明胶酶及其抑制因子在恶性外周神经鞘膜瘤中的表达及意义
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摘要
目的：探讨明胶酶(MMP-2、MMP-9)及其抑制因子(TIMP-2、TIMP-1)在MPNST中的表达特征及其与临床病理及预后的关系。
方法：应用免疫组织化学S-P法，检测58例MPNST中MMP-2、MMP-9及其抑制因子TIMP-2、TIMP-1的表达，并行回顾性随访。
结果：(1)MMP-2在MPNST中阳性表达率为87.9％，表达水平显著高于正常神经及其良性肿瘤中的表达(P<0.05)；其表达程度与肿瘤组织学分级及生存率密切相关(P<0.05)，与病人性别、年龄、肿瘤大小、部位及术后复发率等无明显相关。MMP-9在MPNST中阳性表达率为43.1％，表达水平高于正常神经及其良性肿瘤中的表达，但无显著性差异；其表达程度与病人性别、年龄、肿瘤大小、部位、组织学分级、术后复发率及生存率等均地无明显相关。(2)TIMP-2在MPNST中阳性表达率为62.1％，表达水平显著低于正常神经及其良性肿瘤中的表达(P<0.05)；其表达程度与肿瘤组织学分级及生存率密切相关(P<0.05)，与病人性别、年龄、肿瘤大小、部位及术后复发率等无明显相关。TIMP-1在MPNST中阳性表达率为41.4％，
.卜庆队科大学倾l论文
表达水平低于正常神经及其良性肿瘤中的表达，但无扯著性差异;其
表达程度与病人性别、年龄、肿瘤大小、部位、组织学分级、术后复
发率及生存率等均无明显相关。(3)在有随访资料的28例中，MMP一2
表达分级超过TIMP一2表达分级者15例，MMP一2表达分级低于
TIMP一2表达分级者7例，两组在术后复发率间无显著差异，在生存
率间有显著差异(P<0.05);MMP一9表达分级超过TIMP一1表达分
级者10例，MMP一9表达分级低于TIMP一l表达分级者8例，两组在
术后复发率及生存率间均无撇著差异。
结论:MMP一2、TIMP一2的表达与MPNST的组织学分级及生存
率有关。MMP一2表达卜调和rIMP一2表达卜调可能在MPNST的发生、
发展过程中起重要作用。MMP一2、T 1 MP一2可作为判断MPNST恶性
程度及预后的有用的参考指标。
Objective: To investigate the relationship of the expression of gelatinases(MMP-2 and MMP-9) and their tissue inhibitors(TIMP-2 and TIMP-1) to clinicopathological characteristics and prognosis of MPNST.
Methods: S-P immunohistochemical staining was used to detect the expression of MMP-2, MMP-9, TIMP-2, TIMP-1 in 58 MPNST, and the patients were followed-up.
Resu I ts: (1) The expression of MMP-2 in MPNST was markedly higher than that in normal nerves and benign peripheral nerve sheath tumors(P<0.05). Increased MMP-2 reactivity was significant for histologic grade and survival time(P<0.05), but not for sex, age, tumor size, site or recurrence. The expression of MMP-9 in MPNST was higher than that in normal nerves and benign peripheral nerve sheath tumors, but no significant association was found between them. No significant association was found between the expression of MMP-9 and sex, age, tumor size, site ,histologic grade, recurrence , or survival time. (2) The
expression of T1MP-2 in MPNST was markedly lowerer than that in normal nerves and benign peripheral nerve sheath tumors(P<0.05). Lack of TIMP-2 expression was significant for histologic grade and survival time(P<0.05), but not for sex, age, tumor size, site or recurrence. The expression of TIMP-1 in MPNST was lowerer than that in normal nerves and benign peripheral nerve sheath tumors, but no significant association was found between them. No significant association was found between the expression of TIMP-1 and sex, age, tumor size, site ,histologic grade, recurrence , or survival time. (3) Unbalance expression between MMP-2 and TIMP-2 was significant for survival time(P<0.05), but not for recurrence. Unbalance expression between MMP-9 and TIMP-1 was significant for neither recurrence nor survival time.
Cone I us i ons: The expression of MMP-2 and TIMP-2 is associated with histologic grade and survival time of MPNST. Increased MMP-2 reactivity and lack of TIMP-2 expression may play a role in occurrence and progress of MPNST. MMP-2 and TIMP-2 might be useful to define aggressiveness and prognosis of MPNST.
方法：应用免疫组织化学S-P法，检测58例MPNST中MMP-2、MMP-9及其抑制因子TIMP-2、TIMP-1的表达，并行回顾性随访。
结果：(1)MMP-2在MPNST中阳性表达率为87.9％，表达水平显著高于正常神经及其良性肿瘤中的表达(P<0.05)；其表达程度与肿瘤组织学分级及生存率密切相关(P<0.05)，与病人性别、年龄、肿瘤大小、部位及术后复发率等无明显相关。MMP-9在MPNST中阳性表达率为43.1％，表达水平高于正常神经及其良性肿瘤中的表达，但无显著性差异；其表达程度与病人性别、年龄、肿瘤大小、部位、组织学分级、术后复发率及生存率等均地无明显相关。(2)TIMP-2在MPNST中阳性表达率为62.1％，表达水平显著低于正常神经及其良性肿瘤中的表达(P<0.05)；其表达程度与肿瘤组织学分级及生存率密切相关(P<0.05)，与病人性别、年龄、肿瘤大小、部位及术后复发率等无明显相关。TIMP-1在MPNST中阳性表达率为41.4％，
.卜庆队科大学倾l论文
表达水平低于正常神经及其良性肿瘤中的表达，但无扯著性差异;其
表达程度与病人性别、年龄、肿瘤大小、部位、组织学分级、术后复
发率及生存率等均无明显相关。(3)在有随访资料的28例中，MMP一2
表达分级超过TIMP一2表达分级者15例，MMP一2表达分级低于
TIMP一2表达分级者7例，两组在术后复发率间无显著差异，在生存
率间有显著差异(P<0.05);MMP一9表达分级超过TIMP一1表达分
级者10例，MMP一9表达分级低于TIMP一l表达分级者8例，两组在
术后复发率及生存率间均无撇著差异。
结论:MMP一2、TIMP一2的表达与MPNST的组织学分级及生存
率有关。MMP一2表达卜调和rIMP一2表达卜调可能在MPNST的发生、
发展过程中起重要作用。MMP一2、T 1 MP一2可作为判断MPNST恶性
程度及预后的有用的参考指标。
Objective: To investigate the relationship of the expression of gelatinases(MMP-2 and MMP-9) and their tissue inhibitors(TIMP-2 and TIMP-1) to clinicopathological characteristics and prognosis of MPNST.
Methods: S-P immunohistochemical staining was used to detect the expression of MMP-2, MMP-9, TIMP-2, TIMP-1 in 58 MPNST, and the patients were followed-up.
Resu I ts: (1) The expression of MMP-2 in MPNST was markedly higher than that in normal nerves and benign peripheral nerve sheath tumors(P<0.05). Increased MMP-2 reactivity was significant for histologic grade and survival time(P<0.05), but not for sex, age, tumor size, site or recurrence. The expression of MMP-9 in MPNST was higher than that in normal nerves and benign peripheral nerve sheath tumors, but no significant association was found between them. No significant association was found between the expression of MMP-9 and sex, age, tumor size, site ,histologic grade, recurrence , or survival time. (2) The
expression of T1MP-2 in MPNST was markedly lowerer than that in normal nerves and benign peripheral nerve sheath tumors(P<0.05). Lack of TIMP-2 expression was significant for histologic grade and survival time(P<0.05), but not for sex, age, tumor size, site or recurrence. The expression of TIMP-1 in MPNST was lowerer than that in normal nerves and benign peripheral nerve sheath tumors, but no significant association was found between them. No significant association was found between the expression of TIMP-1 and sex, age, tumor size, site ,histologic grade, recurrence , or survival time. (3) Unbalance expression between MMP-2 and TIMP-2 was significant for survival time(P<0.05), but not for recurrence. Unbalance expression between MMP-9 and TIMP-1 was significant for neither recurrence nor survival time.
Cone I us i ons: The expression of MMP-2 and TIMP-2 is associated with histologic grade and survival time of MPNST. Increased MMP-2 reactivity and lack of TIMP-2 expression may play a role in occurrence and progress of MPNST. MMP-2 and TIMP-2 might be useful to define aggressiveness and prognosis of MPNST.
引文
1. Weiss SW, Goldblum JR. Soft tissue tumors.北京：人民卫生出版社，2002：6～14,1209～1240.
2. Hruban RH, Shiu MH, Senie RT, etc. Malignant peripheral nerve sheath tumors of the buttock and lower extremity: A study of 43 cases. Cancer, 1990,66(6): 1253～1265.
3．杨光华主编．病理学．第五版，北京：人民卫生出版社，2001：89～91．
4. Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol, 1999,189(3):300～308.
5．高进，章静波主编．癌的侵袭与转移基础与临床．北京：科学出版社，2003：86～92
6．汤钊猷主编．肝癌转移复发的基础与临床．上海：上海科技教育出版社，2003：149～154．
7．陈意生，史景泉主编．肿瘤分子细胞生物学．北京：人民军医出版社，2002：65～70．
8．李莉，张卢，林华，等．基质金属蛋白酶和组织金属蛋白酶抑制剂表达失衡与胃癌浸润转移的关系．癌症，2002，21(3)：305～310．
9. Still K, Robson CN, Autzen P, etc. Localization and quantification of mRNA for matrix metalloproteinase-2(MMP-2) and tissue inhibitor of matrix metalloproteinase-2(TIMP-2) in human benign and malignant prostatic tissue. Prostate,2000,42(1):18～25.
10．张如明，藤胜主编．软组织肉瘤现代外科治疗．天津：天津科学技术出版社，2001：23～26．
11. Friedrichs K, Giuba S, Eidtmann H, etc. Overexpression of P53 and prognosis in breast cancer. Cancer. 1993.72(12): 3641～3647.
12．许良中，杨文涛．免疫组织化学反应结果的判定．中国癌症杂志， 1996，6(4)：229～231．
13．武忠弼，杨光华主编．中华外科病理学．北京：人民卫生出版社，2002：2531～2536．
14. Weiss SW, Langloss JM, Enzinger FM. Value of S-100 protein in diagnosis of soft tissue tumors with particular reference to benign and malignant schwann cell tumors. Lab Invest, 1983(3),49:299～308.
15. Matsunou H, Shimoda T, Kakimoto S, etc. Histopathologic and immunohistochemical study of mnalignant tumors of peripheral nerve sheath(malignant schwannoma). Cancer, 1985, 56(9):2269～2279.
16. Wick MR, Swanson PE, Scheithauer BW, etc. Malignant peripheral nerve sheath tumor: an immunohistochemical study of 62 cases. Am J Clin Pathol,1987, 87(4):425～433.
17. Kourea HP, Bilsky MH, Leung DH, etc. Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors: a clinicopathlolgic study of 25 patients and 26 tumors. Cancer, 1998,82(11):2191～2203.
18. Wong WW, Hirose T, Scheithauer BW, etc. Malignant peripheral nerve sheath tumors: analysis of treatment outcome, lnt J Radiat Oncol Biol Phys, 1998,42(2):351～360.
19. Burbridge MF, Coge F, Galizzi JP, etc. The role of the matrix metalloproteinases during in vitro vessel formation. Angiogenesis,2002,5(3):215～226.
20. Johnson C, Sung HJ, Lessner SM, etc. Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching. Circ Res,2004,94(2):262～268.
21. Hanemaaijer R, Verheijen JH, Maguire TM, etc. Increased gelatinase-A and gelatinase-B activities in malignant vs. benign breast tumors, lnt J Cancer, 2000,86(2):204～207.
22. Liu Z, Yan L, Xiang T, etc. Expression of vascular endothelial growth factor and matrix metalloproteinase-2 correlates with the invasion and metastasis of hepatocellular carcinoma. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 2003, 20(2):249～250, 254.
23. Monig SP, Baldus SE, Hennecken JK, etc. Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma. Histopathology. 2001, 39(6):597～602.
24. Matsuyama Y, Takao S, Aikou T, etc. Comparison of matrix metalloproteinase expression between primary tumors with or without liver metastasis in pancreatic and colorectal carcinomas. J Surg Oncol,2002,80(2): 105～110.
25. Deryugina El, Luo GX, Reisfeld RA, etc. Tumor cell invasion through matrigel is regulated by activated matrix metalloproteinase-2. Anticancer Res, 1997,17(5A):3201～3210.
26. Kong L, Fang W, Zhong H, etc. Controlled expression of matrix metalloproteinase 9 promotes expression of invasive phenotype of human melanoma cells. Beijing Da Xue Xue Bao. 2003,18,35(1):7～11.
27. Sakamoto A, Oda Y, lwamoto Y, etc. Expression of membrane type 1 matrix metalloproteinase, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 in
human carilaginous tumors with special emphasis on mesenchymal and dedifferentiated chondrosarcoma. J Cancer Res Clin Oncol, 1999, 125(10):541～548.
28. Toriyama M, Rosenberg AE, Mankin HJ, etc. Matrix metalloproteinase digestion of aggrecan in human cartilage tumors. Eur J Cancer, 1998,34(12): 1969～1973.
29．华成舸，温玉明，王昌美，等．骨和软组织肿瘤中明胶酶的定位与活性分析．华西医大学报,2000,31(1)：82～85．
30. Benassi MS, Gamberi G, Magagnoli G, etc. Metalloproteinase expression and prognosis in soft tissue sarcomas. Ann Oncol,2001,12(1):75～80.
31. Brook JS, Freeman M, Enterline HT. Malignant"Triton"Tumors. Cancer,1985,55: 2543～2549.
32．袁莲香，何伟民，张斌，等．乳腺癌组织MMP-2、MMP-9、TIMP-2蛋白表达与肿瘤的转移及预后．肿瘤,2002,22(4)：294～296．
33. Westermarck J, Kahari VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J,1999,13(8):781～792.
34．王杰军，高勇，许青主编．肿瘤转移机制及诊疗进展．上海：第二军医大学出版社，2002：45
35. Kondapaka SB Fridman R, Reddy KB. Epidermal growth factor and amphiregulin up-regulate matrix metalloproteinase-9(MMP-9) in human breast cancer cells, lnt J Cancer,1997,70(6):722～726.
36. Inoue H, Mimori K, Shiraishi T, etc. Expression of tissue inhibitor of matrix metalloproteinase-1 in human breast carcinoma. Oncol Rep,2000,7(4):871～874.
37. Mimori K, Mori M, Shiraishi T, etc. Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer,1997,76(4): 531～536.
38. Denhardt DT, Khokak, Yagel S, etc. Oncogenic consequences of down-modulating TIMP expression in 3T3 cells with antisense R NA. Matrix Suppl, 1992,1:281～285.
39. Khokha R, Waterhouse P, Yagel S, etc. Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on swiss 3T3 cells. Science, 1989,243(4893): 947～950.
40. Imren S, Kohn DB, Shimada II, etc. Overexpression of tissue inhibitor of metalloproteinases-2 retroviral-mediated gene transfer in vivo inhibits tumor growth and
invasion. Cancer Res, 1996,56(13):2891～2895.
41. Li N, Xu C, Liu W. The effect of tissue inhibitor of metalloproteinase-2 gene (TIMP-2 gene) on gastric carcinoma cells in vitro and in vivo. Zhonghua Bing Li Xue Za Zhi,1998, 27(5):362～365.
42. Shi Y, Parhar RS, Zou M, etc. Gene therapy of melanoma pulmonary metastasis by intramuscular injection of plasmid DNA encoding tissue inhibitor of metalloproteinases-1. Cancer Gene Ther,2002,9(2):126～132.
43. Yamauchi K, Ogata Y, Nagase H, etc. Inhibition of liver metastasis from orthotopically implanted colon cancer in nude mice by transfection of the TIMP-1 gene into KMI2SM cells. Surg Today,2001;31(9):791～798.
44．许克新，侯树坤，杜志军，等．检测金属基质蛋白酶及其抑制物对判断膀胱癌浸润和转移的意义．中华沁尿外科杂志，2002，23(4)：231～233．
45. Pavlaki M, Zucker S. Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase Ⅰor the termination of phase Ⅲ clinical trials. Cancer Metastasis Rev,2003,22(2-3): 177～203.
46. Liu J, Tsao MS, Pagura M, etc. Early combined treatment with carboplatin and the MMP inhibitor, prinomastat, prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung cancer model. Lung Cancer, 2003,42(3):335～344.
47. Yamamoto A, Yano S, Shiraga M, etc. A third-generation matrix metalloproteinase (MMP) inhibitor (ONO-4817) combined with docetaxel suppresses progression of lung micrometastasis of MMP-expressing tumor cells in nude mice. lnt J Cancer, 2003, 103(6):822～828.
2. Hruban RH, Shiu MH, Senie RT, etc. Malignant peripheral nerve sheath tumors of the buttock and lower extremity: A study of 43 cases. Cancer, 1990,66(6): 1253～1265.
3．杨光华主编．病理学．第五版，北京：人民卫生出版社，2001：89～91．
4. Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol, 1999,189(3):300～308.
5．高进，章静波主编．癌的侵袭与转移基础与临床．北京：科学出版社，2003：86～92
6．汤钊猷主编．肝癌转移复发的基础与临床．上海：上海科技教育出版社，2003：149～154．
7．陈意生，史景泉主编．肿瘤分子细胞生物学．北京：人民军医出版社，2002：65～70．
8．李莉，张卢，林华，等．基质金属蛋白酶和组织金属蛋白酶抑制剂表达失衡与胃癌浸润转移的关系．癌症，2002，21(3)：305～310．
9. Still K, Robson CN, Autzen P, etc. Localization and quantification of mRNA for matrix metalloproteinase-2(MMP-2) and tissue inhibitor of matrix metalloproteinase-2(TIMP-2) in human benign and malignant prostatic tissue. Prostate,2000,42(1):18～25.
10．张如明，藤胜主编．软组织肉瘤现代外科治疗．天津：天津科学技术出版社，2001：23～26．
11. Friedrichs K, Giuba S, Eidtmann H, etc. Overexpression of P53 and prognosis in breast cancer. Cancer. 1993.72(12): 3641～3647.
12．许良中，杨文涛．免疫组织化学反应结果的判定．中国癌症杂志， 1996，6(4)：229～231．
13．武忠弼，杨光华主编．中华外科病理学．北京：人民卫生出版社，2002：2531～2536．
14. Weiss SW, Langloss JM, Enzinger FM. Value of S-100 protein in diagnosis of soft tissue tumors with particular reference to benign and malignant schwann cell tumors. Lab Invest, 1983(3),49:299～308.
15. Matsunou H, Shimoda T, Kakimoto S, etc. Histopathologic and immunohistochemical study of mnalignant tumors of peripheral nerve sheath(malignant schwannoma). Cancer, 1985, 56(9):2269～2279.
16. Wick MR, Swanson PE, Scheithauer BW, etc. Malignant peripheral nerve sheath tumor: an immunohistochemical study of 62 cases. Am J Clin Pathol,1987, 87(4):425～433.
17. Kourea HP, Bilsky MH, Leung DH, etc. Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors: a clinicopathlolgic study of 25 patients and 26 tumors. Cancer, 1998,82(11):2191～2203.
18. Wong WW, Hirose T, Scheithauer BW, etc. Malignant peripheral nerve sheath tumors: analysis of treatment outcome, lnt J Radiat Oncol Biol Phys, 1998,42(2):351～360.
19. Burbridge MF, Coge F, Galizzi JP, etc. The role of the matrix metalloproteinases during in vitro vessel formation. Angiogenesis,2002,5(3):215～226.
20. Johnson C, Sung HJ, Lessner SM, etc. Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching. Circ Res,2004,94(2):262～268.
21. Hanemaaijer R, Verheijen JH, Maguire TM, etc. Increased gelatinase-A and gelatinase-B activities in malignant vs. benign breast tumors, lnt J Cancer, 2000,86(2):204～207.
22. Liu Z, Yan L, Xiang T, etc. Expression of vascular endothelial growth factor and matrix metalloproteinase-2 correlates with the invasion and metastasis of hepatocellular carcinoma. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 2003, 20(2):249～250, 254.
23. Monig SP, Baldus SE, Hennecken JK, etc. Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma. Histopathology. 2001, 39(6):597～602.
24. Matsuyama Y, Takao S, Aikou T, etc. Comparison of matrix metalloproteinase expression between primary tumors with or without liver metastasis in pancreatic and colorectal carcinomas. J Surg Oncol,2002,80(2): 105～110.
25. Deryugina El, Luo GX, Reisfeld RA, etc. Tumor cell invasion through matrigel is regulated by activated matrix metalloproteinase-2. Anticancer Res, 1997,17(5A):3201～3210.
26. Kong L, Fang W, Zhong H, etc. Controlled expression of matrix metalloproteinase 9 promotes expression of invasive phenotype of human melanoma cells. Beijing Da Xue Xue Bao. 2003,18,35(1):7～11.
27. Sakamoto A, Oda Y, lwamoto Y, etc. Expression of membrane type 1 matrix metalloproteinase, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 in
human carilaginous tumors with special emphasis on mesenchymal and dedifferentiated chondrosarcoma. J Cancer Res Clin Oncol, 1999, 125(10):541～548.
28. Toriyama M, Rosenberg AE, Mankin HJ, etc. Matrix metalloproteinase digestion of aggrecan in human cartilage tumors. Eur J Cancer, 1998,34(12): 1969～1973.
29．华成舸，温玉明，王昌美，等．骨和软组织肿瘤中明胶酶的定位与活性分析．华西医大学报,2000,31(1)：82～85．
30. Benassi MS, Gamberi G, Magagnoli G, etc. Metalloproteinase expression and prognosis in soft tissue sarcomas. Ann Oncol,2001,12(1):75～80.
31. Brook JS, Freeman M, Enterline HT. Malignant"Triton"Tumors. Cancer,1985,55: 2543～2549.
32．袁莲香，何伟民，张斌，等．乳腺癌组织MMP-2、MMP-9、TIMP-2蛋白表达与肿瘤的转移及预后．肿瘤,2002,22(4)：294～296．
33. Westermarck J, Kahari VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J,1999,13(8):781～792.
34．王杰军，高勇，许青主编．肿瘤转移机制及诊疗进展．上海：第二军医大学出版社，2002：45
35. Kondapaka SB Fridman R, Reddy KB. Epidermal growth factor and amphiregulin up-regulate matrix metalloproteinase-9(MMP-9) in human breast cancer cells, lnt J Cancer,1997,70(6):722～726.
36. Inoue H, Mimori K, Shiraishi T, etc. Expression of tissue inhibitor of matrix metalloproteinase-1 in human breast carcinoma. Oncol Rep,2000,7(4):871～874.
37. Mimori K, Mori M, Shiraishi T, etc. Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer,1997,76(4): 531～536.
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