Pathology and Molecular Mechanisms of Perineural Spread of Tumors
Main Article Content
Abstract
Perineural invasion (PNI) is an important but under-reported route of metastasis of many cancers, in which neoplasm invades and spreads along the nerves. In recent years, PNI has been identified to contribute to the pathology of malignant tumors in the breast, stomach, head and neck, pancreas, prostate and large intestine. PNI of neoplasm may be attributable to poor prognosis of the patients, and sometimes appears to be the only cause of long-distance metastasis. Recent studies have furnished latest insights into the pathology and clinical features of PNI, characterized by continuous and interlinked multiple steps, starting from the formation of a perineural niche, comprising of neural cells, inflammatory cells, stromal cells, extracellular matrix, and blood vessels, in addition to the cancer cells. The critical step of PNI involves the establishment of connections between tumor and nerve through a number of signaling pathways consisting of soluble factors such as nerve growth factor, interleukins, and matrix metalloproteinases. Upon invasion into the nervous system, the cancer cells bring changes to neural cells and their microenvironment, leading to neoplastic spread along the nerves and alteration of normal nerve functions. In this review, we attempt to comprehensively cover the cellular and molecular mechanisms of perineural spread of tumors.
Keywords:
Perineural invasion, Tumor, Perineural spread, Neoplasm, Perineural niche
Article Details
How to Cite
SAYYED, YASRA et al.
Pathology and Molecular Mechanisms of Perineural Spread of Tumors.
Medical Research Archives, [S.l.], v. 9, n. 6, june 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2457>. Date accessed: 05 nov. 2024.
doi: https://doi.org/10.18103/mra.v9i6.2457.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Stambuk HE. Perineural tumor spread involving the central skull base region. Seminars in ultrasound, CT, and MR. Oct 2013;34(5):445-58. doi:10.1053/j.sult.2013.09.002
2. Chen S-H, Zhang B-Y, Zhou B, Zhu C-Z, Sun L-Q, Feng Y-J. Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche. Am J Cancer Res. 2019;9(1):1-21.
3. Ronaghy A, Yaar R, Goldberg LJ, Mahalingam M, Bhawan J. Perineural Involvement: What Does it Mean? The American Journal of Dermatopathology. 2010;32(5)
4. Seifert P, Spitznas M. Tumours may be innervated. Virchows Archiv : an international journal of pathology. 03/01 2001;438:228-31. doi:10.1007/s004280000306
5. Seifert P, Benedic M, Effert P. Nerve fibers in tumors of the human urinary bladder. Virchows Archiv. 2002/03/01 2002;440(3):291-297. doi:10.1007/s004280100496
6. Lü S-H, Zhou Y, Que H-P, Liu S-J. Peptidergic innervation of human esophageal and cardiac carcinoma. World J Gastroenterol. 2003;9(3):399-403. doi:10.3748/wjg.v9.i3.399
7. Liang Y-J, Zhou P, Wongba W, Guardiola J, Walker J, Yu J. Pulmonary innervation, inflammation and carcinogenesis. Sheng li xue bao : [Acta physiologica Sinica]. 06/25 2010;62:191-5.
8. Batsakis JG. Nerves and neurotropic carcinomas. The Annals of otology, rhinology, and laryngology. Jul-Aug 1985;94(4 Pt 1):426-7.
9. Ayala GE, Wheeler TM, Shine HD, et al. In vitro dorsal root ganglia and human prostate cell line interaction: Redefining perineural invasion in prostate cancer. https://doi.org/10.1002/pros.1137. The Prostate. 2001/11/01 2001;49(3):213-223. doi:https://doi.org/10.1002/pros.1137
10. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. Aug 1 2009;115(15):3379-91. doi:10.1002/cncr.24396
11. Lutgendorf SK, DeGeest K, Dahmoush L, et al. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun. 2011;25(2):250-255. doi:10.1016/j.bbi.2010.10.012
12. Hassan S, Karpova Y, Baiz D, et al. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest. Feb 2013;123(2):874-86. doi:10.1172/jci63324
13. Karak S, Quatrano N, Buckley J, Ricci A. Prevalence and significance of perineural invasion in invasive breast carcinoma. Connecticut medicine. 01/01 2010;74:17-21.
14. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer. Cancer. 2009/08/01 2009;115(15):3379-3391. doi:10.1002/cncr.24396
15. Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, Tredici G. Mesenchymal stem cells neuronal differentiation ability: a real perspective for nervous system repair? Current stem cell research & therapy. Jun 2011;6(2):82-92. doi:10.2174/157488811795495486
16. Heikkilä K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. European journal of cancer (Oxford, England : 1990). May 2008;44(7):937-45. doi:10.1016/j.ejca.2008.02.047
17. Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. Journal of enzyme inhibition and medicinal chemistry. 2016;31(sup1):177-183. doi:10.3109/14756366.2016.1161620
18. Aloe L, Rocco ML, Balzamino BO, Micera A. Nerve Growth Factor: A Focus on Neuroscience and Therapy. Curr Neuropharmacol. 2015;13(3):294-303. doi:10.2174/1570159x13666150403231920
19. Gash DM, Gerhardt GA, Slevin JT. GDNF (Including Neurturin)☆. Reference Module in Neuroscience and Biobehavioral Psychology. Elsevier; 2017.
20. Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine & growth factor reviews. Feb 2010;21(1):77-82. doi:10.1016/j.cytogfr.2009.11.001
21. Bakst R, Wong R. Mechanisms of Perineural Invasion. Journal of Neurological Surgery Part B: Skull Base. 03/10 2016;77doi:10.1055/s-0036-1571835
22. Azam SH, Pecot CV. Cancer's got nerve: Schwann cells drive perineural invasion. J Clin Invest. 2016;126(4):1242-1244. doi:10.1172/JCI86801
23. Amit M, Na'ara S, Gil Z. Mechanisms of cancer dissemination along nerves. Nature Reviews Cancer. 2016/06/01 2016;16(6):399-408. doi:10.1038/nrc.2016.38
24. Olar A, He D, Florentin D, Ding Y, Wheeler T, Ayala G. Biological correlates of prostate cancer perineural invasion diameter. Human pathology. Jul 2014;45(7):1365-9. doi:10.1016/j.humpath.2014.02.011
25. Reavis HD, Chen HI, Drapkin R. Tumor Innervation: Cancer Has Some Nerve. Trends in Cancer. 2020/08/14/ 2020;doi:https://doi.org/10.1016/j.trecan.2020.07.005
26. Yates C. Influence of Tumor Microenvironment on the Molecular Regulation of Prostate Cancer Progression. 2009.
27. Li X, Ma Q, Xu Q, et al. SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer letters. 2012;322(2):169-176. doi:10.1016/j.canlet.2012.02.035
28. Zhao C-M, Hayakawa Y, Kodama Y, et al. Denervation suppresses gastric tumorigenesis. Science Translational Medicine. 2014;6(250):250ra115. doi:10.1126/scitranslmed.3009569
29. Samarelli AV, Riccitelli E, Bizzozero L, et al. Neuroligin 1 induces blood vessel maturation by cooperating with the α6 integrin. The Journal of biological chemistry. Jul 11 2014;289(28):19466-76. doi:10.1074/jbc.M113.530972
30. Graziano S, Marchiò S, Bussolino F, Arese M. A peptide from the extracellular region of the synaptic protein α Neurexin stimulates angiogenesis and the vascular specific tyrosine kinase Tie2. Biochemical and Biophysical Research Communications. 2013/03/22/ 2013;432(4):574-579. doi:https://doi.org/10.1016/j.bbrc.2013.02.045
31. Marco Arese FB, Margherita Pergolizzi, Laura Bizzozero, Davide Pascal. Tumor progression: the neuronal input Review. Annals of Translational Medicine. 2018;6(5):89. doi:10.21037/atm.2018.01.01
32. Tan X, Huang Z, Li X. Long Non-Coding RNA MALAT1 Interacts With miR-204 to Modulate Human Hilar Cholangiocarcinoma Proliferation, Migration, and Invasion by Targeting CXCR4. Journal of cellular biochemistry. Nov 2017;118(11):3643-3653. doi:10.1002/jcb.25862
33. Zheng HT, Shi DB, Wang YW, et al. High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer. International journal of clinical and experimental pathology. 2014;7(6):3174-81.
34. Hirata H, Hinoda Y, Shahryari V, et al. Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205. Cancer Res. Apr 1 2015;75(7):1322-31. doi:10.1158/0008-5472.Can-14-2931
35. Yu EH, Tu HF, Wu CH, Yang CC, Chang KW. MicroRNA-21 promotes perineural invasion and impacts survival in patients with oral carcinoma. Journal of the Chinese Medical Association : JCMA. Jun 2017;80(6):383-388. doi:10.1016/j.jcma.2017.01.003
36. Sousa LO, Sobral LM, Matsumoto CS, et al. Lymph node or perineural invasion is associated with low miR-15a, miR-34c and miR-199b levels in head and neck squamous cell carcinoma. BBA Clinical. 2016/12/01/ 2016;6:159-164. doi:https://doi.org/10.1016/j.bbacli.2016.11.001
37. Sim J, Ahn H, Abdul R, et al. High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer. Journal of breast cancer. Dec 2015;18(4):323-8. doi:10.4048/jbc.2015.18.4.323
38. Demir IE, Boldis A, Pfitzinger PL, et al. Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. Journal of the National Cancer Institute. Aug 2014;106(8)doi:10.1093/jnci/dju184
39. Deborde S, Omelchenko T, Lyubchik A, et al. Schwann cells induce cancer cell dispersion and invasion. J Clin Invest. Apr 1 2016;126(4):1538-54. doi:10.1172/jci82658
40. Azam SH, Pecot CV. Cancer's got nerve: Schwann cells drive perineural invasion. J Clin Invest. Apr 1 2016;126(4):1242-4. doi:10.1172/jci86801
41. Tanaka K, Okugawa Y, Toiyama Y, et al. Brain-Derived Neurotrophic Factor (BDNF)-Induced Tropomyosin-Related Kinase B (Trk B) Signaling Is a Potential Therapeutic Target for Peritoneal Carcinomatosis Arising from Colorectal Cancer. PloS one. 2014;9(5):e96410. doi:10.1371/journal.pone.0096410
42. Shan C, Wei J, Hou R, et al. Schwann cells promote EMT and the Schwann-like differentiation of salivary adenoid cystic carcinoma cells via the BDNF/TrkB axis. Oncology reports. Jan 2016;35(1):427-35. doi:10.3892/or.2015.4366
43. Ferdoushi A, Li X, Griffin N, et al. Schwann Cell Stimulation of Pancreatic Cancer Cells: A Proteomic Analysis. Frontiers in oncology. 2020;10:1601. doi:10.3389/fonc.2020.01601
44. Yoko Fujii‐Nishimura KY, Yohei Masugi, Junya Douguchi, Yutaka Kurebayashi, Naoto Kubota, Hidenori Ojima, Minoru Kitago, Masahiro Shinoda, Akinori Hashiguchi, Michiie Sakamoto. Mesenchymal–epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells. Research Article. Pathology International. 19 February 2018 2018;68(4):214-223. doi:doi.org/10.1111/pin.12641
45. Jeffus SK, Gehlot A, Holthoff E, et al. A fibromyxoid stromal response is associated with an infiltrative tumor morphology, perineural invasion, and lymph node metastasis in squamous cell carcinoma of the vulva. The American journal of surgical pathology. Sep 2015;39(9):1226-33. doi:10.1097/pas.0000000000000486
46. Mitani T, Harada N, Nakano Y, Inui H, Yamaji R. Coordinated action of hypoxia-inducible factor-1α and β-catenin in androgen receptor signaling. The Journal of biological chemistry. 2012;287(40):33594-33606. doi:10.1074/jbc.M112.388298
47. Ramakrishnan R, Pena-Martinez P, Agarwal P, et al. CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia. Cell Rep. May 26 2020;31(8):107684. doi:10.1016/j.celrep.2020.107684
48. Gumy LF, Bampton ETW, Tolkovsky AM. Hyperglycaemia inhibits Schwann cell proliferation and migration and restricts regeneration of axons and Schwann cells from adult murine DRG. Molecular and Cellular Neuroscience. 2008/02/01/ 2008;37(2):298-311. doi:https://doi.org/10.1016/j.mcn.2007.10.004
49. Li J, Ma J, Han L, et al. Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer. Cancer Biol Ther. 2015;16(6):912-921. doi:10.1080/15384047.2015.1040952
50. Armaiz-Pena GN, Cole SW, Lutgendorf SK, Sood AK. Neuroendocrine influences on cancer progression. Brain Behav Immun. 2013;30 Suppl(Suppl):S19-S25. doi:10.1016/j.bbi.2012.06.005
51. Cavel O, Shomron O, Shabtay A, et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res. Nov 15 2012;72(22):5733-43. doi:10.1158/0008-5472.Can-12-0764
52. Tang D, Wang D, Yuan Z, et al. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. International journal of cancer. Mar 1 2013;132(5):993-1003. doi:10.1002/ijc.27715
53. Yao J, Li W-Y, Li S-G, Feng X-S, Gao S-G. Midkine promotes perineural invasion in human pancreatic cancer. World Journal of Gastroenterology: WJG. 2014;20(11):3018.
54. Yao J, Li W-Y, Gao S-G. The advances of Midkine with peripheral invasion in pancreatic cancer. American journal of cancer research. 2015;5(9):2912.
55. Yao J, Zhang L-L, Huang X-M, Li W-Y, Gao S-G. Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer. World journal of gastroenterology. 2017;23(21):3907.
56. Yao J, Li W-Y, Li S-G, Feng X-S, Gao S-G. Midkine promotes perineural invasion in human pancreatic cancer. World J Gastroenterol. 2014;20(11):3018-3024. doi:10.3748/wjg.v20.i11.3018
57. Chen P, Cescon M, Bonaldo P. The Role of Collagens in Peripheral Nerve Myelination and Function. Molecular neurobiology. Aug 2015;52(1):216-25. doi:10.1007/s12035-014-8862-y
58. Guo D, Sun W, Zhu LEI, et al. Knockdown of BDNF suppressed invasion of HepG2 and HCCLM3 cells, a mechanism associated with inactivation of RhoA or Rac1 and actin skeleton disorganization. https://doi.org/10.1111/j.1600-0463.2011.02855.x. APMIS. 2012/06/01 2012;120(6):469-476. doi:https://doi.org/10.1111/j.1600-0463.2011.02855.x
59. Cossa G, Gatti L, Cassinelli G, Lanzi C, Zaffaroni N, Perego P. Modulation of sensitivity to antitumor agents by targeting the MAPK survival pathway. Current pharmaceutical design. 2013;19(5):883-94.
60. Gao H, Peng C, Liang B, et al. β6 integrin induces the expression of metalloproteinase-3 and metalloproteinase-9 in colon cancer cells via ERK-ETS1 pathway. Cancer letters. Nov 28 2014;354(2):427-37. doi:10.1016/j.canlet.2014.08.017
61. Xu L, Hou Y, Tu G, et al. Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer. Cell Death & Disease. 2017/03/01 2017;8(3):e2642-e2642. doi:10.1038/cddis.2017.5
62. Xiang T, Xia X, Yan W. Expression of Matrix Metalloproteinases-2/-9 is Associated With Microvessel Density in Pancreatic Cancer. American journal of therapeutics. Jul/Aug 2017;24(4):e431-e434. doi:10.1097/mjt.0000000000000424
63. Klimczak-Bitner AA, Kordek R, Bitner J, Musiał J, Szemraj J. Expression of MMP9, SERPINE1 and miR-134 as prognostic factors in esophageal cancer. Oncol Lett. Nov 2016;12(5):4133-4138. doi:10.3892/ol.2016.5211
64. Juchniewicz A, Kowalczuk O, Milewski R, et al. MMP-10, MMP-7, TIMP-1 and TIMP-2 mRNA expression in esophageal cancer. Acta biochimica Polonica. 2017;64(2):295-299. doi:10.18388/abp.2016_1408
65. Li Q, Wang Y, Lai Y, Xu P, Yang Z. HspB5 correlates with poor prognosis in colorectal cancer and prompts epithelial-mesenchymal transition through ERK signaling. PloS one. 2017;12(8):e0182588. doi:10.1371/journal.pone.0182588
66. Klupp F, Neumann L, Kahlert C, et al. Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients. BMC cancer. Jul 18 2016;16:494. doi:10.1186/s12885-016-2515-7
67. Fu Y-Z, Su S, Gao Y-Q, et al. Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity. Cell Host & Microbe. 2017/02/08/ 2017;21(2):231-243. doi:https://doi.org/10.1016/j.chom.2017.01.001
68. Han Y, Wu Z, Wu T, et al. Tumor-suppressive function of long non-coding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling. Cell Death Dis. Mar 3 2016;7(3):e2123. doi:10.1038/cddis.2015.407
69. Liu D, Duan W, Guo H, Xu X, Bai Y. Meta-analysis of associations between polymorphisms in the promoter regions of matrix metalloproteinases and the risk of colorectal cancer. International Journal of Colorectal Disease. 2011/05/03 2011;26(9):1099. doi:10.1007/s00384-011-1198-4
70. Du J, Zhang L. Analysis of salivary microRNA expression profiles and identification of novel biomarkers in esophageal cancer. Oncol Lett. Aug 2017;14(2):1387-1394. doi:10.3892/ol.2017.6328
71. Nigri J, Gironella M, Bressy C, et al. PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker. Cellular and molecular life sciences : CMLS. Nov 2017;74(22):4231-4243. doi:10.1007/s00018-017-2579-9
72. Mallini P, Lennard T, Kirby J, Meeson A. Epithelial-to-mesenchymal transition: What is the impact on breast cancer stem cells and drug resistance. Cancer Treatment Reviews. 2014/04/01/ 2014;40(3):341-348. doi:https://doi.org/10.1016/j.ctrv.2013.09.008
73. He Q, Zhou X, Li S, et al. MicroRNA-181a suppresses salivary adenoid cystic carcinoma metastasis by targeting MAPK–Snai2 pathway. Biochimica et Biophysica Acta (BBA) - General Subjects. 2013/11/01/ 2013;1830(11):5258-5266. doi:https://doi.org/10.1016/j.bbagen.2013.07.028
74. Scanlon CS, Banerjee R, Inglehart RC, et al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nature communications. Apr 28 2015;6:6885. doi:10.1038/ncomms7885
75. Tilan J, Kitlinska J. Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology. Neuropeptides. Feb 2016;55:55-66. doi:10.1016/j.npep.2015.10.005
76. Huang C, Li Y, Guo Y, et al. MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells. Theranostics. 2018;8(11):3074-3086. doi:10.7150/thno.24281
77. Shen WR, Wang YP, Chang JY, Yu SY, Chen HM, Chiang CP. Perineural invasion and expression of nerve growth factor can predict the progression and prognosis of oral tongue squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. Apr 2014;43(4):258-64. doi:10.1111/jop.12133
78. Mancino M, Ametller E, Gascón P, Almendro V. The neuronal influence on tumor progression. Biochimica et biophysica acta. Dec 2011;1816(2):105-18. doi:10.1016/j.bbcan.2011.04.005
79. Doebele RC, Davis LE, Vaishnavi A, et al. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer discovery. Oct 2015;5(10):1049-57. doi:10.1158/2159-8290.Cd-15-0443
80. Bapat AA, Munoz RM, Von Hoff DD, Han H. Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells. PloS one. 2016;11(10):e0165586. doi:10.1371/journal.pone.0165586
81. Jia S, Wang W, Hu Z, et al. BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in human salivary adenoid cystic carcinoma. Oral Oncology. 2015/01/01/ 2015;51(1):64-70. doi:https://doi.org/10.1016/j.oraloncology.2014.10.008
82. Okugawa Y, Tanaka K, Inoue Y, et al. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. British journal of cancer. Jan 15 2013;108(1):121-30. doi:10.1038/bjc.2012.499
83. Amit M, Na’ara S, Sharma K, et al. Elective Neck Dissection in Patients With Head and Neck Adenoid Cystic Carcinoma: An International Collaborative Study. Annals of Surgical Oncology. 2015/04/01 2015;22(4):1353-1359. doi:10.1245/s10434-014-4106-7
84. 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. 2015;44(1)
85. Bakst RL, Lee N, He S, et al. Radiation impairs perineural invasion by modulating the nerve microenvironment. PloS one. 2012;7(6):e39925. doi:10.1371/journal.pone.0039925
86. He S, Chen C-H, Chernichenko N, et al. GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci U S A. 2014;111(19):E2008-E2017. doi:10.1073/pnas.1402944111
87. DeLancey JO, Wood DP, Jr., He C, et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology. Feb 2013;81(2):354-7. doi:10.1016/j.urology.2012.09.034
88. Chuang J-Y, Tsai C-F, Chang S-W, et al. Glial cell line-derived neurotrophic factor induces cell migration in human oral squamous cell carcinoma. Oral Oncology. 2013/12/01/ 2013;49(12):1103-1112. doi:https://doi.org/10.1016/j.oraloncology.2013.08.009
89. 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. 2015;44(1):134.
90. Gregory E, Dugan R, David G, Song YH. The biology and engineered modeling strategies of cancer-nerve crosstalk. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2020/12/01/ 2020;1874(2):188406. doi:https://doi.org/10.1016/j.bbcan.2020.188406
91. Warren TA, Nagle CM, Bowman J, Panizza BJ. The Natural History and Treatment Outcomes of Perineural Spread of Malignancy within the Head and Neck. Journal of neurological surgery Part B, Skull base. Apr 2016;77(2):107-12. doi:10.1055/s-0036-1579777
92. Tian X, Gu T, Patel S, Bode AM, Lee MH, Dong Z. CRISPR/Cas9 - An evolving biological tool kit for cancer biology and oncology. NPJ precision oncology. 2019;3:8. doi:10.1038/s41698-019-0080-7
93. Koonin EV, Makarova KS. CRISPR-Cas: evolution of an RNA-based adaptive immunity system in prokaryotes. RNA biology. May 2013;10(5):679-86. doi:10.4161/rna.24022
94. Bapat AA, Hostetter G, Von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nature reviews Cancer. Sep 23 2011;11(10):695-707. doi:10.1038/nrc3131
95. Deshmukh SD, Willmann JK, Jeffrey RB. Pathways of extrapancreatic perineural invasion by pancreatic adenocarcinoma: evaluation with 3D volume-rendered MDCT imaging. AJR American journal of roentgenology. Mar 2010;194(3):668-74. doi:10.2214/ajr.09.3285
96. Demir IE, Friess H, Ceyhan GO. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Front Physiol. 2012;3:97-97. doi:10.3389/fphys.2012.00097
97. Yang YH, Liu JB, Gui Y, Lei LL, Zhang SJ. Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer. World J Gastroenterol. Oct 28 2017;23(40):7232-7241. doi:10.3748/wjg.v23.i40.7232
98. Schorn S, Demir IE, Haller B, et al. The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma - A systematic review and meta-analysis. Surgical oncology. Mar 2017;26(1):105-115. doi:10.1016/j.suronc.2017.01.007
99. Jiang N, Deng JY, Liu Y, Ke B, Liu HG, Liang H. Incorporation of perineural invasion of gastric carcinoma into the 7th edition tumor-node-metastasis staging system. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. Sep 2014;35(9):9429-36. doi:10.1007/s13277-014-2258-5
100. España-Ferrufino A, Lino-Silva LS, Salcedo-Hernández RA. Extramural Perineural Invasion in pT3 and pT4 Gastric Carcinomas. Journal of pathology and translational medicine. Mar 2018;52(2):79-84. doi:10.4132/jptm.2017.11.01
101. Aurello P, Berardi G, Tierno SM, et al. Influence of perineural invasion in predicting overall survival and disease-free survival in patients With locally advanced gastric cancer. The American Journal of Surgery. 2017/04/01/ 2017;213(4):748-753. doi:https://doi.org/10.1016/j.amjsurg.2016.05.022
102. Deng J, You Q, Gao Y, et al. Prognostic value of perineural invasion in gastric cancer: a systematic review and meta-analysis. PloS one. 2014;9(2):e88907. doi:10.1371/journal.pone.0088907
103. Tollefson MK, Karnes RJ, Kwon ED, et al. Prostate cancer Ki-67 (MIB-1) expression, perineural invasion, and gleason score as biopsy-based predictors of prostate cancer mortality: the Mayo model. Mayo Clinic proceedings. Mar 2014;89(3):308-18. doi:10.1016/j.mayocp.2013.12.001
104. Zhang LJ, Wu B, Zha ZL, et al. Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. BMC urology. Feb 1 2018;18(1):5. doi:10.1186/s12894-018-0319-6
105. Lubig S, Thiesler T, Müller S, Vorreuther R, Leipner N, Kristiansen G. Quantitative perineural invasion is a prognostic marker in prostate cancer. Pathology. 2018/04/01/ 2018;50(3):298-304. doi:https://doi.org/10.1016/j.pathol.2017.09.013
106. Feo C, Cossu M, Ginesu G, et al. Perineural infiltration as a prognostic factor in surgically treated gallbladder cancer: A single center experience and literature review. Annali italiani di chirurgia. 10/04 2017;6
107. Murakami Y, Uemura K, Sudo T, et al. Perineural Invasion in Extrahepatic Cholangiocarcinoma: Prognostic Impact and Treatment Strategies. Journal of Gastrointestinal Surgery. 2013/08/01 2013;17(8):1429-1439. doi:10.1007/s11605-013-2251-0
108. Wellner UF, Shen Y, Keck T, Jin W, Xu Z. The survival outcome and prognostic factors for distal cholangiocarcinoma following surgical resection: a meta-analysis for the 5-year survival. Surgery today. Mar 2017;47(3):271-279. doi:10.1007/s00595-016-1362-0
109. Quintana JM, González N, Lázaro S, et al. Predictors of 1- and 2-year mortality in patients with rectal cancer. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. Aug 2018;20(8):676-687. doi:10.1111/codi.14250
110. Zare Bandamiri M, Fararouei M, Zohourinia S, Daneshi N, Dianatinasab M. Risk Factors Predicting Colorectal Cancer Recurrence Following Initial Treatment: A 5-year Cohort Study. Asian Pacific journal of cancer prevention: APJCP. 09/18 2017;18:2465-2470. doi:10.22034/APJCP.2017.18.9.2465
111. Huang Y, He L, Dong D, et al. Individualized prediction of perineural invasion in colorectal cancer: development and validation of a radiomics prediction model. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu. Feb 2018;30(1):40-50. doi:10.21147/j.issn.1000-9604.2018.01.05
112. Milica Stojkovic Lalosevic TM, Marjan Micev, Mirjana Stojkovic, Sanja Dragasevic, Milos Stulic, Ivan Rankovic, Vladimir Dugalic, Zoran Krivokapic, Aleksandra Pavlovic Markovic Perineural invasion as a prognostic factor in patients with stage I-III rectal cancer – 5-year follow up. World J Gastrointest Oncol. May 15, 2020; 12(5): 592-600doi:10.4251/wjgo.v12.i5.592
113. Amit M, Eran A, Billan S, et al. Perineural Spread in Noncutaneous Head and Neck Cancer: New Insights into an Old Problem. Journal of neurological surgery Part B, Skull base. Apr 2016;77(2):86-95. doi:10.1055/s-0036-1571834
114. Bakst RL, Glastonbury CM, Parvathaneni U, Katabi N, Hu KS, Yom SS. Perineural Invasion and Perineural Tumor Spread in Head and Neck Cancer. International Journal of Radiation Oncology*Biology*Physics. 2019/04/01/ 2019;103(5):1109-1124. doi:https://doi.org/10.1016/j.ijrobp.2018.12.009
115. Turner FE, Broad S, Khanim FL, et al. Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes. The Journal of biological chemistry. Jul 28 2006;281(30):21321-31. doi:10.1074/jbc.M509731200
116. Zhang L, Fang P, Chai C, et al. Galanin expression is down-regulated in patients with gastric cancer. J Int Med Res. 2019;47(3):1241-1249. doi:10.1177/0300060518819382
117. Körner M, Waser B, Reubi JC. High Expression of Neuropeptide Y Receptors in Tumors of the Human Adrenal Gland and Extra-Adrenal Paraganglia. Clinical Cancer Research. 2004;10(24):8426. doi:10.1158/1078-0432.CCR-04-0821
118. Wu JQ, Jiang N, Yu B. Mechanisms of action of neuropeptide Y on stem cells and its potential applications in orthopaedic disorders. World journal of stem cells. Sep 26 2020;12(9):986-1000. doi:10.4252/wjsc.v12.i9.986
119. Li S, Sun Y, Gao D. Role of the nervous system in cancer metastasis. Oncol Lett. 2013;5(4):1101-1111. doi:10.3892/ol.2013.1168
120. Chen X-Y, Ru G-Q, Ma Y-Y, et al. High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis. Onco Targets Ther. 2016;9:3595-3602. doi:10.2147/OTT.S102356
121. Campenot RB. NGF and the local control of nerve terminal growth. Journal of neurobiology. Jun 1994;25(6):599-611. doi:10.1002/neu.480250603
122. Adriaenssens E, Vanhecke E, Saule P, et al. Nerve Growth Factor Is a Potential Therapeutic Target in Breast Cancer. Cancer Research. 2008;68(2):346. doi:10.1158/0008-5472.CAN-07-1183
123. Shishkina TV, Mishchenko TA, Mitroshina EV, et al. Glial cell line-derived neurotrophic factor (GDNF) counteracts hypoxic damage to hippocampal neural network function in vitro. Brain Research. 2018/01/01/ 2018;1678:310-321. doi:https://doi.org/10.1016/j.brainres.2017.10.023
124. Saffrey MJ. Enteric Nervous System: Neurotrophic Factors☆. Reference Module in Neuroscience and Biobehavioral Psychology. Elsevier; 2017.
125. Dufour S, Broders-Bondon F, Bondurand N. Chapter 13 - β1-Integrin Function and Interplay during Enteric Nervous System Development. In: Pruszak J, ed. Neural Surface Antigens. Academic Press; 2015:153-166.
126. Sawai H, Okada Y, Kazanjian K, 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 Research. 2005;65(24):11536. doi:10.1158/0008-5472.CAN-05-2843
127. Saarma M. GFL Neurotrophic Factors: Physiology and Pharmacology. Encyclopedia of Neuroscience. 01/01 2010:711-720. doi:10.1016/B978-008045046-9.00501-5
128. Schachner M, Leshchyns'ka I, Sytnyk V. Functions of the Neural Cell Adhesion Molecule (NCAM) at the Synapse. 2017.
129. Phimister E, Kiely F, Kemshead JT, Patel K. Expression of neural cell adhesion molecule (NCAM) isoforms in neuroblastoma. J Clin Pathol. Jul 1991;44(7):580-5. doi:10.1136/jcp.44.7.580
130. Schachner M, Leshchyns’ka I, Sytnyk V. Neural Cell Adhesion Molecules and Synapse Regulation. In: Squire LR, ed. Encyclopedia of Neuroscience. Academic Press; 2009:91-96.
131. Merdad A, Karim S, Schulten HJ, et al. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis. Anticancer research. Mar 2014;34(3):1355-66.
132. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular Research. 2006;69(3):562-573. doi:10.1016/j.cardiores.2005.12.002
133. Murphy G. Matrix Metalloproteinases. In: Bradshaw RA, Stahl PD, eds. Encyclopedia of Cell Biology. Academic Press; 2016:621-629.
134. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185-149185. doi:10.1155/2014/149185
135. Carswell-Richards EA, Williamson BD. A man of vision and the discovery of tumor necrosis factor. Cancer Immun. 2012;12:4-4.
136. Muthukumaran N, Miletti-González KE, Ravindranath AK, Rodríguez-Rodríguez L. Tumor Necrosis Factor-α Differentially Modulates CD44 Expression in Ovarian Cancer Cells. Molecular Cancer Research. 2006;4(8):511. doi:10.1158/1541-7786.MCR-05-0232
137. Cruceriu D, Baldasici O, Balacescu O, Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches. Cellular oncology (Dordrecht). Feb 2020;43(1):1-18. doi:10.1007/s13402-019-00489-1
138. Tanabe K, Matsushima-Nishiwaki R, Yamaguchi S, Iida H, Dohi S, Kozawa O. Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells. J Neuroinflammation. 2010;7:16-16. doi:10.1186/1742-2094-7-16
139. Culig Z. Proinflammatory cytokine interleukin-6 in prostate carcinogenesis. Am J Clin Exp Urol. 2014;2(3):231-238.
140. Jones SA, Takeuchi T, Aletaha D, Smolen J, Choy EH, McInnes I. Interleukin 6: The biology behind the therapy. Considerations in Medicine. 2018;2(1):2. doi:10.1136/conmed-2018-000005
141. Heikkilä K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. European Journal of Cancer. 2008/05/01/ 2008;44(7):937-945. doi:https://doi.org/10.1016/j.ejca.2008.02.047
142. Morrison CD, Parvani JG, Schiemann WP. The relevance of the TGF-β Paradox to EMT-MET programs. Cancer letters. Nov 28 2013;341(1):30-40. doi:10.1016/j.canlet.2013.02.048
143. Bierie B, Moses HL. TGF-beta and cancer. Cytokine & growth factor reviews. Feb-Apr 2006;17(1-2):29-40. doi:10.1016/j.cytogfr.2005.09.006
144. Zhao Y, Ma J, Fan Y, et al. TGF-β transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways. Molecular oncology. Mar 2018;12(3):305-321. doi:10.1002/1878-0261.12162
145. Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS, Jr. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. The Journal of biological chemistry. Nov 5 1999;274(45):31868-74. doi:10.1074/jbc.274.45.31868
146. Wang Y, Liu X-H, Li Y-H, Li O. The paradox of IL-10-mediated modulation in cervical cancer. Biomed Rep. 2013;1(3):347-351. doi:10.3892/br.2013.69
2. Chen S-H, Zhang B-Y, Zhou B, Zhu C-Z, Sun L-Q, Feng Y-J. Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche. Am J Cancer Res. 2019;9(1):1-21.
3. Ronaghy A, Yaar R, Goldberg LJ, Mahalingam M, Bhawan J. Perineural Involvement: What Does it Mean? The American Journal of Dermatopathology. 2010;32(5)
4. Seifert P, Spitznas M. Tumours may be innervated. Virchows Archiv : an international journal of pathology. 03/01 2001;438:228-31. doi:10.1007/s004280000306
5. Seifert P, Benedic M, Effert P. Nerve fibers in tumors of the human urinary bladder. Virchows Archiv. 2002/03/01 2002;440(3):291-297. doi:10.1007/s004280100496
6. Lü S-H, Zhou Y, Que H-P, Liu S-J. Peptidergic innervation of human esophageal and cardiac carcinoma. World J Gastroenterol. 2003;9(3):399-403. doi:10.3748/wjg.v9.i3.399
7. Liang Y-J, Zhou P, Wongba W, Guardiola J, Walker J, Yu J. Pulmonary innervation, inflammation and carcinogenesis. Sheng li xue bao : [Acta physiologica Sinica]. 06/25 2010;62:191-5.
8. Batsakis JG. Nerves and neurotropic carcinomas. The Annals of otology, rhinology, and laryngology. Jul-Aug 1985;94(4 Pt 1):426-7.
9. Ayala GE, Wheeler TM, Shine HD, et al. In vitro dorsal root ganglia and human prostate cell line interaction: Redefining perineural invasion in prostate cancer. https://doi.org/10.1002/pros.1137. The Prostate. 2001/11/01 2001;49(3):213-223. doi:https://doi.org/10.1002/pros.1137
10. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. Aug 1 2009;115(15):3379-91. doi:10.1002/cncr.24396
11. Lutgendorf SK, DeGeest K, Dahmoush L, et al. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun. 2011;25(2):250-255. doi:10.1016/j.bbi.2010.10.012
12. Hassan S, Karpova Y, Baiz D, et al. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest. Feb 2013;123(2):874-86. doi:10.1172/jci63324
13. Karak S, Quatrano N, Buckley J, Ricci A. Prevalence and significance of perineural invasion in invasive breast carcinoma. Connecticut medicine. 01/01 2010;74:17-21.
14. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer. Cancer. 2009/08/01 2009;115(15):3379-3391. doi:10.1002/cncr.24396
15. Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, Tredici G. Mesenchymal stem cells neuronal differentiation ability: a real perspective for nervous system repair? Current stem cell research & therapy. Jun 2011;6(2):82-92. doi:10.2174/157488811795495486
16. Heikkilä K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. European journal of cancer (Oxford, England : 1990). May 2008;44(7):937-45. doi:10.1016/j.ejca.2008.02.047
17. Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. Journal of enzyme inhibition and medicinal chemistry. 2016;31(sup1):177-183. doi:10.3109/14756366.2016.1161620
18. Aloe L, Rocco ML, Balzamino BO, Micera A. Nerve Growth Factor: A Focus on Neuroscience and Therapy. Curr Neuropharmacol. 2015;13(3):294-303. doi:10.2174/1570159x13666150403231920
19. Gash DM, Gerhardt GA, Slevin JT. GDNF (Including Neurturin)☆. Reference Module in Neuroscience and Biobehavioral Psychology. Elsevier; 2017.
20. Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine & growth factor reviews. Feb 2010;21(1):77-82. doi:10.1016/j.cytogfr.2009.11.001
21. Bakst R, Wong R. Mechanisms of Perineural Invasion. Journal of Neurological Surgery Part B: Skull Base. 03/10 2016;77doi:10.1055/s-0036-1571835
22. Azam SH, Pecot CV. Cancer's got nerve: Schwann cells drive perineural invasion. J Clin Invest. 2016;126(4):1242-1244. doi:10.1172/JCI86801
23. Amit M, Na'ara S, Gil Z. Mechanisms of cancer dissemination along nerves. Nature Reviews Cancer. 2016/06/01 2016;16(6):399-408. doi:10.1038/nrc.2016.38
24. Olar A, He D, Florentin D, Ding Y, Wheeler T, Ayala G. Biological correlates of prostate cancer perineural invasion diameter. Human pathology. Jul 2014;45(7):1365-9. doi:10.1016/j.humpath.2014.02.011
25. Reavis HD, Chen HI, Drapkin R. Tumor Innervation: Cancer Has Some Nerve. Trends in Cancer. 2020/08/14/ 2020;doi:https://doi.org/10.1016/j.trecan.2020.07.005
26. Yates C. Influence of Tumor Microenvironment on the Molecular Regulation of Prostate Cancer Progression. 2009.
27. Li X, Ma Q, Xu Q, et al. SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer letters. 2012;322(2):169-176. doi:10.1016/j.canlet.2012.02.035
28. Zhao C-M, Hayakawa Y, Kodama Y, et al. Denervation suppresses gastric tumorigenesis. Science Translational Medicine. 2014;6(250):250ra115. doi:10.1126/scitranslmed.3009569
29. Samarelli AV, Riccitelli E, Bizzozero L, et al. Neuroligin 1 induces blood vessel maturation by cooperating with the α6 integrin. The Journal of biological chemistry. Jul 11 2014;289(28):19466-76. doi:10.1074/jbc.M113.530972
30. Graziano S, Marchiò S, Bussolino F, Arese M. A peptide from the extracellular region of the synaptic protein α Neurexin stimulates angiogenesis and the vascular specific tyrosine kinase Tie2. Biochemical and Biophysical Research Communications. 2013/03/22/ 2013;432(4):574-579. doi:https://doi.org/10.1016/j.bbrc.2013.02.045
31. Marco Arese FB, Margherita Pergolizzi, Laura Bizzozero, Davide Pascal. Tumor progression: the neuronal input Review. Annals of Translational Medicine. 2018;6(5):89. doi:10.21037/atm.2018.01.01
32. Tan X, Huang Z, Li X. Long Non-Coding RNA MALAT1 Interacts With miR-204 to Modulate Human Hilar Cholangiocarcinoma Proliferation, Migration, and Invasion by Targeting CXCR4. Journal of cellular biochemistry. Nov 2017;118(11):3643-3653. doi:10.1002/jcb.25862
33. Zheng HT, Shi DB, Wang YW, et al. High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer. International journal of clinical and experimental pathology. 2014;7(6):3174-81.
34. Hirata H, Hinoda Y, Shahryari V, et al. Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205. Cancer Res. Apr 1 2015;75(7):1322-31. doi:10.1158/0008-5472.Can-14-2931
35. Yu EH, Tu HF, Wu CH, Yang CC, Chang KW. MicroRNA-21 promotes perineural invasion and impacts survival in patients with oral carcinoma. Journal of the Chinese Medical Association : JCMA. Jun 2017;80(6):383-388. doi:10.1016/j.jcma.2017.01.003
36. Sousa LO, Sobral LM, Matsumoto CS, et al. Lymph node or perineural invasion is associated with low miR-15a, miR-34c and miR-199b levels in head and neck squamous cell carcinoma. BBA Clinical. 2016/12/01/ 2016;6:159-164. doi:https://doi.org/10.1016/j.bbacli.2016.11.001
37. Sim J, Ahn H, Abdul R, et al. High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer. Journal of breast cancer. Dec 2015;18(4):323-8. doi:10.4048/jbc.2015.18.4.323
38. Demir IE, Boldis A, Pfitzinger PL, et al. Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. Journal of the National Cancer Institute. Aug 2014;106(8)doi:10.1093/jnci/dju184
39. Deborde S, Omelchenko T, Lyubchik A, et al. Schwann cells induce cancer cell dispersion and invasion. J Clin Invest. Apr 1 2016;126(4):1538-54. doi:10.1172/jci82658
40. Azam SH, Pecot CV. Cancer's got nerve: Schwann cells drive perineural invasion. J Clin Invest. Apr 1 2016;126(4):1242-4. doi:10.1172/jci86801
41. Tanaka K, Okugawa Y, Toiyama Y, et al. Brain-Derived Neurotrophic Factor (BDNF)-Induced Tropomyosin-Related Kinase B (Trk B) Signaling Is a Potential Therapeutic Target for Peritoneal Carcinomatosis Arising from Colorectal Cancer. PloS one. 2014;9(5):e96410. doi:10.1371/journal.pone.0096410
42. Shan C, Wei J, Hou R, et al. Schwann cells promote EMT and the Schwann-like differentiation of salivary adenoid cystic carcinoma cells via the BDNF/TrkB axis. Oncology reports. Jan 2016;35(1):427-35. doi:10.3892/or.2015.4366
43. Ferdoushi A, Li X, Griffin N, et al. Schwann Cell Stimulation of Pancreatic Cancer Cells: A Proteomic Analysis. Frontiers in oncology. 2020;10:1601. doi:10.3389/fonc.2020.01601
44. Yoko Fujii‐Nishimura KY, Yohei Masugi, Junya Douguchi, Yutaka Kurebayashi, Naoto Kubota, Hidenori Ojima, Minoru Kitago, Masahiro Shinoda, Akinori Hashiguchi, Michiie Sakamoto. Mesenchymal–epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells. Research Article. Pathology International. 19 February 2018 2018;68(4):214-223. doi:doi.org/10.1111/pin.12641
45. Jeffus SK, Gehlot A, Holthoff E, et al. A fibromyxoid stromal response is associated with an infiltrative tumor morphology, perineural invasion, and lymph node metastasis in squamous cell carcinoma of the vulva. The American journal of surgical pathology. Sep 2015;39(9):1226-33. doi:10.1097/pas.0000000000000486
46. Mitani T, Harada N, Nakano Y, Inui H, Yamaji R. Coordinated action of hypoxia-inducible factor-1α and β-catenin in androgen receptor signaling. The Journal of biological chemistry. 2012;287(40):33594-33606. doi:10.1074/jbc.M112.388298
47. Ramakrishnan R, Pena-Martinez P, Agarwal P, et al. CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia. Cell Rep. May 26 2020;31(8):107684. doi:10.1016/j.celrep.2020.107684
48. Gumy LF, Bampton ETW, Tolkovsky AM. Hyperglycaemia inhibits Schwann cell proliferation and migration and restricts regeneration of axons and Schwann cells from adult murine DRG. Molecular and Cellular Neuroscience. 2008/02/01/ 2008;37(2):298-311. doi:https://doi.org/10.1016/j.mcn.2007.10.004
49. Li J, Ma J, Han L, et al. Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer. Cancer Biol Ther. 2015;16(6):912-921. doi:10.1080/15384047.2015.1040952
50. Armaiz-Pena GN, Cole SW, Lutgendorf SK, Sood AK. Neuroendocrine influences on cancer progression. Brain Behav Immun. 2013;30 Suppl(Suppl):S19-S25. doi:10.1016/j.bbi.2012.06.005
51. Cavel O, Shomron O, Shabtay A, et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res. Nov 15 2012;72(22):5733-43. doi:10.1158/0008-5472.Can-12-0764
52. Tang D, Wang D, Yuan Z, et al. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. International journal of cancer. Mar 1 2013;132(5):993-1003. doi:10.1002/ijc.27715
53. Yao J, Li W-Y, Li S-G, Feng X-S, Gao S-G. Midkine promotes perineural invasion in human pancreatic cancer. World Journal of Gastroenterology: WJG. 2014;20(11):3018.
54. Yao J, Li W-Y, Gao S-G. The advances of Midkine with peripheral invasion in pancreatic cancer. American journal of cancer research. 2015;5(9):2912.
55. Yao J, Zhang L-L, Huang X-M, Li W-Y, Gao S-G. Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer. World journal of gastroenterology. 2017;23(21):3907.
56. Yao J, Li W-Y, Li S-G, Feng X-S, Gao S-G. Midkine promotes perineural invasion in human pancreatic cancer. World J Gastroenterol. 2014;20(11):3018-3024. doi:10.3748/wjg.v20.i11.3018
57. Chen P, Cescon M, Bonaldo P. The Role of Collagens in Peripheral Nerve Myelination and Function. Molecular neurobiology. Aug 2015;52(1):216-25. doi:10.1007/s12035-014-8862-y
58. Guo D, Sun W, Zhu LEI, et al. Knockdown of BDNF suppressed invasion of HepG2 and HCCLM3 cells, a mechanism associated with inactivation of RhoA or Rac1 and actin skeleton disorganization. https://doi.org/10.1111/j.1600-0463.2011.02855.x. APMIS. 2012/06/01 2012;120(6):469-476. doi:https://doi.org/10.1111/j.1600-0463.2011.02855.x
59. Cossa G, Gatti L, Cassinelli G, Lanzi C, Zaffaroni N, Perego P. Modulation of sensitivity to antitumor agents by targeting the MAPK survival pathway. Current pharmaceutical design. 2013;19(5):883-94.
60. Gao H, Peng C, Liang B, et al. β6 integrin induces the expression of metalloproteinase-3 and metalloproteinase-9 in colon cancer cells via ERK-ETS1 pathway. Cancer letters. Nov 28 2014;354(2):427-37. doi:10.1016/j.canlet.2014.08.017
61. Xu L, Hou Y, Tu G, et al. Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer. Cell Death & Disease. 2017/03/01 2017;8(3):e2642-e2642. doi:10.1038/cddis.2017.5
62. Xiang T, Xia X, Yan W. Expression of Matrix Metalloproteinases-2/-9 is Associated With Microvessel Density in Pancreatic Cancer. American journal of therapeutics. Jul/Aug 2017;24(4):e431-e434. doi:10.1097/mjt.0000000000000424
63. Klimczak-Bitner AA, Kordek R, Bitner J, Musiał J, Szemraj J. Expression of MMP9, SERPINE1 and miR-134 as prognostic factors in esophageal cancer. Oncol Lett. Nov 2016;12(5):4133-4138. doi:10.3892/ol.2016.5211
64. Juchniewicz A, Kowalczuk O, Milewski R, et al. MMP-10, MMP-7, TIMP-1 and TIMP-2 mRNA expression in esophageal cancer. Acta biochimica Polonica. 2017;64(2):295-299. doi:10.18388/abp.2016_1408
65. Li Q, Wang Y, Lai Y, Xu P, Yang Z. HspB5 correlates with poor prognosis in colorectal cancer and prompts epithelial-mesenchymal transition through ERK signaling. PloS one. 2017;12(8):e0182588. doi:10.1371/journal.pone.0182588
66. Klupp F, Neumann L, Kahlert C, et al. Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients. BMC cancer. Jul 18 2016;16:494. doi:10.1186/s12885-016-2515-7
67. Fu Y-Z, Su S, Gao Y-Q, et al. Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity. Cell Host & Microbe. 2017/02/08/ 2017;21(2):231-243. doi:https://doi.org/10.1016/j.chom.2017.01.001
68. Han Y, Wu Z, Wu T, et al. Tumor-suppressive function of long non-coding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling. Cell Death Dis. Mar 3 2016;7(3):e2123. doi:10.1038/cddis.2015.407
69. Liu D, Duan W, Guo H, Xu X, Bai Y. Meta-analysis of associations between polymorphisms in the promoter regions of matrix metalloproteinases and the risk of colorectal cancer. International Journal of Colorectal Disease. 2011/05/03 2011;26(9):1099. doi:10.1007/s00384-011-1198-4
70. Du J, Zhang L. Analysis of salivary microRNA expression profiles and identification of novel biomarkers in esophageal cancer. Oncol Lett. Aug 2017;14(2):1387-1394. doi:10.3892/ol.2017.6328
71. Nigri J, Gironella M, Bressy C, et al. PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker. Cellular and molecular life sciences : CMLS. Nov 2017;74(22):4231-4243. doi:10.1007/s00018-017-2579-9
72. Mallini P, Lennard T, Kirby J, Meeson A. Epithelial-to-mesenchymal transition: What is the impact on breast cancer stem cells and drug resistance. Cancer Treatment Reviews. 2014/04/01/ 2014;40(3):341-348. doi:https://doi.org/10.1016/j.ctrv.2013.09.008
73. He Q, Zhou X, Li S, et al. MicroRNA-181a suppresses salivary adenoid cystic carcinoma metastasis by targeting MAPK–Snai2 pathway. Biochimica et Biophysica Acta (BBA) - General Subjects. 2013/11/01/ 2013;1830(11):5258-5266. doi:https://doi.org/10.1016/j.bbagen.2013.07.028
74. Scanlon CS, Banerjee R, Inglehart RC, et al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nature communications. Apr 28 2015;6:6885. doi:10.1038/ncomms7885
75. Tilan J, Kitlinska J. Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology. Neuropeptides. Feb 2016;55:55-66. doi:10.1016/j.npep.2015.10.005
76. Huang C, Li Y, Guo Y, et al. MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells. Theranostics. 2018;8(11):3074-3086. doi:10.7150/thno.24281
77. Shen WR, Wang YP, Chang JY, Yu SY, Chen HM, Chiang CP. Perineural invasion and expression of nerve growth factor can predict the progression and prognosis of oral tongue squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. Apr 2014;43(4):258-64. doi:10.1111/jop.12133
78. Mancino M, Ametller E, Gascón P, Almendro V. The neuronal influence on tumor progression. Biochimica et biophysica acta. Dec 2011;1816(2):105-18. doi:10.1016/j.bbcan.2011.04.005
79. Doebele RC, Davis LE, Vaishnavi A, et al. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer discovery. Oct 2015;5(10):1049-57. doi:10.1158/2159-8290.Cd-15-0443
80. Bapat AA, Munoz RM, Von Hoff DD, Han H. Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells. PloS one. 2016;11(10):e0165586. doi:10.1371/journal.pone.0165586
81. Jia S, Wang W, Hu Z, et al. BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in human salivary adenoid cystic carcinoma. Oral Oncology. 2015/01/01/ 2015;51(1):64-70. doi:https://doi.org/10.1016/j.oraloncology.2014.10.008
82. Okugawa Y, Tanaka K, Inoue Y, et al. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. British journal of cancer. Jan 15 2013;108(1):121-30. doi:10.1038/bjc.2012.499
83. Amit M, Na’ara S, Sharma K, et al. Elective Neck Dissection in Patients With Head and Neck Adenoid Cystic Carcinoma: An International Collaborative Study. Annals of Surgical Oncology. 2015/04/01 2015;22(4):1353-1359. doi:10.1245/s10434-014-4106-7
84. 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. 2015;44(1)
85. Bakst RL, Lee N, He S, et al. Radiation impairs perineural invasion by modulating the nerve microenvironment. PloS one. 2012;7(6):e39925. doi:10.1371/journal.pone.0039925
86. He S, Chen C-H, Chernichenko N, et al. GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci U S A. 2014;111(19):E2008-E2017. doi:10.1073/pnas.1402944111
87. DeLancey JO, Wood DP, Jr., He C, et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology. Feb 2013;81(2):354-7. doi:10.1016/j.urology.2012.09.034
88. Chuang J-Y, Tsai C-F, Chang S-W, et al. Glial cell line-derived neurotrophic factor induces cell migration in human oral squamous cell carcinoma. Oral Oncology. 2013/12/01/ 2013;49(12):1103-1112. doi:https://doi.org/10.1016/j.oraloncology.2013.08.009
89. 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. 2015;44(1):134.
90. Gregory E, Dugan R, David G, Song YH. The biology and engineered modeling strategies of cancer-nerve crosstalk. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2020/12/01/ 2020;1874(2):188406. doi:https://doi.org/10.1016/j.bbcan.2020.188406
91. Warren TA, Nagle CM, Bowman J, Panizza BJ. The Natural History and Treatment Outcomes of Perineural Spread of Malignancy within the Head and Neck. Journal of neurological surgery Part B, Skull base. Apr 2016;77(2):107-12. doi:10.1055/s-0036-1579777
92. Tian X, Gu T, Patel S, Bode AM, Lee MH, Dong Z. CRISPR/Cas9 - An evolving biological tool kit for cancer biology and oncology. NPJ precision oncology. 2019;3:8. doi:10.1038/s41698-019-0080-7
93. Koonin EV, Makarova KS. CRISPR-Cas: evolution of an RNA-based adaptive immunity system in prokaryotes. RNA biology. May 2013;10(5):679-86. doi:10.4161/rna.24022
94. Bapat AA, Hostetter G, Von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nature reviews Cancer. Sep 23 2011;11(10):695-707. doi:10.1038/nrc3131
95. Deshmukh SD, Willmann JK, Jeffrey RB. Pathways of extrapancreatic perineural invasion by pancreatic adenocarcinoma: evaluation with 3D volume-rendered MDCT imaging. AJR American journal of roentgenology. Mar 2010;194(3):668-74. doi:10.2214/ajr.09.3285
96. Demir IE, Friess H, Ceyhan GO. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Front Physiol. 2012;3:97-97. doi:10.3389/fphys.2012.00097
97. Yang YH, Liu JB, Gui Y, Lei LL, Zhang SJ. Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer. World J Gastroenterol. Oct 28 2017;23(40):7232-7241. doi:10.3748/wjg.v23.i40.7232
98. Schorn S, Demir IE, Haller B, et al. The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma - A systematic review and meta-analysis. Surgical oncology. Mar 2017;26(1):105-115. doi:10.1016/j.suronc.2017.01.007
99. Jiang N, Deng JY, Liu Y, Ke B, Liu HG, Liang H. Incorporation of perineural invasion of gastric carcinoma into the 7th edition tumor-node-metastasis staging system. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. Sep 2014;35(9):9429-36. doi:10.1007/s13277-014-2258-5
100. España-Ferrufino A, Lino-Silva LS, Salcedo-Hernández RA. Extramural Perineural Invasion in pT3 and pT4 Gastric Carcinomas. Journal of pathology and translational medicine. Mar 2018;52(2):79-84. doi:10.4132/jptm.2017.11.01
101. Aurello P, Berardi G, Tierno SM, et al. Influence of perineural invasion in predicting overall survival and disease-free survival in patients With locally advanced gastric cancer. The American Journal of Surgery. 2017/04/01/ 2017;213(4):748-753. doi:https://doi.org/10.1016/j.amjsurg.2016.05.022
102. Deng J, You Q, Gao Y, et al. Prognostic value of perineural invasion in gastric cancer: a systematic review and meta-analysis. PloS one. 2014;9(2):e88907. doi:10.1371/journal.pone.0088907
103. Tollefson MK, Karnes RJ, Kwon ED, et al. Prostate cancer Ki-67 (MIB-1) expression, perineural invasion, and gleason score as biopsy-based predictors of prostate cancer mortality: the Mayo model. Mayo Clinic proceedings. Mar 2014;89(3):308-18. doi:10.1016/j.mayocp.2013.12.001
104. Zhang LJ, Wu B, Zha ZL, et al. Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. BMC urology. Feb 1 2018;18(1):5. doi:10.1186/s12894-018-0319-6
105. Lubig S, Thiesler T, Müller S, Vorreuther R, Leipner N, Kristiansen G. Quantitative perineural invasion is a prognostic marker in prostate cancer. Pathology. 2018/04/01/ 2018;50(3):298-304. doi:https://doi.org/10.1016/j.pathol.2017.09.013
106. Feo C, Cossu M, Ginesu G, et al. Perineural infiltration as a prognostic factor in surgically treated gallbladder cancer: A single center experience and literature review. Annali italiani di chirurgia. 10/04 2017;6
107. Murakami Y, Uemura K, Sudo T, et al. Perineural Invasion in Extrahepatic Cholangiocarcinoma: Prognostic Impact and Treatment Strategies. Journal of Gastrointestinal Surgery. 2013/08/01 2013;17(8):1429-1439. doi:10.1007/s11605-013-2251-0
108. Wellner UF, Shen Y, Keck T, Jin W, Xu Z. The survival outcome and prognostic factors for distal cholangiocarcinoma following surgical resection: a meta-analysis for the 5-year survival. Surgery today. Mar 2017;47(3):271-279. doi:10.1007/s00595-016-1362-0
109. Quintana JM, González N, Lázaro S, et al. Predictors of 1- and 2-year mortality in patients with rectal cancer. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. Aug 2018;20(8):676-687. doi:10.1111/codi.14250
110. Zare Bandamiri M, Fararouei M, Zohourinia S, Daneshi N, Dianatinasab M. Risk Factors Predicting Colorectal Cancer Recurrence Following Initial Treatment: A 5-year Cohort Study. Asian Pacific journal of cancer prevention: APJCP. 09/18 2017;18:2465-2470. doi:10.22034/APJCP.2017.18.9.2465
111. Huang Y, He L, Dong D, et al. Individualized prediction of perineural invasion in colorectal cancer: development and validation of a radiomics prediction model. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu. Feb 2018;30(1):40-50. doi:10.21147/j.issn.1000-9604.2018.01.05
112. Milica Stojkovic Lalosevic TM, Marjan Micev, Mirjana Stojkovic, Sanja Dragasevic, Milos Stulic, Ivan Rankovic, Vladimir Dugalic, Zoran Krivokapic, Aleksandra Pavlovic Markovic Perineural invasion as a prognostic factor in patients with stage I-III rectal cancer – 5-year follow up. World J Gastrointest Oncol. May 15, 2020; 12(5): 592-600doi:10.4251/wjgo.v12.i5.592
113. Amit M, Eran A, Billan S, et al. Perineural Spread in Noncutaneous Head and Neck Cancer: New Insights into an Old Problem. Journal of neurological surgery Part B, Skull base. Apr 2016;77(2):86-95. doi:10.1055/s-0036-1571834
114. Bakst RL, Glastonbury CM, Parvathaneni U, Katabi N, Hu KS, Yom SS. Perineural Invasion and Perineural Tumor Spread in Head and Neck Cancer. International Journal of Radiation Oncology*Biology*Physics. 2019/04/01/ 2019;103(5):1109-1124. doi:https://doi.org/10.1016/j.ijrobp.2018.12.009
115. Turner FE, Broad S, Khanim FL, et al. Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes. The Journal of biological chemistry. Jul 28 2006;281(30):21321-31. doi:10.1074/jbc.M509731200
116. Zhang L, Fang P, Chai C, et al. Galanin expression is down-regulated in patients with gastric cancer. J Int Med Res. 2019;47(3):1241-1249. doi:10.1177/0300060518819382
117. Körner M, Waser B, Reubi JC. High Expression of Neuropeptide Y Receptors in Tumors of the Human Adrenal Gland and Extra-Adrenal Paraganglia. Clinical Cancer Research. 2004;10(24):8426. doi:10.1158/1078-0432.CCR-04-0821
118. Wu JQ, Jiang N, Yu B. Mechanisms of action of neuropeptide Y on stem cells and its potential applications in orthopaedic disorders. World journal of stem cells. Sep 26 2020;12(9):986-1000. doi:10.4252/wjsc.v12.i9.986
119. Li S, Sun Y, Gao D. Role of the nervous system in cancer metastasis. Oncol Lett. 2013;5(4):1101-1111. doi:10.3892/ol.2013.1168
120. Chen X-Y, Ru G-Q, Ma Y-Y, et al. High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis. Onco Targets Ther. 2016;9:3595-3602. doi:10.2147/OTT.S102356
121. Campenot RB. NGF and the local control of nerve terminal growth. Journal of neurobiology. Jun 1994;25(6):599-611. doi:10.1002/neu.480250603
122. Adriaenssens E, Vanhecke E, Saule P, et al. Nerve Growth Factor Is a Potential Therapeutic Target in Breast Cancer. Cancer Research. 2008;68(2):346. doi:10.1158/0008-5472.CAN-07-1183
123. Shishkina TV, Mishchenko TA, Mitroshina EV, et al. Glial cell line-derived neurotrophic factor (GDNF) counteracts hypoxic damage to hippocampal neural network function in vitro. Brain Research. 2018/01/01/ 2018;1678:310-321. doi:https://doi.org/10.1016/j.brainres.2017.10.023
124. Saffrey MJ. Enteric Nervous System: Neurotrophic Factors☆. Reference Module in Neuroscience and Biobehavioral Psychology. Elsevier; 2017.
125. Dufour S, Broders-Bondon F, Bondurand N. Chapter 13 - β1-Integrin Function and Interplay during Enteric Nervous System Development. In: Pruszak J, ed. Neural Surface Antigens. Academic Press; 2015:153-166.
126. Sawai H, Okada Y, Kazanjian K, 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 Research. 2005;65(24):11536. doi:10.1158/0008-5472.CAN-05-2843
127. Saarma M. GFL Neurotrophic Factors: Physiology and Pharmacology. Encyclopedia of Neuroscience. 01/01 2010:711-720. doi:10.1016/B978-008045046-9.00501-5
128. Schachner M, Leshchyns'ka I, Sytnyk V. Functions of the Neural Cell Adhesion Molecule (NCAM) at the Synapse. 2017.
129. Phimister E, Kiely F, Kemshead JT, Patel K. Expression of neural cell adhesion molecule (NCAM) isoforms in neuroblastoma. J Clin Pathol. Jul 1991;44(7):580-5. doi:10.1136/jcp.44.7.580
130. Schachner M, Leshchyns’ka I, Sytnyk V. Neural Cell Adhesion Molecules and Synapse Regulation. In: Squire LR, ed. Encyclopedia of Neuroscience. Academic Press; 2009:91-96.
131. Merdad A, Karim S, Schulten HJ, et al. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis. Anticancer research. Mar 2014;34(3):1355-66.
132. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular Research. 2006;69(3):562-573. doi:10.1016/j.cardiores.2005.12.002
133. Murphy G. Matrix Metalloproteinases. In: Bradshaw RA, Stahl PD, eds. Encyclopedia of Cell Biology. Academic Press; 2016:621-629.
134. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185-149185. doi:10.1155/2014/149185
135. Carswell-Richards EA, Williamson BD. A man of vision and the discovery of tumor necrosis factor. Cancer Immun. 2012;12:4-4.
136. Muthukumaran N, Miletti-González KE, Ravindranath AK, Rodríguez-Rodríguez L. Tumor Necrosis Factor-α Differentially Modulates CD44 Expression in Ovarian Cancer Cells. Molecular Cancer Research. 2006;4(8):511. doi:10.1158/1541-7786.MCR-05-0232
137. Cruceriu D, Baldasici O, Balacescu O, Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches. Cellular oncology (Dordrecht). Feb 2020;43(1):1-18. doi:10.1007/s13402-019-00489-1
138. Tanabe K, Matsushima-Nishiwaki R, Yamaguchi S, Iida H, Dohi S, Kozawa O. Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells. J Neuroinflammation. 2010;7:16-16. doi:10.1186/1742-2094-7-16
139. Culig Z. Proinflammatory cytokine interleukin-6 in prostate carcinogenesis. Am J Clin Exp Urol. 2014;2(3):231-238.
140. Jones SA, Takeuchi T, Aletaha D, Smolen J, Choy EH, McInnes I. Interleukin 6: The biology behind the therapy. Considerations in Medicine. 2018;2(1):2. doi:10.1136/conmed-2018-000005
141. Heikkilä K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. European Journal of Cancer. 2008/05/01/ 2008;44(7):937-945. doi:https://doi.org/10.1016/j.ejca.2008.02.047
142. Morrison CD, Parvani JG, Schiemann WP. The relevance of the TGF-β Paradox to EMT-MET programs. Cancer letters. Nov 28 2013;341(1):30-40. doi:10.1016/j.canlet.2013.02.048
143. Bierie B, Moses HL. TGF-beta and cancer. Cytokine & growth factor reviews. Feb-Apr 2006;17(1-2):29-40. doi:10.1016/j.cytogfr.2005.09.006
144. Zhao Y, Ma J, Fan Y, et al. TGF-β transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways. Molecular oncology. Mar 2018;12(3):305-321. doi:10.1002/1878-0261.12162
145. Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS, Jr. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. The Journal of biological chemistry. Nov 5 1999;274(45):31868-74. doi:10.1074/jbc.274.45.31868
146. Wang Y, Liu X-H, Li Y-H, Li O. The paradox of IL-10-mediated modulation in cervical cancer. Biomed Rep. 2013;1(3):347-351. doi:10.3892/br.2013.69