Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Mechanisms of cancer dissemination along nerves

Nature Reviews Cancer volume 16, pages 399–408 (2016)Cite this article

Subjects

Abstract

The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Regulation of neural tracking of cancer cells by the perineural niche.
Figure 2: Molecular signalling of neural tracking.

Similar content being viewed by others

References

  1. Liebig, C., Ayala, G., Wilks, J. A., Berger, D. H. & Albo, D. Perineural invasion in cancer: a review of the literature. Cancer 115, 3379–3391 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Amit, M. et al. International collaborative validation of intraneural invasion as a prognostic marker in adenoid cystic carcinoma of the head and neck. Head Neck 37, 1038–1045 (2015).

    Article  PubMed  Google Scholar 

  3. Chatterjee, D. et al. Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma. Am. J. Surg. Pathol. 36, 409–417 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cheng, L. et al. Preoperative prediction of surgical margin status in patients with prostate cancer treated by radical prostatectomy. J. Clin. Oncol. 18, 2862–2868 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Batsakis, J. G. Nerves and neurotropic carcinomas. Ann. Otol. Rhinol. Laryngol. 94, 426–427 (1985).

    Article  CAS  PubMed  Google Scholar 

  6. Dodd, G. D., Dolan, P. A., Ballantyne, A. J., Ibanez, M. L. & Chau, P. The dissemination of tumors of the head and neck via the cranial nerves. Radiol. Clin. North Am. 8, 445–461 (1970).

    CAS  PubMed  Google Scholar 

  7. Ballantyne, A. J., McCarten, A. B. & Ibanez, M. L. The extension of cancer of the head and neck through peripheral nerves. Am. J. Surg. 106, 651–667 (1963).

    Article  CAS  PubMed  Google Scholar 

  8. Hassan, M. O. & Maksem, J. The prostatic perineural space and its relation to tumor spread: an ultrastructural study. Am. J. Surg. Pathol. 4, 143–148 (1980).

    Article  CAS  PubMed  Google Scholar 

  9. Rodin, A. E., Larson, D. L. & Roberts, D. K. Nature of the perineural space invaded by prostatic carcinoma. Cancer 20, 1772–1779 (1967).

    Article  CAS  PubMed  Google Scholar 

  10. Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Scanlon, C. S. et al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nat. Commun. 6, 6885 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Ayala, G. E. et al. Stromal antiapoptotic paracrine loop in perineural invasion of prostatic carcinoma. Cancer Res. 66, 5159–5164 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Gil, Z. et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J. Natl Cancer Inst. 102, 107–118 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ayala, G. E. et al. Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res. 64, 6082–6090 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Yang, G., Wheeler, T. M., Kattan, M. W., Scardino, P. T. & Thompson, T. C. Perineural invasion of prostate carcinoma cells is associated with reduced apoptotic index. Cancer 78, 1267–1271 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Lindsay, T. H. et al. Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression. Pain 119, 233–246 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Jobling, P. et al. Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res. 75, 1777–1781 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. 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 8, e60529 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 Res. 72, 5733–5743 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Bockman, D. E., Buchler, M. & Beger, H. G. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage. Gastroenterology 107, 219–230 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Park, D. S. et al. Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. J. Neurosci. 20, 3104–3114 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang, Y. et al. Pim-1 kinase as activator of the cell cycle pathway in neuronal death induced by DNA damage. J. Neurochem. 112, 497–510 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Demir, I. E. et al. Neural invasion in pancreatic cancer: the past, present and future. Cancers (Basel) 2, 1513–1527 (2010).

    Article  CAS  Google Scholar 

  25. Bapat, A. A., Hostetter, G., Von Hoff, D. D. & Han, H. Perineural invasion and associated pain in pancreatic cancer. Nat. Rev. Cancer 11, 695–707 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Coulpier, M., Anders, J. & Ibanez, C. F. Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survival. J. Biol. Chem. 277, 1991–1999 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. De Oliveira, T. et al. Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. Mol. Cancer 11, 19 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Swanson, B. J. et al. 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, 10222–10229 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Marchesi, F. et al. The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res. 68, 9060–9069 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Moos, M. et al. Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin. Nature 334, 701–703 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. Abiatari, I. et al. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma. Mol. Cancer Ther. 8, 1494–1504 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Burnett, M. G. & Zager, E. L. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg. Focus 16, E1 (2004).

    Article  PubMed  Google Scholar 

  34. Marchesi, F. et al. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J. Neuroimmunol. 224, 39–44 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. He, S. et al. The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Mol. Cancer Res. 13, 380–390 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Ben, Q. W. et al. Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. Ann. Surg. Oncol. 17, 2213–2221 (2010).

    Article  PubMed  Google Scholar 

  37. Ayala, G. E. et al. Bystin in perineural invasion of prostate cancer. Prostate 66, 266–272 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Ammer, A. G. et al. Saracatinib impairs head and neck squamous cell carcinoma invasion by disrupting invadopodia function. J. Cancer Sci. Ther. 1, 52–61 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Li, X. et al. Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin. Cancer Res. 20, 4326–4338 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Karja, V. et al. Tumour-infiltrating lymphocytes: a prognostic factor of PSA-free survival in patients with local prostate carcinoma treated by radical prostatectomy. Anticancer Res. 25, 4435–4438 (2005).

    PubMed  Google Scholar 

  41. Vesalainen, S., Lipponen, P., Talja, M. & Syrjanen, K. Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur. J. Cancer 30A, 1797–1803 (1994).

  42. Schwartz, E. S. et al. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140, 1283–1291 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Schwartz, E. S. et al. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J. Neurosci. 33, 5603–5611 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Van Steenwinckel, J. et al. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J. Neurosci. 31, 5865–5875 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Amit, M., Na'ara S., Binenbaum, Y. & Gil, Z. Marrow-derived macrophages mediate invasion of pancreatic adenocarcinoma by RET activation. Cancer Res. 75 (15 Suppl.), 2355 (2015).

    Google Scholar 

  48. Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Vonlaufen, A. et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 68, 2085–2093 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Apte, M. V. et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29, 179–187 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Ceyhan, G. O. et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology 136, 177–186 (2009).

    Article  PubMed  Google Scholar 

  52. Samkharadze, T. et al. Pigment epithelium-derived factor associates with neuropathy and fibrosis in pancreatic cancer. Am. J. Gastroenterol. 106, 968–980 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Apte, M. V., Wilson, J. S., Lugea, A. & Pandol, S. J. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144, 1210–1219 (2013).

    Article  PubMed  Google Scholar 

  54. Friess, H. et al. Enhanced expression of TGF-betas and their receptors in human acute pancreatitis. Ann. Surg. 227, 95–104 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Masamune, A., Watanabe, T., Kikuta, K. & Shimosegawa, T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin. Gastroenterol. Hepatol. 7, S48–S54 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Tang, D. et al. Pancreatic satellite cells derived galectin-1 increase the progression and less survival of pancreatic ductal adenocarcinoma. PLoS ONE 9, e90476 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hsia, D. A. et al. Differential regulation of cell motility and invasion by FAK. J. Cell Biol. 160, 753–767 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pantel, K. & Brakenhoff, R. H. Dissecting the metastatic cascade. Nat. Rev. Cancer 4, 448–456 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Scholz, J. & Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361–1368 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Gaudet, A. D., Popovich, P. G. & Ramer, M. S. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J. Neuroinflamm. 8, 110 (2011).

    Article  Google Scholar 

  61. Demir, I. E. et al. Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J. Natl Cancer Inst. 106, dju184 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Chan, J. R., Cosgaya, J. M., Wu, Y. J. & Shooter, E. M. Neurotrophins are key mediators of the myelination program in the peripheral nervous system. Proc. Natl Acad. Sci. USA 98, 14661–14668 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen-Tsai, C. P., Colome-Grimmer, M. & Wagner, R. F. Jr. Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB, TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas. Dermatol. Surg. 30, 1009–1016 (2004).

    PubMed  Google Scholar 

  64. Sakamoto, Y. et al. Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma. Oncol. Rep. 8, 477–484 (2001).

    CAS  PubMed  Google Scholar 

  65. Ivanov, S. V. et al. TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior. Oncogene 32, 3698–3710 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Airaksinen, M. S. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. He, S. et al. GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc. Natl Acad. Sci. USA 111, E2008–E2017 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang, K. et al. The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer. Carcinogenesis 35, 103–113 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Ceyhan, G. O. et al. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann. Surg. 244, 274–281 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Iwahashi, N. et al. Expression of glial cell line-derived neurotrophic factor correlates with perineural invasion of bile duct carcinoma. Cancer 94, 167–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Esseghir, S. et al. A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha1 receptor up-regulation in breast cancer. Cancer Res. 67, 11732–11741 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Paratcha, G. et al. Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29, 171–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Carlomagno, F. et al. The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res. 62, 1077–1082 (2002).

    CAS  PubMed  Google Scholar 

  74. Klein, R., Jing, S. Q., Nanduri, V., O'Rourke, E. & Barbacid, M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65, 189–197 (1991).

    Article  CAS  PubMed  Google Scholar 

  75. Zhu, Z. et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J. Clin. Oncol. 17, 2419–2428 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Zhang, S. et al. Chemokine CXCL12 and its receptor CXCR4 expression are associated with perineural invasion of prostate cancer. J. Exp. Clin. Cancer Res. 27, 62 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Geldof, A. A., De Kleijn, M. A., Rao, B. R. & Newling, D. W. Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells. J. Cancer Res. Clin. Oncol. 123, 107–112 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Liebl, F. et al. The severity of neural invasion is associated with shortened survival in colon cancer. Clin. Cancer Res. 19, 50–61 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Andres, R. et al. Multiple effects of artemin on sympathetic neurone generation, survival and growth. Development 128, 3685–3695 (2001).

    CAS  PubMed  Google Scholar 

  80. Gao, L., Bo, H., Wang, Y., Zhang, J. & Zhu, M. Neurotrophic factor artemin promotes invasiveness and neurotrophic function of pancreatic adenocarcinoma in vivo and in vitro. Pancreas 44, 134–143 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sawai, H. et al. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 65, 11536–11544 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Vinuesa, C. G., Tangye, S. G., Moser, B. & Mackay, C. R. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 5, 853–865 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. El-Haibi, C. P., Singh, R., Sharma, P. K., Singh, S. & Lillard, J. W. Jr. CXCL13 mediates prostate cancer cell proliferation through JNK signalling and invasion through ERK activation. Cell Prolif. 44, 311–319 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhu, Z. et al. CXCL13–CXCR5 axis promotes the growth and invasion of colon cancer cells via PI3K/AKT pathway. Mol. Cell. Biochem. 400, 287–295 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Singh, S. et al. Clinical and biological significance of CXCR5 expressed by prostate cancer specimens and cell lines. Int. J. Cancer 125, 2288–2295 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Qi, X. W. et al. Expression features of CXCR5 and its ligand, CXCL13 associated with poor prognosis of advanced colorectal cancer. Eur. Rev. Med. Pharmacol. Sci. 18, 1916–1924 (2014).

    PubMed  Google Scholar 

  88. Feng, Y. J., Zhang, B. Y., Yao, R. Y. & Lu, Y. Muscarinic acetylcholine receptor M3 in proliferation and perineural invasion of cholangiocarcinoma cells. Hepatobiliary Pancreat. Dis. Int. 11, 418–423 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  90. Entschladen, F., Drell, T. L.t., Lang, K., Joseph, J. & Zaenker, K. S. Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol. 5, 254–258 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Li, Z. J. & Cho, C. H. Neurotransmitters, more than meets the eye—neurotransmitters and their perspectives in cancer development and therapy. Eur. J. Pharmacol. 667, 17–22 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Kiba, T. Relationships between the autonomic nervous system and the pancreas including regulation of regeneration and apoptosis: recent developments. Pancreas 29, e51–e58 (2004).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Guo, K. et al. Interaction of the sympathetic nerve with pancreatic cancer cells promotes perineural invasion through the activation of STAT3 signaling. Mol. Cancer Ther. 12, 264–273 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Palma, C. Tachykinins and their receptors in human malignancies. Curr. Drug Targets 7, 1043–1052 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Hokfelt, T., Pernow, B. & Wahren, J. Substance P: a pioneer amongst neuropeptides. J. Intern. Med. 249, 27–40 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Li, X. et al. Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells. Mol. Cancer Res. 11, 294–302 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Banerjee, R., Henson, B. S., Russo, N., Tsodikov, A. & D'Silva, N. J. Rap1 mediates galanin receptor 2-induced proliferation and survival in squamous cell carcinoma. Cell Signal. 23, 1110–1118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sugimoto, T. et al. The galanin signaling cascade is a candidate pathway regulating oncogenesis in human squamous cell carcinoma. Genes Chromosomes Cancer 48, 132–142 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Henson, B. S. et al. Galanin receptor 1 has anti-proliferative effects in oral squamous cell carcinoma. J. Biol. Chem. 280, 22564–22571 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Merati, K. et al. Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters. Am. J. Clin. Oncol. 24, 447–452 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Behrens, J. The role of cell adhesion molecules in cancer invasion and metastasis. Breast Cancer Res. Treat. 24, 175–184 (1993).

    Article  CAS  PubMed  Google Scholar 

  104. Roy, L. D. et al. MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30, 1449–1459 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Schafer, M. K. & Altevogt, P. L1CAM malfunction in the nervous system and human carcinomas. Cell. Mol. Life Sci. 67, 2425–2437 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Gavert, N., Ben-Shmuel, A., Raveh, S. & Ben-Ze'ev, A. L1-CAM in cancerous tissues. Expert Opin. Biol. Ther. 8, 1749–1757 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Kiefel, H. et al. L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression. Oncogene 29, 4766–4778 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Kiefel, H., Pfeifer, M., Bondong, S., Hazin, J. & Altevogt, P. Linking L1CAM-mediated signaling to NF-κB activation. Trends Mol. Med. 17, 178–187 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Romano, N. H., Madl, C. M. & Heilshorn, S. C. Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth. Acta Biomater. 11, 48–57 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Raveh, S., Gavert, N. & Ben-Ze'ev, A. L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 282, 137–145 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Jansson, K. H. et al. Identification of β-2 as a key cell adhesion molecule in PCa cell neurotropic behavior: a novel ex vivo and biophysical approach. PLoS ONE 9, e98408 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sroka, I. C. et al. The laminin binding integrin α6β1 in prostate cancer perineural invasion. J. Cell. Physiol. 224, 283–288 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Aoki, R. & Fukuda, M. N. Recent molecular approaches to elucidate the mechanism of embryo implantation: trophinin, bystin, and tastin as molecules involved in the initial attachment of blastocysts to the uterus in humans. Semin. Reprod. Med. 18, 265–271 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Fukuda, M. N. & Nozawa, S. Trophinin, tastin, and bystin: a complex mediating unique attachment between trophoblastic and endometrial epithelial cells at their respective apical cell membranes. Semin. Reprod. Endocrinol. 17, 229–234 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Zhang, Y. et al. The Chk1/Cdc25A pathway as activators of the cell cycle in neuronal death induced by camptothecin. J. Neurosci. 26, 8819–8828 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Galbiati, F. et al. Expression of caveolin-1 and -2 in differentiating PC12 cells and dorsal root ganglion neurons: caveolin-2 is up-regulated in response to cell injury. Proc. Natl Acad. Sci. USA 95, 10257–10262 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dai, H. et al. Pim-2 upregulation: biological implications associated with disease progression and perineural invasion in prostate cancer. Prostate 65, 276–286 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Fox, C. J. et al. The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev. 17, 1841–1854 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhang, B., Zhang, Y., Dagher, M. C. & Shacter, E. Rho GDP dissociation inhibitor protects cancer cells against drug-induced apoptosis. Cancer Res. 65, 6054–6062 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Zhang, Y. & Zhang, B. D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res. 66, 5592–5598 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Eugenin, E. A. & Berman, J. W. Chemokine-dependent mechanisms of leukocyte trafficking across a model of the blood–brain barrier. Methods 29, 351–361 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Na'ara, S., Gil, Z. & Amit, M. Paracrine interactions between Schwann cells and cancer cells promotes perineural invasion via L1cam secretion. Cancer Res. AACR 2016 Annual Meeting, abstract 5072 (2016).

  124. Takahashi, T. et al. Perineural invasion by ductal adenocarcinoma of the pancreas. J. Surg. Oncol. 65, 164–170 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Hirai, I. et al. Perineural invasion in pancreatic cancer. Pancreas 24, 15–25 (2002).

    Article  PubMed  Google Scholar 

  126. Duraker, N., Sisman, S. & Can, G. The significance of perineural invasion as a prognostic factor in patients with gastric carcinoma. Surg. Today 33, 95–100 (2003).

    Article  PubMed  Google Scholar 

  127. He, P. et al. Multivariate statistical analysis of clinicopathologic factors influencing survival of patients with bile duct carcinoma. World J. Gastroenterol. 8, 943–946 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Su, C. H. et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann. Surg. 223, 384–394 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nagakawa, T. et al. Perineural invasion of carcinoma of the pancreas and biliary tract. Br. J. Surg. 80, 619–621 (1993).

    Article  CAS  PubMed  Google Scholar 

  130. Maru, N., Ohori, M., Kattan, M. W., Scardino, P. T. & Wheeler, T. M. Prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens. Hum. Pathol. 32, 828–833 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Lee, I. H. et al. Perineural invasion is a marker for pathologically advanced disease in localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 68, 1059–1064 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Carter, R. L., Foster, C. S., Dinsdale, E. A. & Pittam, M. R. Perineural spread by squamous carcinomas of the head and neck: a morphological study using antiaxonal and antimyelin monoclonal antibodies. J. Clin. Pathol. 36, 269–275 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  134. Soo, K. C. et al. Prognostic implications of perineural spread in squamous carcinomas of the head and neck. Laryngoscope 96, 1145–1148 (1986).

    Article  CAS  PubMed  Google Scholar 

  135. Goepfert, H., Dichtel, W. J., Medina, J. E., Lindberg, R. D. & Luna, M. D. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am. J. Surg. 148, 542–547 (1984).

    Article  CAS  PubMed  Google Scholar 

  136. Liebig, C. et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J. Clin. Oncol. 27, 5131–5137 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Horn, A., Dahl, O. & Morild, I. Venous and neural invasion as predictors of recurrence in rectal adenocarcinoma. Dis. Colon Rectum 34, 798–804 (1991).

    Article  CAS  PubMed  Google Scholar 

  138. Matsushima, T., Mori, M., Kido, A., Adachi, Y. & Sugimachi, K. Preoperative estimation of neural invasion in rectal carcinoma. Oncol. Rep. 5, 73–76 (1998).

    CAS  PubMed  Google Scholar 

  139. Krasna, M. J., Flancbaum, L., Cody, R. P., Shneibaum, S. & Ben Ari, G. Vascular and neural invasion in colorectal carcinoma. Incidence and prognostic significance. Cancer 61, 1018–1023 (1988).

    Article  CAS  PubMed  Google Scholar 

  140. Schaefer, A. W. et al. Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization. J. Biol. Chem. 274, 37965–37973 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Silletti, S. et al. Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion. J. Biol. Chem. 279, 28880–28888 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

C. Cohen is thanked for her editorial assistance. N. Rada is thanked for her artistic work. Supported by the Israeli Science Foundation, Binational US–Israel Science Foundation, Israeli Cancer Research Found, Israel Cancer Association, Rappaport Institute at the Technion and the Clinical Research Institute at Rambam.

Author information

Authors and Affiliations

  1. Department of Otolaryngology Head and Neck Surgery, Laboratory for Applied Cancer Research, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel

    Moran Amit, Shorook Na'ara & Ziv Gil

Authors
  1. Moran Amit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shorook Na'ara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ziv Gil
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ziv Gil.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information S1 (table) (PDF 306 kb)

PowerPoint slides

Glossary

Desmoplastic reaction

Also known as desmoplasia, the desmoplastic reaction is the growth of fibrous tissue secondary to an insult such as a tumour or surgery.

Dorsal root ganglia

(DRG). Also known as spinal ganglia, DRG are clusters of nerve cell bodies (a ganglia) in a posterior root of a spinal nerve.

Endoneurial space

The anatomical space between the deepest layer of nerve covering, called the endoneurium, and the peripheral nerve fibres.

Euclidean velocity

Directional vector of velocity defined not only by magnitude, but also by direction.

Pancreatic afferents

These afferent nerve fibres are sensory neurons extending far from the nerve cell body in the coeliac ganglia. They conduct pain sensation by carrying nerve impulses from sensory receptors towards the central nervous system.

Parasympathetic cholinergic fibres

These components of the autonomic nervous system are responsible for the body's activities when it is at rest. They are called cholinergic after the main neurotransmitter, acetylcholine.

Perineural space

The anatomical space between the most superficial nerve covering, also known as the epineurium layer, and the middle layer, called the perineurium, in peripheral nerves.

Perineurium

Peripheral fibres are each wrapped in a protective sheath known as the endoneurium. These are bundled together into fascicles, each surrounded by a protective sheath known as the perineurium.

Peripheral glial cell

Schwann cells are the principal peripheral glial cells that function to support neurons in the peripheral nervous system.

Sensory fibres

Nerve fibres that deliver sensory information (for example, pain), from a peripheral organ to the central nervous system.

Sympathetic nervous system

A component of the autonomic nervous system responsible for maintaining homeostasis and stimulating the body for flight-or-fight response. In peripheral nerves, the main postganglionic sympathetic neurotransmitter is noradrenaline, which activates α- and β-adrenergic receptors.

Visceral hypersensitivity

Cancer-associated altered visceral perception caused by hyperexcitability of the neurons in the visceral afferent nervous system. Characterized by a lowered threshold for abdominal pain and discomfort.

Wallerian degeneration

A process that results after a nerve injury, in which the part of the axon separated from the cell body of the neuron degenerates distal to the injury.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amit, M., Na'ara, S. & Gil, Z. Mechanisms of cancer dissemination along nerves. Nat Rev Cancer 16, 399–408 (2016). https://doi.org/10.1038/nrc.2016.38

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2016.38

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer