• 西安交通大學醫(yī)學院第一附屬醫(yī)院腫瘤外科（陜西西安 710061）;

目的綜述胰腺癌細胞神經(jīng)周浸潤（perineural invasion, PNI）的發(fā)生機理，為胰腺癌治療尋找新的靶點。方法對包含有關(guān)胰腺癌PNI、嗜神經(jīng)浸潤、神經(jīng)-腫瘤微環(huán)境和神經(jīng)生長因子的文獻進行分析，總結(jié)有關(guān)PNI的發(fā)生機理。結(jié)果胰腺組織本身具有的豐富神經(jīng)支配和神經(jīng)纖維鞘具有裂隙樣的結(jié)構(gòu)是PNI的解剖基礎(chǔ)。癌細胞表達神經(jīng)源性標志物或獲得嗜神經(jīng)浸潤表型可能是PNI的病理基礎(chǔ)。腫瘤-神經(jīng)微環(huán)境或神經(jīng)生長因子家族及其相應受體可能是PNI的分子基礎(chǔ)。 對于PNI，不僅僅在于癌細胞本身具有的嗜神經(jīng)浸潤能力，也可能是癌細胞和神經(jīng)纖維之間相互作用的結(jié)果。結(jié)論PNI的機理較復雜，尚沒有明確的定論，但相關(guān)機理將可能為胰腺癌的治療提供新的靶點。

引用本文： 張勇,閆宇,黨誠學. 胰腺癌細胞的嗜神經(jīng)性與神經(jīng)周浸潤機理的研究進展△. 中國普外基礎(chǔ)與臨床雜志, 2011, 18(1): 21-25. doi: 復制

1. Kleeff J, Michalski C, Friess H, et al. Pancreatic cancer: from bench to 5year survival [J]. Pancreas, 2006, 33(2): 111118.
2. Van den Broeck A, Sergeant G, Ectors N, et al. Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma [J]. Eur J Surg Oncol, 2009, 35(6): 600604.
3. Keleg S, Büchler P, Ludwig R, et al. Invasion and metastasis in pancreatic cancer [J]. Mol Cancer, 2003, 2: 14.
4. Akert K, Sandri C, Weibel ER, et al. The fine structure of the perineural endothelium [J]. Cell Tissue Res, 1976, 165(3): 281295.
5. Batsakis JG. Nerves and neurotropic carcinomas [J]. Ann Otol Rhinol Laryngol, 1985, 94(4 Pt 1): 426427.
6. Okamoto M, Nakamura Y, Imaizumi M. Peripheral nerve structure [J]. Saishin Igaku, 1968, 23(11): 22402252.
7. 黨誠學, 王健生, 任予, 等. 胰腺癌神經(jīng)浸潤途徑的探討和臨床意義的研究 [J]. 中華肝膽外科雜志, 2001, 7(6): 357358.
8. Rodin AE, Larson DL, Roberts DK. Nature of the perineural space invaded by prostatic carcinoma [J]. Cancer, 1967, 20(10): 17721779.
9. Ballantyne AJ, Mccarten AB, Ibanez ML. The extension of cancer of the head and neck through peripheral nerves [J]. Am J Surg， 1963, 106: 651667.
10. Kayahara M, Nakagawara H, Kitagawa H, et al. The nature of neural invasion by pancreatic cancer [J]. Pancreas, 2007, 35(3): 218223.
11. Beger HG, Rau B, Gansauge F, et al. Treatment of pancreatic cancer: challenge of the facts [J]. World J Surg, 2003, 27(10): 10751084.
12. Dang C, Zhang Y, Ma Q, et al. Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer [J]. J Gastroenterol Hepatol, 2006, 21(5): 850858.
13. Zhu Z, Friess H, diMola FF, et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer [J]. J Clin Oncol, 1999, 17(8): 24192428.
14. di Mola FF, di Sebastiano P. Pain and pain generation in pancreatic cancer [J]. Langenbecks Arch Surg, 2008, 393(6): 919922.
15. Pour PM, Bell RH, Batra SK. Neural invasion in the staging of pancreatic cancer [J]. Pancreas, 2003, 26(4): 322325.
16. Ozaki H, Hiraoka T, Mizumoto R, et al. The prognostic significance of lymph node metastasis and intrapancreatic perineural invasion in pancreatic cancer after curative resection [J]. Surg Today, 1999, 29(1): 1622.
17. Cruveilhier J, Maladies des nerfs. Anatomic Pathologique du Corps Humain [M]. 2nd ed. Paris: J.B. Baillière, 1835: 3335.
18. Ernst P. Uber das Wachstum und die Verbeitung bosartiger Geshwulstte, insbesondere des Krebes in den Lymphbahnen der Nerven [J]. Beitr Path Anat, 1905, 7(Suppl): 2951.
19. Kuwayti K, Baggenstoss AH, Stauffer MH, et al. Carcinoma of the major intrahepatic and the extrahepatic bile ducts exclusive of the papilla of Vater [J]. Surg Gynecol Obstet, 1957, 104(3): 357366.
20. Dunn M, Morgan MB, Beer TW. Perineural invasion: identification, significance, and a standardized definition [J]. Dermatol Surg, 2009, 35(2): 214221.
21. Liebig C, Ayala G, Wilks JA, et al. Perineural invasion in cancer: a review of the literature [J]. Cancer, 2009, 115(15): 33793391.
22. Znker KS, Entschladen F (eds): Neuronal activity in tumor tissue [A]. In: Progression in Experimental Tumor Research [M]. Basel: Karger, 2007: 132133.
23. Eibl G, Reber HA. A xenograft nude mouse model for perineural invasion and recurrence in pancreatic cancer [J]. Pancreas, 2005, 31(3): 258262.
24. Carlson JA, Dickersin GR, Sober AJ, et al. Desmoplastic neurotropic melanoma. A clinicopathologic analysis of 28 cases [J]. Cancer, 1995, 75(2): 478494.
25. Watanabe H, Mizutani T, Haraguchi T, et al. SWI/SNF complex is essential for NRSFmediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines [J]. Oncogene, 2006, 25(3): 470479.
26. Chédotal A, Kerjan G, MoreauFauvarque C. The brain within the tumor: new roles for axon guidance molecules in cancers [J]. Cell Death Differ, 2005, 12(8): 10441056.
27. Zhu Z, Kleeff J, Kayed H, et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic carcinomas cells [J]. Mol Carcinog, 2002, 35(3): 138147.
28. Zhang Y, Dang C, Ma Q, et al. Expression of nerve growth factor receptors and their prognostic value in human pancreatic cancer [J]. Oncol Rep, 2005, 14(1): 161171.
29. Bockman DE, Büchler M, Beger HG. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage [J]. Gastroenterology, 1994, 107(1): 219230.
30. 鄭善川, 梁麗, 張玉茹, 等. GDNF及其受體Ret在腺樣囊性癌嗜神經(jīng)侵襲和細胞增殖中作用的初步研究 [J]. 口腔醫(yī)學研究, 2010, 26(3): 380383.
31. Ceyhan GO, Giese NA, Erkan M, et al. The neurotrophic factor artemin promotes pancreatic cancer invasion [J]. Ann Surg, 2006, 244(2): 274281.
32. 朱棟良, 羅地來, 羅剛, 等. Artemin、GFRα3在胰腺癌中的表達及其與胰腺癌神經(jīng)浸潤轉(zhuǎn)移的相關(guān)性 [J]. 南方醫(yī)科大學學報, 2009, 29(3): 428431.
33. Ben QW, Wang JC, Liu J, et al. Positive expression of L1CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma [J]. Ann Surg Oncol, 2010, 17(8): 22132221.
34. Farrow B, Albo D, Berger DH. The role of the tumor microenvironment in the progression of pancreatic cancer [J]. J Surg Res, 2008, 149(2): 319328.
35. Ma J, Jiang Y, Jiang Y, et al. Expression of nerve growth factor and tyrosine kinase receptor A and correlation with perineural invasion in pancreatic cancer [J]. J Gastroenterol Hepatol, 2008, 23(12): 18521859.
36. Okada Y, Eibl G, Duffy JP, et al. Glial cellderived neurotrophic factor upregulates the expression and activation of matrix metalloproteinase9 in human pancreatic cancer [J]. Surgery, 2003, 134(2): 293299.
37. Iwahashi N, Nagasaka T, Tezel G, et al. Expression of glial cell linederived neurotrophic factor correlates with perineural invasion of bile duct carcinoma [J]. Cancer, 2002, 94(1): 167174.
38. Podratz JL, Rodriguez E, Windebank AJ. Role of the extracellular matrix in myelination of peripheral nerve [J]. Glia, 2001, 35(1): 3540.
39. Hill RE, Williams RE. A quantitative analysis of perineurial cell basement membrane collagen Ⅳ, laminin and fibronectin in diabetic and nondiabetic human sural nerve [J]. J Anat, 2002, 201(2): 185192.
40. Vega JA, Esteban I, Naves FJ, et al. Immunohistochemical localization of laminin and type Ⅳ collagen in human cutaneous sensory nerve formations [J]. Anat Embryol (Berl), 1995, 191(1): 3339.
41. Ryschich E, Khamidjanov A, Kerkadze V, et al. Promotion of tumor cell migration by extracellular matrix proteins in human pancreatic cancer [J]. Pancreas, 2009, 38(7): 804810.
42. Wang W, Zhao H, Zhang S, et al. Patterns of expression and function of the p75NGFR protein in pancreatic cancer cells and tumours [J]. Eur J Surg Oncol, 2009, 35(8): 826832.
43. Yao J, Ma Q, Wang L, et al. Pleiotrophin expression in human pancreatic cancer and its correlation with clinicopathological features, perineural invasion, and prognosis [J]. Dig Dis Sci, 2009, 54(4): 895901.
44. Abiatari I, DeOliveira T, Kerkadze V, et al. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma [J]. Mol Cancer Ther, 2009, 8(6): 14941504.
  1. 1. Kleeff J, Michalski C, Friess H, et al. Pancreatic cancer: from bench to 5year survival [J]. Pancreas, 2006, 33(2): 111118.
  2. 2. Van den Broeck A, Sergeant G, Ectors N, et al. Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma [J]. Eur J Surg Oncol, 2009, 35(6): 600604.
  3. 3. Keleg S, Büchler P, Ludwig R, et al. Invasion and metastasis in pancreatic cancer [J]. Mol Cancer, 2003, 2: 14.
  4. 4. Akert K, Sandri C, Weibel ER, et al. The fine structure of the perineural endothelium [J]. Cell Tissue Res, 1976, 165(3): 281295.
  5. 5. Batsakis JG. Nerves and neurotropic carcinomas [J]. Ann Otol Rhinol Laryngol, 1985, 94(4 Pt 1): 426427.
  6. 6. Okamoto M, Nakamura Y, Imaizumi M. Peripheral nerve structure [J]. Saishin Igaku, 1968, 23(11): 22402252.
  7. 7. 黨誠學, 王健生, 任予, 等. 胰腺癌神經(jīng)浸潤途徑的探討和臨床意義的研究 [J]. 中華肝膽外科雜志, 2001, 7(6): 357358.
  8. 8. Rodin AE, Larson DL, Roberts DK. Nature of the perineural space invaded by prostatic carcinoma [J]. Cancer, 1967, 20(10): 17721779.
  9. 9. Ballantyne AJ, Mccarten AB, Ibanez ML. The extension of cancer of the head and neck through peripheral nerves [J]. Am J Surg， 1963, 106: 651667.
  10. 10. Kayahara M, Nakagawara H, Kitagawa H, et al. The nature of neural invasion by pancreatic cancer [J]. Pancreas, 2007, 35(3): 218223.
  11. 11. Beger HG, Rau B, Gansauge F, et al. Treatment of pancreatic cancer: challenge of the facts [J]. World J Surg, 2003, 27(10): 10751084.
  12. 12. Dang C, Zhang Y, Ma Q, et al. Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer [J]. J Gastroenterol Hepatol, 2006, 21(5): 850858.
  13. 13. Zhu Z, Friess H, diMola FF, et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer [J]. J Clin Oncol, 1999, 17(8): 24192428.
  14. 14. di Mola FF, di Sebastiano P. Pain and pain generation in pancreatic cancer [J]. Langenbecks Arch Surg, 2008, 393(6): 919922.
  15. 15. Pour PM, Bell RH, Batra SK. Neural invasion in the staging of pancreatic cancer [J]. Pancreas, 2003, 26(4): 322325.
  16. 16. Ozaki H, Hiraoka T, Mizumoto R, et al. The prognostic significance of lymph node metastasis and intrapancreatic perineural invasion in pancreatic cancer after curative resection [J]. Surg Today, 1999, 29(1): 1622.
  17. 17. Cruveilhier J, Maladies des nerfs. Anatomic Pathologique du Corps Humain [M]. 2nd ed. Paris: J.B. Baillière, 1835: 3335.
  18. 18. Ernst P. Uber das Wachstum und die Verbeitung bosartiger Geshwulstte, insbesondere des Krebes in den Lymphbahnen der Nerven [J]. Beitr Path Anat, 1905, 7(Suppl): 2951.
  19. 19. Kuwayti K, Baggenstoss AH, Stauffer MH, et al. Carcinoma of the major intrahepatic and the extrahepatic bile ducts exclusive of the papilla of Vater [J]. Surg Gynecol Obstet, 1957, 104(3): 357366.
  20. 20. Dunn M, Morgan MB, Beer TW. Perineural invasion: identification, significance, and a standardized definition [J]. Dermatol Surg, 2009, 35(2): 214221.
  21. 21. Liebig C, Ayala G, Wilks JA, et al. Perineural invasion in cancer: a review of the literature [J]. Cancer, 2009, 115(15): 33793391.
  22. 22. Znker KS, Entschladen F (eds): Neuronal activity in tumor tissue [A]. In: Progression in Experimental Tumor Research [M]. Basel: Karger, 2007: 132133.
  23. 23. Eibl G, Reber HA. A xenograft nude mouse model for perineural invasion and recurrence in pancreatic cancer [J]. Pancreas, 2005, 31(3): 258262.
  24. 24. Carlson JA, Dickersin GR, Sober AJ, et al. Desmoplastic neurotropic melanoma. A clinicopathologic analysis of 28 cases [J]. Cancer, 1995, 75(2): 478494.
  25. 25. Watanabe H, Mizutani T, Haraguchi T, et al. SWI/SNF complex is essential for NRSFmediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines [J]. Oncogene, 2006, 25(3): 470479.
  26. 26. Chédotal A, Kerjan G, MoreauFauvarque C. The brain within the tumor: new roles for axon guidance molecules in cancers [J]. Cell Death Differ, 2005, 12(8): 10441056.
  27. 27. Zhu Z, Kleeff J, Kayed H, et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic carcinomas cells [J]. Mol Carcinog, 2002, 35(3): 138147.
  28. 28. Zhang Y, Dang C, Ma Q, et al. Expression of nerve growth factor receptors and their prognostic value in human pancreatic cancer [J]. Oncol Rep, 2005, 14(1): 161171.
  29. 29. Bockman DE, Büchler M, Beger HG. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage [J]. Gastroenterology, 1994, 107(1): 219230.
  30. 30. 鄭善川, 梁麗, 張玉茹, 等. GDNF及其受體Ret在腺樣囊性癌嗜神經(jīng)侵襲和細胞增殖中作用的初步研究 [J]. 口腔醫(yī)學研究, 2010, 26(3): 380383.
  31. 31. Ceyhan GO, Giese NA, Erkan M, et al. The neurotrophic factor artemin promotes pancreatic cancer invasion [J]. Ann Surg, 2006, 244(2): 274281.
  32. 32. 朱棟良, 羅地來, 羅剛, 等. Artemin、GFRα3在胰腺癌中的表達及其與胰腺癌神經(jīng)浸潤轉(zhuǎn)移的相關(guān)性 [J]. 南方醫(yī)科大學學報, 2009, 29(3): 428431.
  33. 33. Ben QW, Wang JC, Liu J, et al. Positive expression of L1CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma [J]. Ann Surg Oncol, 2010, 17(8): 22132221.
  34. 34. Farrow B, Albo D, Berger DH. The role of the tumor microenvironment in the progression of pancreatic cancer [J]. J Surg Res, 2008, 149(2): 319328.
  35. 35. Ma J, Jiang Y, Jiang Y, et al. Expression of nerve growth factor and tyrosine kinase receptor A and correlation with perineural invasion in pancreatic cancer [J]. J Gastroenterol Hepatol, 2008, 23(12): 18521859.
  36. 36. Okada Y, Eibl G, Duffy JP, et al. Glial cellderived neurotrophic factor upregulates the expression and activation of matrix metalloproteinase9 in human pancreatic cancer [J]. Surgery, 2003, 134(2): 293299.
  37. 37. Iwahashi N, Nagasaka T, Tezel G, et al. Expression of glial cell linederived neurotrophic factor correlates with perineural invasion of bile duct carcinoma [J]. Cancer, 2002, 94(1): 167174.
  38. 38. Podratz JL, Rodriguez E, Windebank AJ. Role of the extracellular matrix in myelination of peripheral nerve [J]. Glia, 2001, 35(1): 3540.
  39. 39. Hill RE, Williams RE. A quantitative analysis of perineurial cell basement membrane collagen Ⅳ, laminin and fibronectin in diabetic and nondiabetic human sural nerve [J]. J Anat, 2002, 201(2): 185192.
  40. 40. Vega JA, Esteban I, Naves FJ, et al. Immunohistochemical localization of laminin and type Ⅳ collagen in human cutaneous sensory nerve formations [J]. Anat Embryol (Berl), 1995, 191(1): 3339.
  41. 41. Ryschich E, Khamidjanov A, Kerkadze V, et al. Promotion of tumor cell migration by extracellular matrix proteins in human pancreatic cancer [J]. Pancreas, 2009, 38(7): 804810.
  42. 42. Wang W, Zhao H, Zhang S, et al. Patterns of expression and function of the p75NGFR protein in pancreatic cancer cells and tumours [J]. Eur J Surg Oncol, 2009, 35(8): 826832.
  43. 43. Yao J, Ma Q, Wang L, et al. Pleiotrophin expression in human pancreatic cancer and its correlation with clinicopathological features, perineural invasion, and prognosis [J]. Dig Dis Sci, 2009, 54(4): 895901.
  44. 44. Abiatari I, DeOliveira T, Kerkadze V, et al. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma [J]. Mol Cancer Ther, 2009, 8(6): 14941504.

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