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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
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).
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).
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).
Batsakis, J. G. Nerves and neurotropic carcinomas. Ann. Otol. Rhinol. Laryngol. 94, 426–427 (1985).
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).
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).
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).
Rodin, A. E., Larson, D. L. & Roberts, D. K. Nature of the perineural space invaded by prostatic carcinoma. Cancer 20, 1772–1779 (1967).
Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
Scanlon, C. S. et al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nat. Commun. 6, 6885 (2015).
Ayala, G. E. et al. Stromal antiapoptotic paracrine loop in perineural invasion of prostatic carcinoma. Cancer Res. 66, 5159–5164 (2006).
Gil, Z. et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J. Natl Cancer Inst. 102, 107–118 (2010).
Ayala, G. E. et al. Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res. 64, 6082–6090 (2004).
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).
Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008).
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).
Jobling, P. et al. Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res. 75, 1777–1781 (2015).
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).
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).
Bockman, D. E., Buchler, M. & Beger, H. G. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage. Gastroenterology 107, 219–230 (1994).
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).
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).
Demir, I. E. et al. Neural invasion in pancreatic cancer: the past, present and future. Cancers (Basel) 2, 1513–1527 (2010).
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).
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).
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).
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).
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).
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).
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).
Abiatari, I. et al. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma. Mol. Cancer Ther. 8, 1494–1504 (2009).
Burnett, M. G. & Zager, E. L. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg. Focus 16, E1 (2004).
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).
He, S. et al. The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Mol. Cancer Res. 13, 380–390 (2015).
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).
Ayala, G. E. et al. Bystin in perineural invasion of prostate cancer. Prostate 66, 266–272 (2006).
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).
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).
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).
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).
Schwartz, E. S. et al. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140, 1283–1291 (2011).
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).
Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).
Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).
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).
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).
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).
Vonlaufen, A. et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 68, 2085–2093 (2008).
Apte, M. V. et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29, 179–187 (2004).
Ceyhan, G. O. et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology 136, 177–186 (2009).
Samkharadze, T. et al. Pigment epithelium-derived factor associates with neuropathy and fibrosis in pancreatic cancer. Am. J. Gastroenterol. 106, 968–980 (2011).
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).
Friess, H. et al. Enhanced expression of TGF-betas and their receptors in human acute pancreatitis. Ann. Surg. 227, 95–104 (1998).
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).
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).
Hsia, D. A. et al. Differential regulation of cell motility and invasion by FAK. J. Cell Biol. 160, 753–767 (2003).
Pantel, K. & Brakenhoff, R. H. Dissecting the metastatic cascade. Nat. Rev. Cancer 4, 448–456 (2004).
Scholz, J. & Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361–1368 (2007).
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).
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).
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).
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).
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).
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).
Airaksinen, M. S. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394 (2002).
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).
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).
Ceyhan, G. O. et al. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann. Surg. 244, 274–281 (2006).
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).
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).
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).
Carlomagno, F. et al. The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res. 62, 1077–1082 (2002).
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).
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).
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).
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).
Liebl, F. et al. The severity of neural invasion is associated with shortened survival in colon cancer. Clin. Cancer Res. 19, 50–61 (2013).
Andres, R. et al. Multiple effects of artemin on sympathetic neurone generation, survival and growth. Development 128, 3685–3695 (2001).
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).
Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).
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).
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).
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).
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).
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).
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).
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).
Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
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).
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).
Kiba, T. Relationships between the autonomic nervous system and the pancreas including regulation of regeneration and apoptosis: recent developments. Pancreas 29, e51–e58 (2004).
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).
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).
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).
Palma, C. Tachykinins and their receptors in human malignancies. Curr. Drug Targets 7, 1043–1052 (2006).
Hokfelt, T., Pernow, B. & Wahren, J. Substance P: a pioneer amongst neuropeptides. J. Intern. Med. 249, 27–40 (2001).
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).
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).
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).
Henson, B. S. et al. Galanin receptor 1 has anti-proliferative effects in oral squamous cell carcinoma. J. Biol. Chem. 280, 22564–22571 (2005).
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).
Behrens, J. The role of cell adhesion molecules in cancer invasion and metastasis. Breast Cancer Res. Treat. 24, 175–184 (1993).
Roy, L. D. et al. MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30, 1449–1459 (2011).
Schafer, M. K. & Altevogt, P. L1CAM malfunction in the nervous system and human carcinomas. Cell. Mol. Life Sci. 67, 2425–2437 (2010).
Gavert, N., Ben-Shmuel, A., Raveh, S. & Ben-Ze'ev, A. L1-CAM in cancerous tissues. Expert Opin. Biol. Ther. 8, 1749–1757 (2008).
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).
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).
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).
Raveh, S., Gavert, N. & Ben-Ze'ev, A. L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 282, 137–145 (2009).
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).
Sroka, I. C. et al. The laminin binding integrin α6β1 in prostate cancer perineural invasion. J. Cell. Physiol. 224, 283–288 (2010).
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).
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).
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).
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).
Dai, H. et al. Pim-2 upregulation: biological implications associated with disease progression and perineural invasion in prostate cancer. Prostate 65, 276–286 (2005).
Fox, C. J. et al. The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev. 17, 1841–1854 (2003).
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).
Zhang, Y. & Zhang, B. D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res. 66, 5592–5598 (2006).
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).
Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).
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).
Takahashi, T. et al. Perineural invasion by ductal adenocarcinoma of the pancreas. J. Surg. Oncol. 65, 164–170 (1997).
Hirai, I. et al. Perineural invasion in pancreatic cancer. Pancreas 24, 15–25 (2002).
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).
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).
Su, C. H. et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann. Surg. 223, 384–394 (1996).
Nagakawa, T. et al. Perineural invasion of carcinoma of the pancreas and biliary tract. Br. J. Surg. 80, 619–621 (1993).
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).
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).
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).
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).
Soo, K. C. et al. Prognostic implications of perineural spread in squamous carcinomas of the head and neck. Laryngoscope 96, 1145–1148 (1986).
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).
Liebig, C. et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J. Clin. Oncol. 27, 5131–5137 (2009).
Horn, A., Dahl, O. & Morild, I. Venous and neural invasion as predictors of recurrence in rectal adenocarcinoma. Dis. Colon Rectum 34, 798–804 (1991).
Matsushima, T., Mori, M., Kido, A., Adachi, Y. & Sugimachi, K. Preoperative estimation of neural invasion in rectal carcinoma. Oncol. Rep. 5, 73–76 (1998).
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).
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).
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).
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
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary information
Supplementary information S1 (table) (PDF 306 kb)
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
About this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrc.2016.38
This article is cited by
-
A prediction nomogram for perineural invasion in colorectal cancer patients: a retrospective study
BMC Surgery (2024)
-
Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma
British Journal of Cancer (2024)
-
Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance
Cellular Oncology (2024)
-
Development and Validation of a Prognostic Model for Postoperative Anastomotic Recurrence in Siewert II or III Adenocarcinomas Without Neoadjuvant Therapy in an East Asian Population
Journal of Gastrointestinal Cancer (2024)
-
Combining perineural invasion with staging improve the prognostic accuracy in colorectal cancer: a retrospective cohort study
BMC Cancer (2023)