Perineural growth in head and neck squamous cell carcinoma: A review

Oral Oncology

Volumn 51, Issue 1, 2015, Pages 16-23

  Roh, Joseph ^a   Muelleman, Thomas ^a   Tawfik, Ossama ^a   Thomas, Sufi M ^a  

^a UNIVERSITY OF KANSAS CANCER CENTER   (United States)

Author keywords

Chemokines; Neurotrophic factors; Neurotrophin; Perineural growth; Perineural invasion; Squamous cell carcinoma

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; CHEMOKINE; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; NERVE CELL ADHESION MOLECULE; NERVE GROWTH FACTOR; NEUROTROPHIN 3; NEUROTROPHIN 4; PROTEIN TYROSINE KINASE A; SUBSTANCE P;

CANCER GROWTH; CANCER PROGNOSIS; CANCER RECURRENCE; DISEASE FREE SURVIVAL; ENDONEURIUM; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; REVIEW; TUMOR INVASION; HEAD AND NECK TUMOR; METASTASIS; PATHOLOGY; SQUAMOUS CELL CARCINOMA;

CARCINOMA, SQUAMOUS CELL; HEAD AND NECK NEOPLASMS; HUMANS; NEOPLASM METASTASIS;

EID: 84920527582     PISSN: 13688375     EISSN: 18790593     Source Type: Journal    
DOI: 10.1016/j.oraloncology.2014.10.004     Document Type: Review

References (109)

1. Skarsgard DP, Groome PA, Mackillop WJ, Zhou S, Rothwell D, Dixon PF, et al. Cancers of the upper aerodigestive tract in Ontario, Canada, and the United States. Cancer 2000;88:1728-38.
2. Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282-7.
3. Vineis P, Alavanja M, Buffler P, Fontham E, Franceschi S, Gao YT, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst 2004;96:99-106.
4. D'Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Casecontrol study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944-56.
5. Ceyhan GO, Demir IE, Altintas B, Rauch U, Thiel G, Muller MW, et al. Neural invasion in pancreatic cancer: a mutual tropism between neurons and cancer cells. Biochem Biophys Res Commun 2008;374:442-7.
6. Ayala GE, Dai H, Ittmann M, Li R, Powell M, Frolov A, et al. Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res 2004;64:6082-90.
7. Liebig C, Ayala G, Wilks J, Verstovsek G, Liu H, Agarwal N, et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol 2009;27:5131-7.
8. Hirai I, Kimura W, Ozawa K, Kudo S, Suto K, Kuzu H, et al. Perineural invasion in pancreatic cancer. Pancreas 2002;24:15-25.
9. Liu B, Lu KY. Neural invasion in pancreatic carcinoma. Hepatobiliary Pancreat Dis Int 2002;1:469-76.
10. Huh JW, Kim HR, Kim YJ. Prognostic value of perineural invasion in patients with stage II colorectal cancer. Ann Surg Oncol 2010;17:2066-72.
11. Horn A, Dahl O, Morild I. Venous and neural invasion as predictors of recurrence in rectal adenocarcinoma. Dis Colon Rectum 1991;34:798-804.
12. Bapat AA, Hostetter G, Von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer 2011;11:695-707.
13. Boerman RH, Maassen EM, Joosten J, Kaanders HA, Marres HA, van Overbeeke J, et al. Trigeminal neuropathy secondary to perineural invasion of head and neck carcinomas. Neurology 1999;53:213-6.
14. Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN, Johnson JT. Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1998;124:637-40.
15. Tai SK, Li WY, Yang MH, Chu PY, Wang YF. Perineural invasion in T1 oral squamous cell carcinoma indicates the need for aggressive elective neck dissection. Am J Surg Pathol 2013;37:1164-72.
16. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer 2009;115:3379-91.
17. Ong CK, Chong VF. Imaging of perineural spread in head and neck tumours. Cancer Imag 2010;10(A):S92-8.
18. Panizza B, Warren TA, Solares CA, Boyle GM, Lambie D, Brown I. Histopathological features of clinical perineural invasion of cutaneous squamous cell carcinoma of the head and neck and the potential implications for treatment. Head Neck 2013. http://dx.doi.org/10.1002/hed.23509 [Epub].
19. Nemzek WR, Hecht S, Gandour-Edwards R, Donald P, McKennan K. Perineural spread of head and neck tumors: how accurate is MR imaging? AJNR Am J Neuroradiol 1998;19:701-6.
20. Yousem DM, Gad K, Tufano RP. Resectability issues with head and neck cancer. AJNR Am J Neuroradiol 2006;27:2024-36.
21. Ginsberg LE. Imaging of perineural tumor spread in head and neck cancer. Semin Ultrasound CT MR 1999;20:175-86.
22. Teymoortash A, Zieger L, Hoch S, Pagenstecher A, Hofer MJ. Distinct microscopic features of perineural invasion in adenoid cystic carcinoma of the head and neck. Histopathology 2014;64:1037-9.
23. Barrett AW, Speight PM. Perineural invasion in adenoid cystic carcinoma of the salivary glands: a valid prognostic indicator? Oral Oncol 2009;45:936-40.
24. Pinto FR, de Matos LL, Palermo FC, Kulcsar MA, Cavalheiro BG, de Mello ES, et al. Tumor thickness as an independent risk factor of early recurrence in oral cavity squamous cell carcinoma. Eur Arch Otorhinolaryngol 2014;271:1747-54.
25. Hilly O, Shkedy Y, Hod R, Soudry E, Mizrachi A, Hamzany Y, et al. Carcinoma of the oral tongue in patients younger than 30 years: comparison with patients older than 60 years. Oral Oncol 2013;49:987-90.
26. Sinha P, Hackman T, Nussenbaum B, Wu N, Lewis Jr JS, Haughey BH. Transoral laser microsurgery for oral squamous cell carcinoma: oncologic outcomes and prognostic factors. Head Neck 2014;36:340-51.
27. Binmadi NO, Basile JR. Perineural invasion in oral squamous cell carcinoma: a discussion of significance and review of the literature. Oral Oncol 2011;47:1005-10.
28. Mendenhall WM, Amdur RJ, Williams LS, Mancuso AA, Stringer SP, Price Mendenhall N. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck 2002;24:78-83.
29. Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol 2010;3:39-48.
30. Galloway TJ, Morris CG, Mancuso AA, Amdur RJ, Mendenhall WM. Impact of radiographic findings on prognosis for skin carcinoma with clinical perineural invasion. Cancer 2005;103:1254-7.
31. Warden KF, Parmar H, Trobe JD. Perineural spread of cancer along the three trigeminal divisions. J Neuroophthalmol 2009;29:300-7.
32. Catalano PJ, Sen C, Biller HF. Cranial neuropathy secondary to perineural spread of cutaneous malignancies. Am J Otol 1995;16:772-7.
33. Schmalfuss IM, Tart RP, Mukherji S, Mancuso AA. Perineural tumor spread along the auriculotemporal nerve. AJNR Am J Neuroradiol 2002;23:303-11.
34. Garcia-Serra A, Hinerman RW, Mendenhall WM, Amdur RJ, Morris CG, Williams LS, et al. Carcinoma of the skin with perineural invasion. Head Neck 2003;25:1027-33.
35. Daniels DL, Mark LP, Ulmer JL, Mafee MF, McDaniel J, Shah NC, et al. Osseous anatomy of the pterygopalatine fossa. AJNR Am J Neuroradiol 1998;19:1423-32.
36. Dodd GD, Dolan PA, Ballantyne AJ, Ibanez ML, Chau P. The dissemination of tumors of the head and neck via the cranial nerves. Radiol Clin North Am 1970;8:445-61.
37. Ginsberg LE, De Monte F, Gillenwater AM. Greater superficial petrosal nerve: anatomy and MR findings in perineural tumor spread. AJNR Am J Neuroradiol 1996;17:389-93.
38. Gandhi D, Gujar S, Mukherji SK. Magnetic resonance imaging of perineural spread of head and neck malignancies. Top Magn Reson Imag 2004;15:79-85.
39. Mancino M, Ametller E, Gascon P, Almendro V. The neuronal influence on tumor progression. Biochim Biophys Acta 2011;1816:105-18.
40. Dolle L, El Yazidi-Belkoura I, Adriaenssens E, Nurcombe V, Hondermarck H. Nerve growth factor overexpression and autocrine loop in breast cancer cells. Oncogene 2003;22:5592-601.
41. Chedotal A, Kerjan G, Moreau-Fauvarque C. The brain within the tumor: new roles for axon guidance molecules in cancers. Cell Death Differ 2005;12:1044-56.
42. Geldof AA, Van Haarst EP, Newling DW. Neurotrophic factors in prostate and prostatic cancer. Prostate Cancer Prostatic Dis 1998;1:236-41.
43. Ricci A, Greco S, Mariotta S, Felici L, Bronzetti E, Cavazzana A, et al. Neurotrophins and neurotrophin receptors in human lung cancer. Am J Respir Cell Mol Biol 2001;25:439-46.
44. Li S, Sun Y, Gao D. Role of the nervous system in cancer metastasis. Oncol Lett 2013;5:1101-11.
45. Li X, Ma G, Ma Q, Li W, Liu J, Han L, et al. Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells. Mol Cancer Res 2013;11:294-302.
46. Barde YA. Neurotrophins: a family of proteins supporting the survival of neurons. Prog Clin Biol Res 1994;390:45-56.
47. Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987;237:1154-62.
48. Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 2003;4:299-309.
49. Kowalski PJ, Paulino AF. Perineural invasion in adenoid cystic carcinoma: its causation/promotion by brain-derived neurotrophic factor. Hum Pathol 2002;33:933-6.
50. Miknyoczki SJ, Lang D, Huang L, Klein-Szanto AJ, Dionne CA, Ruggeri BA. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 1999;81:417-27.
51. Okugawa Y, Tanaka K, Inoue Y, Kawamura M, Kawamoto A, Hiro J, et al. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. Br J Cancer 2013;108:121-30.
52. Yilmaz T, Jiffar T, de la Garza G, Lin H, Milas Z, Takahashi Y, et al. Theraputic targeting of Trk suppresses tumor proliferation and enhances cisplatin activity in HNSCC. Cancer Biol Ther 2010;10:644-53.
53. Dudas J, Bitsche M, Schartinger V, Falkeis C, Sprinzl GM, Riechelmann H. Fibroblasts produce brain-derived neurotrophic factor and induce mesenchymal transition of oral tumor cells. Oral Oncol 2011;47:98-103.
54. Kupferman ME, Jiffar T, El-Naggar A, Yilmaz T, Zhou G, Xie T, et al. TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma. Oncogene 2010;29:2047-59.
55. Zhu L, Werner JA, Mandic R. Implications of tropomyosin-related kinase B (TrkB) in head and neck cancer. Anticancer Res 2007;27:3121-6.
56. Descamps S, Pawlowski V, Revillion F, Hornez L, Hebbar M, Boilly B, et al. Expression of nerve growth factor receptors and their prognostic value in human breast cancer. Cancer Res 2001;61:4337-40.
57. Descamps S, Toillon RA, Adriaenssens E, Pawlowski V, Cool SM, Nurcombe V, et al. Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways. J Biol Chem 2001;276:17864-70.
58. Zhu Z, Friess H, diMola FF, Zimmermann A, Graber HU, Korc M, et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J Clin Oncol 1999;17:2419-28.
59. Kolokythas A, Cox DP, Dekker N, Schmidt BL. Nerve growth factor and tyrosine kinase A receptor in oral squamous cell carcinoma: is there an association with perineural invasion? J Oral Maxillofac Surg 2010;68:1290-5.
60. Ye Y, Dang D, Zhang J, Viet CT, Lam DK, Dolan JC, et al. Nerve growth factor links oral cancer progression, pain, and cachexia. Mol Cancer Ther 2011;10:1667-76.
61. Chen-Tsai CP, Colome-Grimmer M, Wagner Jr RF. 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 2004;30:1009-16.
62. Ketterer K, Rao S, Friess H, Weiss J, Buchler MW, Korc M. Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer. Clin Cancer Res 2003;9:5127-36.
63. Bouzas-Rodriguez J, Cabrera JR, Delloye-Bourgeois C, Ichim G, Delcros JG, Raquin MA, et al. Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis. J Clin Invest 2010;120:850-8.
64. Okada Y, Takeyama H, Sato M, Morikawa M, Sobue K, Asai K, et al. Experimental implication of celiac ganglionotropic invasion of pancreatic-cancer cells bearing c-ret proto-oncogene with reference to glial-cell-line-derived neurotrophic factor (GDNF). Int J Cancer 1999;81:67-73.
65. Wiesenhofer B, Stockhammer G, Kostron H, Maier H, Hinterhuber H, Humpel C. Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta Neuropathol 2000;99:131-7.
66. Funahashi H, Okada Y, Sawai H, Takahashi H, Matsuo Y, Takeyama H, et al. The role of glial cell line-derived neurotrophic factor (GDNF) and integrins for invasion and metastasis in human pancreatic cancer cells. J Surg Oncol 2005;91:77-83.
67. Bakst RL, Lee N, He S, Chernichenko N, Chen CH, Linkov G, et al. Radiation impairs perineural invasion by modulating the nerve microenvironment. PLoS One 2012;7:e39925.
68. Iwahashi N, Nagasaka T, Tezel G, Iwashita T, Asai N, Murakumo Y, et al. Expression of glial cell line-derived neurotrophic factor correlates with perineural invasion of bile duct carcinoma. Cancer 2002;94:167-74.
69. Zeng Q, Cheng Y, Zhu Q, Yu Z, Wu X, Huang K, et al. The relationship between over-expression of glial cell-derived neurotrophic factor and its RET receptor with progression and prognosis of human pancreatic cancer. J Int Med Res 2008;36:656-64.
70. He S, Chen CH, Chernichenko N, He S, Bakst RL, Barajas F, et al. GFRalpha1 released by nerves enhances cancer cell perineural invasion through GDNFRET signaling. Proc Natl Acad Sci U S A 2014;111:E2008-17.
71. Liu H, Li X, Xu Q, Lv S, Li J, Ma Q. Role of glial cell line-derived neurotrophic factor in perineural invasion of pancreatic cancer. Biochim Biophys Acta 2012;1826:112-20.
72. Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 2005;16:441-67.
73. Ito Y, Okada Y, Sato M, Sawai H, Funahashi H, Murase T, et al. Expression of glial cell line-derived neurotrophic factor family members and their receptors in pancreatic cancers. Surgery 2005;138:788-94.
74. Ceyhan GO, Giese NA, Erkan M, Kerscher AG, Wente MN, Giese T, et al. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg 2006;244:274-81.
75. Chuang JY, Tsai CF, Chang SW, Chiang IP, Huang SM, Lin HY, et al. Glial cell line-derived neurotrophic factor induces cell migration in human oral squamous cell carcinoma. Oral Oncol 2013;49:1103-12.
76. Song H, Moon A. Glial cell-derived neurotrophic factor (GDNF) promotes low-grade Hs683 glioma cell migration through JNK, ERK-1/2 and p38 MAPK signaling pathways. Neurosci Res 2006;56:29-38.
77. Fan HX, Li HX, Chen D, Gao ZX, Zheng JH. Changes in the expression of MMP2, MMP9, and ColIV in stromal cells in oral squamous tongue cell carcinoma: relationships and prognostic implications. J Exp Clin Cancer Res 2012;31:90.
78. Luukkaa M, Vihinen P, Kronqvist P, Vahlberg T, Pyrhonen S, Kahari VM, et al. Association between high collagenase-3 expression levels and poor prognosis in patients with head and neck cancer. Head Neck 2006;28:225-34.
79. Shang J, Sheng L, Wang K, Shui Y, Wei Q. Expression of neural cell adhesion molecule in salivary adenoid cystic carcinoma and its correlation with perineural invasion. Oncol Rep 2007;18:1413-6.
80. Vural E, Hutcheson J, Korourian S, Kechelava S, Hanna E. Correlation of neural cell adhesion molecules with perineural spread of squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 2000;122:717-20.
81. Solares CA, Brown I, Boyle GM, Parsons PG, Panizza B. Neural cell adhesion molecule expression: no correlation with perineural invasion in cutaneous squamous cell carcinoma of the head and neck. Head Neck 2009;31:802-6.
82. Edvardsen K, Bock E, Jirus S, Frandsen TL, Holst-Hansen C, Moser C, et al. Effect of NCAM-transfection on growth and invasion of a human cancer cell line. APMIS 1997;105:919-30.
83. Owens GC, Orr EA, DeMasters BK, Muschel RJ, Berens ME, Kruse CA. Overexpression of a transmembrane isoform of neural cell adhesion molecule alters the invasiveness of rat CNS-1 glioma. Cancer Res 1998;58:2020-8.
84. Brener S, Gonzalez-Moles MA, Tostes D, Esteban F, Gil-Montoya JA, Ruiz-Avila I, et al. A role for the substance P/NK-1 receptor complex in cell proliferation in oral squamous cell carcinoma. Anticancer Res 2009;29:2323-9.
85. Iwamoto S, Odland PB, Piepkorn M, Bothwell M. Evidence that the p75 neurotrophin receptor mediates perineural spread of desmoplastic melanoma. J Am Acad Dermatol 1996;35:725-31.
86. Chan MM, Tahan SR. Low-affinity nerve growth factor receptor (P75 NGFR) as a marker of perineural invasion in malignant melanomas. J Cutan Pathol 2010;37:336-43.
87. Nykjaer A, Willnow TE, Petersen CM. P75NTR-live or let die. Curr Opin Neurobiol 2005;15:49-57.
88. Barker PA. P75NTR is positively promiscuous: novel partners and new insights. Neuron 2004;42:529-33.
89. Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 2002;67:203-33.
90. Kume T, Nishikawa H, Tomioka H, Katsuki H, Akaike A, Kaneko S, et al. P75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures. Brain Res 2000;852:279-89.
91. Yan C, Liang Y, Nylander KD, Wong J, Rudavsky RM, Saragovi HU, et al. P75-nerve growth factor as an antiapoptotic complex: independence versus cooperativity in protection from enediyne chemotherapeutic agents. Mol Pharmacol 2002;61:710-9.
92. Friedman WJ, Greene LA. Neurotrophin signaling via Trks and p75. Exp Cell Res 1999;253:131-42.
93. Zlotnik A. Chemokines and cancer. Int J Cancer 2006;119:2026-9.
94. Zeelenberg IS, Ruuls-Van Stalle L, Roos E. The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res 2003;63:3833-9.
95. Chen Y, Stamatoyannopoulos G, Song CZ. Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. Cancer Res 2003;63:4801-4.
96. Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol 2004;14:171-9.
97. Katayama A, Ogino T, Bandoh N, Nonaka S, Harabuchi Y. Expression of CXCR4 and its down-regulation by IFN-gamma in head and neck squamous cell carcinoma. Clin Cancer Res 2005;11:2937-46.
98. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4:540-50.
99. Marchesi F, Locatelli M, Solinas G, Erreni M, Allavena P, Mantovani A. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J Neuroimmunol 2010;224:39-44.
100. Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev 2010;21:77-82.
101. Muller A, Sonkoly E, Eulert C, Gerber PA, Kubitza R, Schirlau K, et al. Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy. Int J Cancer 2006;118:2147-57.
102. Muller MW, Giese NA, Swiercz JM, Ceyhan GO, Esposito I, Hinz U, et al. Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int J Cancer 2007;121:2421-33.
103. Trapp BD, Andrews SB, Cootauco C, Quarles R. The myelin-associated glycoprotein is enriched in multivesicular bodies and periaxonal membranes of actively myelinating oligodendrocytes. J Cell Biol 1989;109:2417-26.
104. Swanson BJ, McDermott KM, Singh PK, Eggers JP, Crocker PR, Hollingsworth MA. MUC1 is a counter-receptor for myelin-associated glycoprotein (Siglec-4a) and their interaction contributes to adhesion in pancreatic cancer perineural invasion. Cancer Res 2007;67:10222-9.
105. Ben QW, Wang JC, Liu J, Zhu Y, Yuan F, Yao WY, et al. Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. Ann Surg Oncol 2010;17:2213-21.
106. Dang C, Zhang Y, Ma Q, Shimahara Y. Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer. J Gastroenterol Hepatol 2006;21:850-8.
107. Wang L, Sun M, Jiang Y, Yang L, Lei D, Lu C, et al. Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior. J Oral Maxillofac Surg 2006;64:636-41.
108. Gil Z, Cavel O, Kelly K, Brader P, Rein A, Gao SP, et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst 2010;102:107-18.
109. Liu H, Ma Q, Xu Q, Lei J, Li X, Wang Z, et al. Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. Curr Pharm Des 2012;18:2395-403.