Schwann cells shape the neuro-immune environs and control cancer progression

Abstract

At present, significant experimental and clinical data confirm the active involvement of the peripheral nervous system (PNS) in different phases of cancer development and progression. Most of the research effort focuses on the impact of distinct neuronal types, e.g., adrenergic, cholinergic, dopaminergic, etc. in carcinogenesis, generally ignoring neuroglia. The very fact that these cells far outnumber the other cellular types may also play an important role worthy of study in this context. The most prevalent neuroglia within the PNS consists of Schwann cells (SCs). These cells play a substantial role in maintaining homeostasis within the nervous system. They possess distinct immunomodulatory, inflammatory and regenerative capacities—also, one should consider their broad distribution throughout the body; this makes them a perfect target for malignant cells during the initial stages of cancer development and the very formation of the tumor microenvironment itself. We show that SCs in the tumor milieu attract different subsets of immune regulators and augment their ability to suppress effector T cells. SCs may also up-regulate invasiveness of tumor cells and support metastatic disease. We outline the interactive potential of SCs juxtaposed with cancerous cells, referring to data from various external sources alongside data of our own.

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Abbreviations

CNS:

Central nervous system

DFTD:

Devil facial tumor disease

DRG:

Dorsal root ganglion

EMT:

Epithelial–mesenchymal transition

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HMGB1:

High-mobility group box 1

MAG:

Myelin-associated glycoprotein

MDSC:

Myeloid-derived suppressor cell(s)

MET:

Mesenchymal–epithelial transition

NB:

Neuroblastoma

Nrg:

Neuregulin

PGP 9.5:

Protein gene product 9.5

PNI:

Perineural invasion

PNS:

Peripheral nervous system

SC:

Schwann cell(s)

SDF-1α:

Stromal cell-derived factor 1 (CXCL12)

SPARC:

Secreted protein acidic and rich in cysteine

TµE:

Tumor microenvironment

References

  1. 1.

    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30

    Google Scholar 

  2. 2.

    Shurin MR (2012) Cancer as an immune-mediated disease. Immunotargets Ther 1:1–6

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Witz IP (2009) The tumor microenvironment: the making of a paradigm. Cancer Microenviron 2(Suppl 1):9–17

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125(Pt 23):5591–5596

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    McDonald PG, Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, Stefanek M, Sood AK (2005) A biobehavioral perspective of tumor biology. Discov Med 5(30):520–526

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bruni JE, Montemurro DG (1971) Effect of hypothalamic lesions on the genesis of spontaneous mammary gland tumors in the mouse. Cancer Res 31(6):854–863

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Thaker PH, Lutgendorf SK, Sood AK (2007) The neuroendocrine impact of chronic stress on cancer. Cell Cycle 6(4):430–433

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Suhail N, Bilal N, Hasan S, Ahmad A, Ashraf GM, Banu N (2015) Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12-dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice. Cell Stress Chaperones 20(6):1023–1036

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, Stefanek M, Sood AK (2006) The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6(3):240–248

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Glaser R, Kiecolt-Glaser JK (2005) Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5(3):243–251

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Cole SW, Sood AK (2012) Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res 18(5):1201–1206

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Hara MR, Kovacs JJ, Whalen EJ, Rajagopal S, Strachan RT, Grant W, Towers AJ, Williams B, Lam CM, Xiao K, Shenoy SK, Gregory SG, Ahn S, Duckett DR, Lefkowitz RJ (2011) A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 477(7364):349–353

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Catala M, Kubis N (2013) Gross anatomy and development of the peripheral nervous system. Handb Clin Neurol 115:29–41

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Krizanova O, Babula P, Pacak K (2016) Stress, catecholaminergic system and cancer. Stress 19(4):419–428

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Dang N, Meng X, Song H (2016) Nicotinic acetylcholine receptors and cancer. Biomed Rep 4(5):515–518

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Nie H, Cao Q, Zhu L, Gong Y, Gu J, He Z (2013) Acetylcholine acts on androgen receptor to promote the migration and invasion but inhibit the apoptosis of human hepatocarcinoma. PLoS One 8(4):e61678

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341(6142):1236361

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    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

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, Shine D, Kadmon D, Thompson T, Miles BJ, Ittmann MM, Rowley D (2008) Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res 14(23):7593–7603

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Albo D, Akay CL, Marshall CL, Wilks JA, Verstovsek G, Liu H, Agarwal N, Berger DH, Ayala GE (2011) Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes. Cancer 117(21):4834–4845

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    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

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    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

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Campbell LK, Thomas JR, Lamps LW, Smoller BR, Folpe AL (2003) Protein gene product 9.5 (PGP 9.5) is not a specific marker of neural and nerve sheath tumors: an immunohistochemical study of 95 mesenchymal neoplasms. Mod Pathol 16(10):963–969

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Jessen KR, Mirsky R (2005) The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci 6(9):671–682

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Kidd GJ, Ohno N, Trapp BD (2013) Biology of Schwann cells. Handb Clin Neurol 11555–11579

  27. 27.

    Armati PJ, Mathey EK (2013) An update on Schwann cell biology–immunomodulation, neural regulation and other surprises. J Neurol Sci 333(1–2):68–72

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Vargas ME, Barres BA (2007) Why is Wallerian degeneration in the CNS so slow? Annu Rev Neurosci 30:153–179

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Jang SY, Shin YK, Park SY, Park JY, Lee HJ, Yoo YH, Kim JK, Park HT (2016) Autophagic myelin destruction by Schwann cells during Wallerian degeneration and segmental demyelination. Glia 64(5):730–742

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Chen P, Piao X, Bonaldo P (2015) Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. Acta Neuropathol 130(5):605–618

    CAS  Google Scholar 

  31. 31.

    Xiao Y, Faucherre A, Pola-Morell L, Heddleston JM, Liu TL, Chew TL, Sato F, Sehara-Fujisawa A, Kawakami K, Lopez-Schier H (2015) High-resolution live imaging reveals axon-glia interactions during peripheral nerve injury and repair in zebrafish. Dis Model Mech 8(6):553–564

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Jessen KR, Mirsky R (2008) Negative regulation of myelination: relevance for development, injury, and demyelinating disease. GLIA 56(14):1552–1565

    Google Scholar 

  33. 33.

    Jessen KR, Mirsky R (2016) The repair Schwann cell and its function in regenerating nerves. J Physiol 594(13):3521–3531

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Shamash S, Reichert F, Rotshenker S (2002) The cytokine network of wallerian degeneration: tumor necrosis factor-α, interleukin-1α, and interleukin-1β. J Neurosci 22(8):3052–3060

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Perrin FE, Lacroix S, Avilés-Trieueros M, David S (2005) Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1α and interleukin-1β Wallerian degeneration. Brain 128(4):854–866

    Google Scholar 

  36. 36.

    Conti G, De Pol A, Scarpini E, Vaccina F, De Riz M, Baron P, Tiriticco M, Scarlato G (2002) Interleukin-1beta and interferon-gamma induce proliferation and apoptosis in cultured Schwann cells. J Neuroimmunol 124(1–2):29–35

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Napoli I, Noon L, Ribeiro S, Kerai A, Parrinello S, Rosenberg L, Collins M, Harrisingh M, White I, Woodhoo A, Lloyd A (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

    CAS  Google Scholar 

  38. 38.

    Ide C (1996) Peripheral nerve regeneration. Neurosci Res 25(2):101–121

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    DeFrancesco-Lisowitz A, Lindborg JA, Niemi JP, Zigmond RE (2015) The neuroimmunology of degeneration and regeneration in the peripheral nervous system. Neuroscience 302:174–203

    CAS  Google Scholar 

  40. 40.

    Reichert F, Levitzky R, Rotshenker S (1996) Interleukin 6 in intact and injured mouse peripheral nerves. Eur J Neurosci 8(3):530–535

    CAS  Google Scholar 

  41. 41.

    Thoma EC, Merkl C, Heckel T, Haab R, Knoflach F, Nowaczyk C, Flint N, Jagasia R, Jensen Zoffmann S, Truong HH, Petitjean P, Jessberger S, Graf M, Iacone R (2014) Chemical conversion of human fibroblasts into functional Schwann cells. Stem Cell Reports 3(4):539–547

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Chlenski A, Liu S, Crawford SE, Volpert OV, DeVries GH, Evangelista A, Yang Q, Salwen HR, Farrer R, Bray J, Cohn SL (2002) SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. Cancer Res 62(24):7357–7363

    CAS  Google Scholar 

  43. 43.

    Crawford SE, Stellmach V, Ranalli M, Huang X, Huang L, Volpert O, De Vries GH, Abramson LP, Bouck N (2001) Pigment epithelium-derived factor (PEDF) in neuroblastoma: a multifunctional mediator of Schwann cell antitumor activity. J Cell Sci 114(Pt 24):4421–4428

    CAS  Google Scholar 

  44. 44.

    Reynolds ML, Woolf CJ (1993) Reciprocal Schwann cell-axon interactions. Curr Opin Neurobiol 3(5):683–693

    CAS  Google Scholar 

  45. 45.

    Ambros IM, Ambros PF (1995) Schwann cells in neuroblastoma. Eur J Cancer 31(4):429–434

    Google Scholar 

  46. 46.

    Parfejevs V, Debbache J, Shakhova O, Schaefer SM, Glausch M, Wegner M, Suter U, Riekstina U, Werner S, Sommer L (2018) Injury-activated glial cells promote wound healing of the adult skin in mice. Nat Commun 9(1):236

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Clements MP, Byrne E, Guerrero LF, Cattin AL, Zakka L, Ashraf A, Burden JJ, Khadayate S, Lloyd AC, Marguerat S, Parrinello S (2017) The wound microenvironment reprograms Schwann cells to invasive mesenchymal-like cells to drive peripheral nerve regeneration. Neuron 96(1):98–114 e117

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Massoll C, Mando W, Chintala SK (2013) Excitotoxicity upregulates SARM1 protein expression and promotes Wallerian-like degeneration of retinal ganglion cells and their axons. Invest Ophthalmol Vis Sci 54(4):2771–2780

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Dyachuk V, Furlan A, Shahidi MK, Giovenco M, Kaukua N, Konstantinidou C, Pachnis V, Memic F, Marklund U, Muller T, Birchmeier C, Fried K, Ernfors P, Adameyko I (2014) Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. Science 345(6192):82–87

    CAS  Google Scholar 

  50. 50.

    Kaucka M, Adameyko I (2014) Non-canonical functions of the peripheral nerve. Exp Cell Res 321(1):17–24

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Pye RJ, Woods GM, Kreiss A (2016) Devil facial tumor disease. Vet Pathol 53(4):726–736

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Karu N, Wilson R, Hamede R, Jones M, Woods GM, Hilder EF, Shellie RA (2016) Discovery of biomarkers for tasmanian devil cancer (DFTD) by metabolic profiling of serum. J Proteome Res 15(10):3827–3840

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Lachish S, Jones M, McCallum H (2007) The impact of disease on the survival and population growth rate of the tasmanian devil. J Anim Ecol 76(5):926–936

    Google Scholar 

  54. 54.

    Loh R, Hayes D, Mahjoor A, O’Hara A, Pyecroft S, Raidal S (2006) The immunohistochemical characterization of devil facial tumor disease (DFTD) in the tasmanian devil (Sarcophilus harrisii). Vet Pathol 43(6):896–903

    CAS  Google Scholar 

  55. 55.

    Clark HB, Minesky JJ, Agrawal D, Agrawal HC (1985) Myelin basic protein and P2 protein are not immunohistochemical markers for Schwann cell neoplasms. A comparative study using antisera to S-100, P2, and myelin basic proteins. Am J Pathol 121(1):96–101

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Murchison EP, Tovar C, Hsu A, Bender HS, Kheradpour P, Rebbeck CA, Obendorf D, Conlan C, Bahlo M, Blizzard CA, Pyecroft S, Kreiss A, Kellis M, Stark A, Harkins TT, Marshall Graves JA, Woods GM, Hannon GJ, Papenfuss AT (2010) The tasmanian devil transcriptome reveals Schwann Cell origins of a clonally transmissible cancer. Science 327(5961):84–87

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Gollamudi M, Nethery D, Liu J, Kern JA (2004) Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines. Lung Cancer 43(2):135–143

    Google Scholar 

  58. 58.

    Kern JA, Slebos RJ, Top B, Rodenhuis S, Lager D, Robinson RA, Weiner D, Schwartz DA (1994) C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest 93(2):516–520

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Kern JA, Torney L, Weiner D, Gazdar A, Shepard HM, Fendly B (1993) Inhibition of human lung cancer cell line growth by an anti-p185HER2 antibody. Am J Respir Cell Mol Biol 9(4):448–454

    CAS  Google Scholar 

  60. 60.

    Pytel P, Karrison T, Can G, Tonsgard JH, Krausz T, Montag AG (2010) Neoplasms with schwannian differentiation express transcription factors known to regulate normal schwann cell development. Int J Surg Pathol 18(6):449–457

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Bunimovich YL, Keskinov AA, Shurin GV, Shurin MR (2017) Schwann cells: a new player in the tumor microenvironment. Cancer Immunol Immunother 66(8):959–968

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Cheung NK, Dyer MA (2013) Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer 13(6):397–411

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma Lancet 369(9579):2106–2120

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B, Stram DO, Gerbing RB, Lukens JN, Matthay KK, Castleberry RP (1999) The international neuroblastoma pathology classification (the Shimada system). Cancer 86(2):364–372

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Liu S, Tian Y, Chlenski A, Yang Q, Zage P, Salwen HR, Crawford SE, Cohn SL (2005) Cross-talk between Schwann cells and neuroblasts influences the biology of neuroblastoma Xenografts. Am J Pathol 166(3):891–900

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Ambros IM, Attarbaschi A, Rumpler S, Luegmayr A, Turkof E, Gadner H, Ambros PF (2001) Neuroblastoma cells provoke Schwann cell proliferation in vitro. Med Pediatr Oncol 36(1):163–168

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Kwiatkowski JL, Rutkowski JL, Yamashiro DJ, Tennekoon GI, Brodeur GM (1998) Schwann cell-conditioned medium promotes neuroblastoma survival and differentiation. Cancer Res 58(20):4602–4606

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Liu Y, Song L (2015) HMGB1-induced autophagy in Schwann cells promotes neuroblastoma proliferation. Int J Clin Experiment Pathol 8(1):504–510

    CAS  Google Scholar 

  70. 70.

    Mantyh PW (2006) Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Neurosci 7(10):797–809

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Everdingen MH, Rijke JM, Kessels AG, Schouten HC, Kleef M, Patijn J (2007) Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 18(9):1437–1449

    Google Scholar 

  72. 72.

    Schmidt BL, Hamamoto DT, Simone DA, Wilcox GL (2010) Mechanism of Cancer Pain. Mol Interven 10(3):164–178

    CAS  Google Scholar 

  73. 73.

    Mantyh PW (2014) Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care 8(2):83–90

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Vendrell I, Macedo D, Alho I, Dionsio MR, Costa L (2015) Treatment of cancer pain by targeting cytokines. Mediat Inflam 984570:11

    Google Scholar 

  75. 75.

    Jimenez-Andrade JM, Ghilardi JR, Castaneda-Corral G, Kuskowski MA, Mantyh PW (2011) Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain. Pain 152(11):2564–2574

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Campana WM (2007) Schwann cells: activated peripheral glia and their role in neuropathic pain. Brain Behav Immun 21(5):522–527

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Hoke A (2006) Mechanisms of disease: what factors limit the success of peripheral nerve regeneration in humans? Nat Clin Pract Neurol 2(8):448–454

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24(8):450–455

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Hald A, Nedergaard S, Hansen RR, Ding M, Heegaard AM (2009) Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. Eur J Pain 13(2):138–145

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Ducourneau VR, Dolique T, Hachem-Delaunay S, Miraucourt LS, Amadio A, Blaszczyk L, Jacquot F, Ly J, Devoize L, Oliet SH, Dallel R, Mothet JP, Nagy F, Fenelon VS, Voisin DL (2014) Cancer pain is not necessarily correlated with spinal overexpression of reactive glia markers. Pain 155(2):275–291

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Zhou YQ, Liu Z, Liu HQ, Liu DQ, Chen SP, Ye DW, Tian YK (2016) Targeting glia for bone cancer pain. Expert Opin Ther Targets 20(11):1365–1374

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Demir IE, Tieftrunk E, Schorn S, Saricaoglu OC, Pfitzinger PL, Teller S, Wang K, Waldbaur C, Kurkowski MU, Wormann SM, Shaw VE, Kehl T, Laschinger M, Costello E, Algul H, Friess H, Ceyhan GO (2016) Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia. Gut 65(6):1001–1014

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

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

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Jobling P, Pundavela J, Oliveira SM, Roselli S, Walker MM, Hondermarck H (2015) Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res 75(9):1777–1781

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Li S, Sun Y, Gao D (2013) Role of the nervous system in cancer metastasis. Oncol Lett 5(4):1101–1111

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    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

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Batsakis JG (1985) Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol 94(4 Pt 1):426–427

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Bapat AA, Hostetter G, Von Hoff DD, Han H (2011) Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer 11(10):695–707

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Varsha BK, Radhika MB, Makarla S, Kuriakose MA, Kiran GS, Padmalatha GV (2015) Perineural invasion in oral squamous cell carcinoma: case series and review of literature. J Oral Maxillofac Pathol 19(3):335–341

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Knijn N, Mogk SC, Teerenstra S, Simmer F, Nagtegaal ID (2016) Perineural invasion is a strong prognostic factor in colorectal cancer: a systematic review. Am J Surg Pathol 40(1):103–112

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Kuol N, Stojanovska L, Apostolopoulos V, Nurgali K (2018) Role of the nervous system in cancer metastasis. J Exp Clin Cancer Res 37(1):5–17

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Cui L, Shi Y, Zhang GN (2015) Perineural invasion as a prognostic factor for cervical cancer: a systematic review and meta-analysis. Arch Gynecol Obstet 292(1):13–19

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Gao A, Wang L, Li J, Li H, Han Y, Ma X, Sun Y (2016) Prognostic value of perineural invasion in esophageal and esophagogastric junction carcinoma: a meta-analysis. Dis Markers 5:7340180

    Google Scholar 

  94. 94.

    Olar A, He D, Florentin D, Ding Y, Ayala G (2014) Biological correlates of prostate cancer perineural invasion diameter. Human Pathol 45(7):1365–1369

    Google Scholar 

  95. 95.

    Demir IE, Boldis A, Pfitzinger PL, Teller S, Brunner E, Klose N, Kehl T, Maak M, Lesina M, Laschinger M, Janssen KP, Algul H, Friess H, Ceyhan GO (2014) Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J Natl Cancer Inst 106(8):1

    Google Scholar 

  96. 96.

    Deborde S, Omelchenko T, Lyubchik A, Zhou Y, He S, McNamara WF, Chernichenko N, Lee SY, Barajas F, Chen CH, Bakst RL, Vakiani E, Hall A, Wong RJ (2016) Schwann cells induce cancer cell dispersion and invasion. J Clin Invest 126(4):1538–1554

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Bakst RL, Wong RJ (2016) Mechanisms of Perineural Invasion. J Neurol Surg B Skull Base 77(2):96–106

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    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

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Fujii-Nishimura Y, Yamazaki K, Masugi Y, Douguchi J, Kurebayashi Y, Kubota N, Ojima H, Kitago M, Shinoda M, Hashiguchi A, Sakamoto M (2018) Mesenchymal-epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells. Pathol Int 68(4):214–223

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Shan C, Wei J, Hou R, Wu B, Yang Z, Wang L, Lei D, Yang X (2016) Schwann cells promote EMT and the Schwann-like differentiation of salivary adenoid cystic carcinoma cells via the BDNF/TrkB axis. Oncol Rep 35(1):427–435

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Zhou Y, Shurin GV, Zhong H, Bunimovich YL, Han B, Shurin MR (2018) Schwann cells augment cell spreading and metastasis of lung cancer. Cancer Res 78(20):5927–5939

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Quarles RH (2007) Myelin-associated glycoprotein (MAG): past, present and beyond. J Neurochem 100(6):1431–1448

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    McKerracher L, Rosen KM (2015) MAG, myelin and overcoming growth inhibition in the CNS. Front Mol Neurosci 8:51–56

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Zhao CM, Hayakawa Y, Kodama Y, Muthupalani S, Westphalen CB, Andersen GT, Flatberg A, Johannessen H, Friedman RA, Renz BW, Sandvik AK, Beisvag V, Tomita H, Hara A, Quante M, Li Z, Gershon MD, Kaneko K, Fox JG, Wang TC, Chen D (2014) Denervation suppresses gastric tumorigenesis. Sci Transl Med 6(250):250ra115

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Bakst RL, Barajas F, He S, Chernichenko N, Chen C, He S, McNamara W, Lee S, Deborde S, Wong RJ (2013) Are Schwann cells a target in radiation for perineural invasion? Int J Radiat Oncol Biol Phys 87(25):S629

    Google Scholar 

  106. 106.

    Lehmann HC, Hoke A (2010) Schwann cells as a therapeutic target for peripheral neuropathies. CNS Neurol Disord Drug Targets 9(6):801–806

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Magnaghi V, Procacci P, Tata AM (2009) Chap. 15: novel pharmacological approaches to Schwann cells as neuroprotective agents for peripheral nerve regeneration. Int Rev Neurobiol 87:295–315

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by London Foundation Grant (to M. R. Shurin) and University of Pittsburgh Cancer Institute (UPCI) Melanoma and SPORE in Skin Cancer Career Enhancement Program Award NIH P50CA121973 (to Y. L. Bunimovich).

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Conceptualization, MRS, AAK and YLB; Methodology, GVS, and MRS; Investigation, GVS and YLB; Writing —Original Draft, GVM and MRS; Writing—Review and Editing, GVM and MRS; Funding Acquisition, MRS and YLB; Resources, MRS and AAK; Supervision, GVS and MRS.

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Correspondence to Michael R. Shurin.

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The author reports no conflicts of interest in this work.

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Martyn, G.V., Shurin, G.V., Keskinov, A.A. et al. Schwann cells shape the neuro-immune environs and control cancer progression. Cancer Immunol Immunother 68, 1819–1829 (2019). https://doi.org/10.1007/s00262-018-02296-3

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Keywords

  • Schwann cells
  • Cancer
  • Neuroglia
  • Tumor microenvironment
  • MDSC
  • PIVAC 18