P, O’Connell M, Lutgendorf SK (2013) Psychoneuroimmunology and cancer: a decade of discovery, paradigm shifts, and methodological innovations. Brain Behav Immun 30(Suppl):S1–S9. doi:10.1016/j.bbi.2013.01.003

    Article  PubMed  Google Scholar 

  5. Tashiro M, Itoh M, Kubota K, Kumano H, Masud MM, Moser E et al (2001) Relationship between trait anxiety, brain activity and natural killer cell activity in cancer patients: a preliminary PET study. Psychooncology 10(6):541–546

    Article  CAS  PubMed  Google Scholar 

  6. Tashiro M, Kubota K, Itoh M, Nakagawa Y, Kamada M, Takahashi Y et al (2001) Regional cerebral glucose metabolism of patients with malignant diseases in different clinical phases. Med Sci Monit 7(2):226–232

    CAS  PubMed  Google Scholar 

  7. Golan H, Kennedy JA, Frenkel A, Parmet Y, Feintuch A, Levi O et al (2009) Brain mapping of patients with lung cancer and controls: inquiry into tumor-to-brain communication. J Nucl Med 50(7):1072–1075. doi:10.2967/jnumed.108.061085

    Article  PubMed  Google Scholar 

  8. Reiche EM, Nunes SO, Morimoto HK (2004) Stress, depression, the immune system, and cancer. Lancet Oncol 5(10):617–625. doi:10.1016/S1470-2045(04)01597-9

    Article  CAS  PubMed  Google Scholar 

  9. Spiegel D, Giese-Davis J (2003) Depression and cancer: mechanisms and disease progression. Biol Psychiatry 54(3):269–282

    Article  PubMed  Google Scholar 

  10. Palesh O, Butler LD, Koopman C, Giese-Davis J, Carlson R, Spiegel D (2007) Stress history and breast cancer recurrence. J Psychosom Res 63(3):233–239. doi:10.1016/j.jpsychores.2007.05.012

    Article  PubMed  PubMed Central  Google Scholar 

  11. Satin JR, Linden W, Phillips MJ (2009) Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer 115(22):5349–5361. doi:10.1002/cncr.24561

    Article  PubMed  CAS  Google Scholar 

  12. Andersen BL, Farrar WB, Golden-Kreutz D, Emery CF, Glaser R, Crespin T et al (2007) Distress reduction from a psychological intervention contributes to improved health for cancer patients. Brain Behav Immun 21(7):953–961. doi:10.1016/j.bbi.2007.03.005

    Article  PubMed  PubMed Central  Google Scholar 

  13. Coyne JC, Stefanek M, Palmer SC (2007) Psychotherapy and survival in cancer: the conflict between hope and evidence. Psychol Bull 133(3):367–394. doi:10.1037/0033-2909.133.3.367

    Article  PubMed  Google Scholar 

  14. Stefanek ME, Palmer SC, Thombs BD, Coyne JC (2009) Finding what is not there: unwarranted claims of an effect of psychosocial intervention on recurrence and survival. Cancer 115(24):5612–5616. doi:10.1002/cncr.24671

    Article  PubMed  Google Scholar 

  15. Andersen BL, Yang HC, Farrar WB, Golden-Kreutz DM, Emery CF, Thornton LM et al (2008) Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial. Cancer 113(12):3450–3458. doi:10.1002/cncr.23969

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kissane DW, Grabsch B, Clarke DM, Smith GC, Love AW, Bloch S et al (2007) Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial. Psychooncology 16(4):277–286. doi:10.1002/pon.1185

    Article  PubMed  Google Scholar 

  17. Lutgendorf SK, Sood AK, Antoni MH (2010) Host factors and cancer progression: biobehavioral signaling pathways and interventions. J Clin Oncol 28(26):4094–4099. doi:10.1200/JCO.2009.26.9357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87(3):873–904. doi:10.1152/physrev.00041.2006

    Article  PubMed  Google Scholar 

  19. Ebner K, Rupniak NM, Saria A, Singewald N (2004) Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci USA 101(12):4280–4285. doi:10.1073/pnas.0400794101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sephton S, Spiegel D (2003) Circadian disruption in cancer: a neuroendocrine-immune pathway from stress to disease? Brain Behav Immun 17(5):321–328

    Article  CAS  PubMed  Google Scholar 

  21. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D (2000) Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst 92(12):994–1000

    Article  CAS  PubMed  Google Scholar 

  22. Sephton SE, Lush E, Dedert EA, Floyd AR, Rebholz WN, Dhabhar FS et al (2013) Diurnal cortisol rhythm as a predictor of lung cancer survival. Brain Behav Immun 30(Suppl):S163–S170. doi:10.1016/j.bbi.2012.07.019

    Article  CAS  PubMed  Google Scholar 

  23. Schlossmacher G, Stevens A, White A (2011) Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. J Endocrinol 211(1):17–25. doi:10.1530/JOE-11-0135

    Article  CAS  PubMed  Google Scholar 

  24. Abduljabbar R, Negm OH, Lai CF, Jerjees DA, Al-Kaabi M, Hamed MR et al (2015) Clinical and biological significance of glucocorticoid receptor (GR) expression in breast cancer. Breast Cancer Res Treat 150(2):335–346. doi:10.1007/s10549-015-3335-1

    Article  CAS  PubMed  Google Scholar 

  25. Antonova L, Mueller CR (2008) Hydrocortisone down-regulates the tumor suppressor gene BRCA1 in mammary cells: a possible molecular link between stress and breast cancer. Genes Chromosomes Cancer 47(4):341–352. doi:10.1002/gcc.20538

    Article  CAS  PubMed  Google Scholar 

  26. Sephton SE, Dhabhar FS, Keuroghlian AS, Giese-Davis J, McEwen BS, Ionan AC et al (2009) Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer. Brain Behav Immun 23(8):1148–1155. doi:10.1016/j.bbi.2009.07.007

    Article  CAS  PubMed  Google Scholar 

  27. Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK (2015) Sympathetic nervous system regulation of the tumour microenvironment. Nat Rev Cancer 15(9):563–572. doi:10.1038/nrc3978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA et al (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124(2):407–421. doi:10.1016/j.cell.2005.10.041

    Article  CAS  PubMed  Google Scholar 

  29. Lutgendorf SK, DeGeest K, Sung CY, Arevalo JM, Penedo F, Lucci J 3rd et al (2009) Depression, social support, and beta-adrenergic transcription control in human ovarian cancer. Brain Behav Immun 23(2):176–183. doi:10.1016/j.bbi.2008.04.155

    Article  CAS  PubMed  Google Scholar 

  30. Powell ND, Sloan EK, Bailey MT, Arevalo JM, Miller GE, Chen E et al (2013) Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis. Proc Natl Acad Sci USA 110(41):16574–16579. doi:10.1073/pnas.1310655110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hanoun M, Maryanovich M, Arnal-Estape A, Frenette PS (2015) Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86(2):360–373. doi:10.1016/j.neuron.2015.01.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schuller HM (2008) Neurotransmission and cancer: implications for prevention and therapy. Anticancer Drugs 19(7):655–671. doi:10.1097/CAD.0b013e3283025b58

    Article  CAS  PubMed  Google Scholar 

  33. Cole SW, Sood AK (2012) Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res 18(5):1201–1206. doi:10.1158/1078-0432.CCR-11-0641

    Article  CAS  PubMed  Google Scholar 

  34. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ et al (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341(6142):1236361. doi:10.1126/science.1236361

    Article  PubMed  Google Scholar 

  35. Powe DG, Entschladen F (2011) Targeted therapies: using beta-blockers to inhibit breast cancer progression. Nat Rev Clin Oncol 8(9):511–512. doi:10.1038/nrclinonc.2011.123

    Article  PubMed  Google Scholar 

  36. Lamy S, Lachambre MP, Lord-Dufour S, Beliveau R (2010) Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol 53(5–6):200–208. doi:10.1016/j.vph.2010.08.002

    Article  CAS  PubMed  Google Scholar 

  37. Lemeshow S, Sorensen HT, Phillips G, Yang EV, Antonsen S, Riis AH et al (2011) Beta-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomarkers Prev 20(10):2273–2279. doi:10.1158/1055-9965.EPI-11-0249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang D, Ma QY, Hu HT, Zhang M (2010) Beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkappaB and AP-1. Cancer Biol Ther 10(1):19–29

    Article  CAS  PubMed  Google Scholar 

  39. Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, Zaltsman A et al (2014) Chronic variable stress activates hematopoietic stem cells. Nat Med 20(7):754–758. doi:10.1038/nm.3589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI et al (2009) Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun 23(2):267–275. doi:10.1016/j.bbi.2008.10.005

    Article  CAS  PubMed  Google Scholar 

  41. Moretti S, Massi D, Farini V, Baroni G, Parri M, Innocenti S et al (2013) Beta-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab Invest 93(3):279–290. doi:10.1038/labinvest.2012.175

    Article  CAS  PubMed  Google Scholar 

  42. Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB et al (2006) Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res 66(21):10357–10364. doi:10.1158/0008-5472.CAN-06-2496

    Article  CAS  PubMed  Google Scholar 

  43. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C et al (2006) Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12(8):939–944. doi:10.1038/nm1447

    Article  CAS  PubMed  Google Scholar 

  44. Nilsson MB, Armaiz-Pena G, Takahashi R, Lin YG, Trevino J, Li Y et al (2007) Stress hormones regulate interleukin-6 expression by human ovarian carcinoma cells through a Src-dependent mechanism. J Biol Chem 282(41):29919–29926. doi:10.1074/jbc.M611539200

    Article  CAS  PubMed  Google Scholar 

  45. Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V et al (2010) The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70(18):7042–7052. doi:10.1158/0008-5472.CAN-10-0522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Armaiz-Pena GN, Gonzalez-Villasana V, Nagaraja AS, Rodriguez-Aguayo C, Sadaoui NC, Stone RL et al (2015) Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. Oncotarget 6(6):4266–4273. doi:10.18632/oncotarget.2887

    Article  PubMed  Google Scholar 

  47. Armaiz-Pena GN, Allen JK, Cruz A, Stone RL, Nick AM, Lin YG et al (2013) Src activation by beta-adrenoreceptors is a key switch for tumour metastasis. Nat Commun 4:1403. doi:10.1038/ncomms2413

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Shi M, Liu D, Duan H, Qian L, Wang L, Niu L et al (2011) The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat 125(2):351–362. doi:10.1007/s10549-010-0822-2

    Article  CAS  PubMed  Google Scholar 

  49. Hara MR, Kovacs JJ, Whalen EJ, Rajagopal S, Strachan RT, Grant W et al (2011) A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 477(7364):349–353. doi:10.1038/nature10368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wolter JK, Wolter NE, Blanch A, Partridge T, Cheng L, Morgenstern DA et al (2014) Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma. Oncotarget 5(1):161–172. doi:10.18632/oncotarget.1083

    Article  PubMed  Google Scholar 

  51. Peterson SC, Eberl M, Vagnozzi AN, Belkadi A, Veniaminova NA, Verhaegen ME et al (2015) Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell Stem Cell 16(4):400–412. doi:10.1016/j.stem.2015.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Saloman JL, Albers KM, Li D, Hartman DJ, Crawford HC, Muha EA et al (2016) Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc Natl Acad Sci USA 113(11):3078–3083. doi:10.1073/pnas.1512603113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Miller RJ, Jung H, Bhangoo SK, White FA (2009) Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol 194:417–449. doi:10.1007/978-3-540-79090-7_12

    Article  CAS  Google Scholar 

  54. Bhangoo SK, Ren D, Miller RJ, Chan DM, Ripsch MS, Weiss C et al (2007) CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. Brain Behav Immun 21(5):581–591. doi:10.1016/j.bbi.2006.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Leo M, Argalski S, Schäfers M, Hagenacker T (2015) Modulation of voltage-gated sodium channels by activation of tumor necrosis factor receptor-1 and receptor-2 in small DRG neurons of rats. Mediators Inflamm 2015:124942. doi:10.1155/2015/124942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ramesh G, MacLean AG, Philipp MT (2013) Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators Inflamm 2013:480739. doi:10.1155/2013/480739

    PubMed  PubMed Central  Google Scholar 

  57. Nicotra L, Loram LC, Watkins LR, Hutchinson MR (2012) Toll-like receptors in chronic pain. Exp Neurol 234(2):316–329. doi:10.1016/j.expneurol.2011.09.038

    Article  CAS  PubMed  Google Scholar 

  58. Averbeck B, Izydorczyk I, Kress M (2000) Inflammatory mediators release calcitonin gene-related peptide from dorsal root ganglion neurons of the rat. Neuroscience 98(1):135–140

    Article  CAS  PubMed  Google Scholar 

  59. Rosa AC, Fantozzi R (2013) The role of histamine in neurogenic inflammation. Br J Pharmacol 170(1):38–45. doi:10.1111/bph.12266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Khasabova IA, Stucky CL, Harding-Rose C, Eikmeier L, Beitz AJ, Coicou LG et al (2007) Chemical interactions between fibrosarcoma cancer cells and sensory neurons contribute to cancer pain. J Neurosci 27(38):10289–10298. doi:10.1523/JNEUROSCI.2851-07.2007

    Article  CAS  PubMed  Google Scholar 

  61. Selvaraj D, Kuner R (2015) Molecular players of tumor-nerve interactions. Pain 156(1):6–7. doi:10.1016/j.pain.0000000000000010

    Article  PubMed  Google Scholar 

  62. He S, Chen CH, Chernichenko N, He S, Bakst RL, Barajas F et al (2014) GFRalpha1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci USA 111(19):E2008–E2017. doi:10.1073/pnas.1402944111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Stopczynski RE, Normolle DP, Hartman DJ, Ying H, DeBerry JJ, Bielefeldt K et al (2014) Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res 74(6):1718–1727. doi:10.1158/0008-5472.CAN-13-2050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Keskinov AA, Tapias V, Watkins SC, Ma Y, Shurin MR, Shurin GV (2016) Impact of the sensory neurons on melanoma growth in vivo. PLoS ONE 11(5):e0156095. doi:10.1371/journal.pone.0156095

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Ayala GE, Wheeler TM, Shine HD, Schmelz M, Frolov A, Chakraborty S et al (2001) In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. Prostate 49(3):213–223

    Article  CAS  PubMed  Google Scholar 

  66. Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM et al (2008) Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res 14(23):7593–7603. doi:10.1158/1078-0432.CCR-08-1164

    Article  CAS  PubMed  Google Scholar 

  67. Li JH, Ma QY, Shen SG, Hu HT (2008) Stimulation of dorsal root ganglion neurons activity by pancreatic cancer cell lines. Cell Biol Int 32(12):1530–1535. doi:10.1016/j.cellbi.2008.08.022

    Article  CAS  PubMed  Google Scholar 

  68. Albo D, Akay CL, Marshall CL, Wilks JA, Verstovsek G, Liu H et al (2011) Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes. Cancer 117(21):4834–4845. doi:10.1002/cncr.26117

    Article  CAS  PubMed  Google Scholar 

  69. Ceyhan GO, Demir IE, Altintas B, Rauch U, Thiel G, Muller MW et al (2008) Neural invasion in pancreatic cancer: a mutual tropism between neurons and cancer cells. Biochem Biophys Res Commun 374(3):442–447. doi:10.1016/j.bbrc.2008.07.035

    Article  CAS  PubMed  Google Scholar 

  70. Dai H, Li R, Wheeler T, Ozen M, Ittmann M, Anderson M et al (2007) Enhanced survival in perineural invasion of pancreatic cancer: an in vitro approach. Hum Pathol 38(2):299–307. doi:10.1016/j.humpath.2006.08.002

    Article  CAS  PubMed  Google Scholar 

  71. Gil Z, Cavel O, Kelly K, Brader P, Rein A, Gao SP et al (2010) Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst 102(2):107–118. doi:10.1093/jnci/djp456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Seifert P, Benedic M, Effert P (2002) Nerve fibers in tumors of the human urinary bladder. Virchows Arch 440(3):291–297. doi:10.1007/s004280100496

    Article  CAS  PubMed  Google Scholar 

  73. Seifert P, Spitznas M (2002) Axons in human choroidal melanoma suggest the participation of nerves in the control of these tumors. Am J Ophthalmol 133(5):711–713

    Article  PubMed  Google Scholar 

  74. Lu SH, Zhou Y, Que HP, Liu SJ (2003) Peptidergic innervation of human esophageal and cardiac carcinoma. World J Gastroenterol 9(3):399–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mitchell BS, Schumacher U, Stauber VV, Kaiserling E (1994) Are breast tumours innervated? Immunohistological investigations using antibodies against the neuronal marker protein gene product 9.5 (PGP 9.5) in benign and malignant breast lesions. Eur J Cancer 30A(8):1100–1103

    Article  CAS  PubMed  Google Scholar 

  76. Terada T, Matsunaga Y (2001) S-100-positive nerve fibers in hepatocellular carcinoma and intrahepatic cholangiocarcinoma: an immunohistochemical study. Pathol Int 51(2):89–93

    Article  CAS  PubMed  Google Scholar 

  77. Zhou M, Patel A, Rubin MA (2001) Prevalence and location of peripheral nerve found on prostate needle biopsy. Am J Clin Pathol 115(1):39–43. doi:10.1309/2APJ-YKBD-97EH-67GW

    Article  CAS  PubMed  Google Scholar 

  78. Tomita T (2012) Localization of nerve fibers in colonic polyps, adenomas, and adenocarcinomas by immunocytochemical staining for PGP 9.5. Dig Dis Sci 57(2):364–370. doi:10.1007/s10620-011-1876-7

    Article  CAS  PubMed  Google Scholar 

  79. Tanga FY, Nutile-McMenemy N, DeLeo JA (2005) The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 102(16):5856–5861. doi:10.1073/pnas.0501634102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK et al (2007) A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 282(20):14975–14983. doi:10.1074/jbc.M607277200

    Article  CAS  PubMed  Google Scholar 

  81. Lee H, Lee S, Cho IH, Lee SJ (2013) Toll-like receptors: sensor molecules for detecting damage to the nervous system. Curr Protein Pept Sci 14(1):33–42

    Article  CAS  PubMed  Google Scholar 

  82. Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353(6301):777–783. doi:10.1126/science.aag2590

    Article  CAS  PubMed  Google Scholar 

  83. Chiu CC, Liao YE, Yang LY, Wang JY, Tweedie D, Karnati HK et al (2016) Neuroinflammation in animal models of traumatic brain injury. J Neurosci Methods 272:38–49. doi:10.1016/j.jneumeth.2016.06.018

    Article  PubMed  PubMed Central  Google Scholar 

  84. Eyo UB, Murugan M, Wu LJ (2016) Microglia-neuron communication in epilepsy. Glia. doi:10.1002/glia.23006

    PubMed  Google Scholar 

  85. Nakano Y, Kanda T (2015) Pathology of the peripheral nervous system in Guillain–Barre Syndrome. Brain Nerve 67(11):1329–1339. doi:10.11477/mf.1416200303

    PubMed  Google Scholar 

  86. Martini R, Willison H (2016) Neuroinflammation in the peripheral nerve: cause, modulator, or bystander in peripheral neuropathies? Glia 64(4):475–486. doi:10.1002/glia.22899

    Article  PubMed  Google Scholar 

  87. Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A et al (2016) Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533(7604):493–498. doi:10.1038/nature18268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kim SJ, Kim JS, Park ES, Lee JS, Lin Q, Langley RR et al (2011) Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13(3):286–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fidler IJ (2015) The biology of brain metastasis: challenges for therapy. Cancer J 21(4):284–293. doi:10.1097/PPO.0000000000000126

    Article  CAS  PubMed  Google Scholar 

  90. Taveggia C (2016) Schwann cells-axon interaction in myelination. Curr Opin Neurobiol 39:24–29. doi:10.1016/j.conb.2016.03.006

    Article  CAS  PubMed  Google Scholar 

  91. Jessen KR, Mirsky R, Lloyd AC (2015) Schwann cells: development and role in nerve repair. Cold Spring Harb Perspect Biol 7(7):a020487. doi:10.1101/cshperspect.a020487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Woodhoo A, Sommer L (2008) Development of the Schwann cell lineage: from the neural crest to the myelinated nerve. Glia 56(14):1481–1490. doi:10.1002/glia.20723

    Article  PubMed  Google Scholar 

  93. Mika J, Zychowska M, Popiolek-Barczyk K, Rojewska E, Przewlocka B (2013) Importance of glial activation in neuropathic pain. Eur J Pharmacol 716(1–3):106–119. doi:10.1016/j.ejphar.2013.01.072

    Article  CAS  PubMed  Google Scholar 

  94. Demir IE, Tieftrunk E, Schorn S, Saricaoglu OC, Pfitzinger PL, Teller S et al (2016) Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia. Gut 65(6):1001–1014. doi:10.1136/gutjnl-2015-309784

    Article  PubMed  Google Scholar 

  95. Campana WM (2007) Schwann cells: activated peripheral glia and their role in neuropathic pain. Brain Behav Immun 21(5):522–527. doi:10.1016/j.bbi.2006.12.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Brodeur GM (1996) Schwann cells as antineuroblastoma agents. N Engl J Med 334(23):1537–1539. doi:10.1056/NEJM199606063342311

    Article  CAS  PubMed  Google Scholar 

  97. Liu S, Tian Y, Chlenski A, Yang Q, Zage P, Salwen HR et al (2005) Cross-talk between Schwann cells and neuroblasts influences the biology of neuroblastoma xenografts. Am J Pathol 166(3):891–900. doi:10.1016/S0002-9440(10)62309-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Huang D, Rutkowski JL, Brodeur GM, Chou PM, Kwiatkowski JL, Babbo A et al (2000) Schwann cell-conditioned medium inhibits angiogenesis. Cancer Res 60(21):5966–5971

    CAS  PubMed  Google Scholar 

  99. Pajtler KW, Mahlow E, Odersky A, Lindner S, Stephan H, Bendix I et al (2014) Neuroblastoma in dialog with its stroma: NTRK1 is a regulator of cellular cross-talk with Schwann cells. Oncotarget 5(22):11180–11192. doi:10.18632/oncotarget.2611

    Article  PubMed  PubMed Central  Google Scholar 

  100. Newbern J, Birchmeier C (2010) Nrg1/ErbB signaling networks in Schwann cell development and myelination. Semin Cell Dev Biol 21(9):922–928. doi:10.1016/j.semcdb.2010.08.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wilzen A, Krona C, Sveinbjornsson B, Kristiansson E, Dalevi D, Ora I et al (2013) ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours. Mol Cancer 12(1):70. doi:10.1186/1476-4598-12-70

    Article  PubMed  PubMed Central  Google Scholar 

  102. Reschke M, Mihic-Probst D, van der Horst EH, Knyazev P, Wild PJ, Hutterer M et al (2008) HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res 14(16):5188–5197. doi:10.1158/1078-0432.CCR-08-0186

    Article  CAS  PubMed  Google Scholar 

  103. Arranz L, Sanchez-Aguilera A, Martin-Perez D, Isern J, Langa X, Tzankov A et al (2014) Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512(7512):78–81. doi:10.1038/nature13383

    CAS  PubMed  Google Scholar 

  104. Isern J, Garcia-Garcia A, Martin AM, Arranz L, Martin-Perez D, Torroja C et al (2014) The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function. Elife 3:e03696. doi:10.7554/eLife.03696

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Mora J, Cheung NK, Juan G, Illei P, Cheung I, Akram M et al (2001) Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell. Cancer Res 61(18):6892–6898

    CAS  PubMed  Google Scholar 

  106. Bourdeaut F, Ribeiro A, Paris R, Pierron G, Couturier J, Peuchmaur M et al (2008) In neuroblastic tumours, Schwann cells do not harbour the genetic alterations of neuroblasts but may nevertheless share the same clonal origin. Oncogene 27(21):3066–3071. doi:10.1038/sj.onc.1210965

    Article  CAS  PubMed  Google Scholar 

  107. Iyengar B, Singh AV (2010) Patterns of neural differentiation in melanomas. J Biomed Sci 17:87. doi:10.1186/1423-0127-17-87

    Article  PubMed  PubMed Central  Google Scholar 

  108. Banerjee SS, Eyden B (2008) Divergent differentiation in malignant melanomas: a review. Histopathology 52(2):119–129. doi:10.1111/j.1365-2559.2007.02823.x

    CAS  PubMed  Google Scholar 

  109. Van Raamsdonk CD, Deo M (2013) Links between Schwann cells and melanocytes in development and disease. Pigment Cell Melanoma Res 26(5):634–645. doi:10.1111/pcmr.12134

    Article  PubMed  CAS  Google Scholar 

  110. Demir IE, Boldis A, Pfitzinger PL, Teller S, Brunner E, Klose N et al (2014) Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J Natl Cancer Inst. doi:10.1093/jnci/dju184

    PubMed Central  Google Scholar 

  111. Liu H, Li X, Xu Q, Lv S, Li J, Ma Q (1826) Role of glial cell line-derived neurotrophic factor in perineural invasion of pancreatic cancer. Biochim Biophys Acta 1:112–120. doi:10.1016/j.bbcan.2012.03.010

    Google Scholar 

  112. Sroka IC, Chopra H, Das L, Gard JM, Nagle RB, Cress AE (2016) Schwann cells increase prostate and pancreatic tumor cell invasion using laminin binding A6 integrin. J Cell Biochem 117(2):491–499. doi:10.1002/jcb.25300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Deborde S, Omelchenko T, Lyubchik A, Zhou Y, He S, McNamara WF et al (2016) Schwann cells induce cancer cell dispersion and invasion. J Clin Invest 126(4):1538–1554. doi:10.1172/JCI82658

    Article  PubMed  PubMed Central  Google Scholar 

  114. Swanson BJ, McDermott KM, Singh PK, Eggers JP, Crocker PR, Hollingsworth MA (2007) MUC1 is a counter-receptor for myelin-associated glycoprotein (Siglec-4a) and their interaction contributes to adhesion in pancreatic cancer perineural invasion. Cancer Res 67(21):10222–10229. doi:10.1158/0008-5472.CAN-06-2483

    Article  CAS  PubMed  Google Scholar 

  115. Kidd GJ, Ohno N, Trapp BD (2013) Biology of Schwann cells. Handb Clin Neurol 115:55–79. doi:10.1016/B978-0-444-52902-2.00005-9

    Article  PubMed  Google Scholar 

  116. Glenn TD, Talbot WS (2013) Signals regulating myelination in peripheral nerves and the Schwann cell response to injury. Curr Opin Neurobiol 23(6):1041–1048. doi:10.1016/j.conb.2013.06.010

    Article  CAS  PubMed  Google Scholar 

  117. Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 8:110. doi:10.1186/1742-2094-8-110

    Article  PubMed  PubMed Central  Google Scholar 

  118. Sheu JY, Kulhanek DJ, Eckenstein FP (2000) Differential patterns of ERK and STAT3 phosphorylation after sciatic nerve transection in the rat. Exp Neurol 166(2):392–402. doi:10.1006/exnr.2000.7508

    Article  CAS  PubMed  Google Scholar 

  119. Woodhoo A, Alonso MB, Droggiti A, Turmaine M, D’Antonio M, Parkinson DB et al (2009) Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci 12(7):839–847. doi:10.1038/nn.2323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Stassart RM, Fledrich R, Velanac V, Brinkmann BG, Schwab MH, Meijer D et al (2013) A role for Schwann cell-derived neuregulin-1 in remyelination. Nat Neurosci 16(1):48–54. doi:10.1038/nn.3281

    Article  CAS  PubMed  Google Scholar 

  121. Tofaris GK, Patterson PH, Jessen KR, Mirsky R (2002) Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 22(15):6696–6703

    CAS  PubMed  Google Scholar 

  122. Benowitz LI, Popovich PG (2011) Inflammation and axon regeneration. Curr Opin Neurol 24(6):577–583. doi:10.1097/WCO.0b013e32834c208d

    Article  CAS  PubMed  Google Scholar 

  123. Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S, Rosenberg LH et al (2012) A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73(4):729–742. doi:10.1016/j.neuron.2011.11.031

    Article  CAS  PubMed  Google Scholar 

  124. Pesic M, Greten FR (2016) Inflammation and cancer: tissue regeneration gone awry. Curr Opin Cell Biol 43:55–61. doi:10.1016/j.ceb.2016.07.010

    Article  CAS  PubMed  Google Scholar 

  125. Stratton JA, Shah PT, Kumar R, Stykel MG, Shapira Y, Grochmal J et al (2016) The immunomodulatory properties of adult skin-derived precursor Schwann cells: implications for peripheral nerve injury therapy. Eur J Neurosci 43(3):365–375. doi:10.1111/ejn.13006

    Article  PubMed  Google Scholar 

  126. Stratton JA, Shah PT (2016) Macrophage polarization in nerve injury: do Schwann cells play a role? Neural Regen Res 11(1):53–57. doi:10.4103/1673-5374.175042

    Article  PubMed  PubMed Central  Google Scholar 

  127. Komohara Y, Fujiwara Y, Ohnishi K, Takeya M (2016) Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev 99(Pt B):180–185. doi:10.1016/j.addr.2015.11.009

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The research is supported by P50CA121973 NIH Career Development Award to Y.L. Bunimovich.

Author information

Authors and Affiliations

  1. Departments of Dermatology, University of Pittsburgh Medical Center, E1157 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA, 15213, USA

    Yuri L. Bunimovich

  2. Departments of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Anton A. Keskinov, Galina V. Shurin & Michael R. Shurin

  3. Departments of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Michael R. Shurin

Authors
  1. Yuri L. Bunimovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anton A. Keskinov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Galina V. Shurin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael R. Shurin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuri L. Bunimovich.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th–19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bunimovich, Y.L., Keskinov, A.A., Shurin, G.V. et al. Schwann cells: a new player in the tumor microenvironment. Cancer Immunol Immunother 66, 959–968 (2017). https://doi.org/10.1007/s00262-016-1929-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-016-1929-z

Keywords

Search

Navigation