应用组织芯片技术研究基质金属蛋白酶13，14及抑制剂2在人乳腺癌中的表达及意义
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摘要
目的：基质金属蛋白酶(matrix metalloproteinases MMPs)通过对细胞外基质(extracell matrix，ECM)降解促进癌细胞对周围组织的浸润，而基质金属蛋白酶组织抑制因子(tissue inhibitor of metalloproteinase TIMPs)则是通过降解金属蛋白酶的活性而抑制肿瘤的侵袭和转移。本实验检测人乳腺癌及癌旁组织中MMP-13、MMP-14及TIMP2的表达，分析(1)乳腺癌中是否存在MMP-13、MMP-14及TIMP2的表达、(2)其表达与乳腺癌的发生、发展及淋巴道转移的关系，(3)MMPs／TIMPs的平衡状况与恶性肿瘤进展的关系。方法：应用组织芯片仪制作了88例乳腺癌及46例癌旁组织的组织芯片；采用免疫组织化学PV9000方法检测其MMP-13、MMP-14、TIMP-2的表达。所得结果采用卡方检验和spearman等级相关分析。结果：①MMP-13、MMP-14及TIMP-2癌旁乳腺组织中多呈弱阳性(+)表达，而乳腺组织中呈弱阳性(+)及强阳性(++)表达；②88例乳腺癌中MMP-13、MMP-14及TIMP-2阳性表达分别为63例、86例、65例，分别占71.6％、97.7％、73.9％；46例癌旁组织中MMP-13、MMP-14及TIMP-2阳性表达分别为24例、38例、28例，分别占52.2％、82.6％、60.9％，MMP-13、MMP-14及TIMP-2在乳腺癌中的表达均强于癌旁组织(P＜0.05)；③MMP-13、TIMP-2的表达与乳腺癌的淋巴结有无转移均呈正相关(P＜0.05)，与肿瘤的分级、大小、患者的年龄无关(P＞0.05)；MMP-14的表达与乳腺癌的分级、淋巴结转移及年龄均有关(P＜0.05)，但与乳腺癌的大小无关(P＞0.05)；④MMP-13、MMP-14及TIMP-2两两之间无相关性(P＞0.05)。结论：
(1)MMP-13、MMP-14、TIMP-2在乳腺癌中呈高表达。
(2)在乳腺癌的发生、发展及淋巴结的转移中MMP-13、MMP-14可能起重要作用，而TIMP-2极有可能为一重要的抑制因子。
(3)MMPs／TIMPs之间的相互作用及平衡状态是恶性肿瘤侵袭转移分子生物学机制中的重要环节。
Objective: It was said that matrix metalloproteinases (MMPs) can improve tumor invasion and metastasis by degrading extracell matrix.and tissue inhibitor of metalloproteinase(TIMPs) can inhibit tumor invasion and metastasis by degrading the activity of matrix metalloproteinases.By researching the expression of matrix metalloproteinases(MMP-13, MMP-14) and their inhibitor( TIMP-2) in breast cancers and around tumor area., we want to explor①whether the expression of MMP-13,14 and TIMP-2 is present in breast carcinoma;②the relation between the their expression and the tumor invasion and metastasis;③the relation of MMPs/TIMPs and tumor progrssionMethods: 88 cases of breast carcinoma and 46 cases of the tissues nearby were detected on Tissue Microarries. The expression of MMP-13,MMP-14 and their inhibitor TIMP-2 were detected by immunohistochemical P-V9000 method. The results were tested by statistics method square test、Spearman' rank correlation).Results: Among 88 breast cancers, 63 cases were positive for MMP-13 (71.6 %), 86 cases were positive for MMP-14( 97.7%), 65 cases were positive for TIMP-2 (73.9%), In areae of tumor tissue nearby , 24/46 cases were positive for MMP-13 (52.2 %), 38/46 cases were positive for MMP-14( 82.6%), 28/46 cases were positive for TIMP-2 (60.9%), The distinction between the two sites is marked (P<0.05) The expression of MMP-13 and TIMP-2 related with histological grade, and lymph node metastasis (p<0.05), and has no connection with histological grade ,the size of cancer and age(p>0.05). The expression of MMP-14 related with histological grade, lymph node metastasis and age (p<0.05), and has no connection with the size of cancer (p>0.05).But they have no relation each other.Conclusion: (1) The expression of MMP-13 and MMP-14 was stronger in which with breast cancers than breast tissues near to cancer.(2) MMP-13, MMP-14 may be play an important role on the development and lymph node metastasis of breast cancers .It shows that TIMP-2 may be a key action in blocking cancer metastasis.(3) The balance between MMPs and TIMPs is a critical factor which affecte tumor invasion and metastasis.
(1)MMP-13、MMP-14、TIMP-2在乳腺癌中呈高表达。
(2)在乳腺癌的发生、发展及淋巴结的转移中MMP-13、MMP-14可能起重要作用，而TIMP-2极有可能为一重要的抑制因子。
(3)MMPs／TIMPs之间的相互作用及平衡状态是恶性肿瘤侵袭转移分子生物学机制中的重要环节。
Objective: It was said that matrix metalloproteinases (MMPs) can improve tumor invasion and metastasis by degrading extracell matrix.and tissue inhibitor of metalloproteinase(TIMPs) can inhibit tumor invasion and metastasis by degrading the activity of matrix metalloproteinases.By researching the expression of matrix metalloproteinases(MMP-13, MMP-14) and their inhibitor( TIMP-2) in breast cancers and around tumor area., we want to explor①whether the expression of MMP-13,14 and TIMP-2 is present in breast carcinoma;②the relation between the their expression and the tumor invasion and metastasis;③the relation of MMPs/TIMPs and tumor progrssionMethods: 88 cases of breast carcinoma and 46 cases of the tissues nearby were detected on Tissue Microarries. The expression of MMP-13,MMP-14 and their inhibitor TIMP-2 were detected by immunohistochemical P-V9000 method. The results were tested by statistics method square test、Spearman' rank correlation).Results: Among 88 breast cancers, 63 cases were positive for MMP-13 (71.6 %), 86 cases were positive for MMP-14( 97.7%), 65 cases were positive for TIMP-2 (73.9%), In areae of tumor tissue nearby , 24/46 cases were positive for MMP-13 (52.2 %), 38/46 cases were positive for MMP-14( 82.6%), 28/46 cases were positive for TIMP-2 (60.9%), The distinction between the two sites is marked (P<0.05) The expression of MMP-13 and TIMP-2 related with histological grade, and lymph node metastasis (p<0.05), and has no connection with histological grade ,the size of cancer and age(p>0.05). The expression of MMP-14 related with histological grade, lymph node metastasis and age (p<0.05), and has no connection with the size of cancer (p>0.05).But they have no relation each other.Conclusion: (1) The expression of MMP-13 and MMP-14 was stronger in which with breast cancers than breast tissues near to cancer.(2) MMP-13, MMP-14 may be play an important role on the development and lymph node metastasis of breast cancers .It shows that TIMP-2 may be a key action in blocking cancer metastasis.(3) The balance between MMPs and TIMPs is a critical factor which affecte tumor invasion and metastasis.
引文
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59 Kallioniemi OP. Biochip technologies in cancer re2 search. Ann Med ,2001 ,33(2) : 1422147.
60 Kononen J , Bubendorf L , Kallioniemi , A , et al.Tissue microarrays for high2throughput molecular profiling of tumor specimens. Nat Med , 1998 ,4(7) : 8442847.
61 Fejzo M , Slamon D. Frozen tumor tissue microarray technology for analysis of tumor RNA , DNA , and proteins. Am J Pathol ,2001 ,59(5) :164521650.
62 Camp R , Charette L , Rimm D. Validation of tissue microarray technology in breast carcinoma. Lab In2 vest ,2000 ,80(12) :194321949.
63 Hoos A , Cordon2Cardo C. Tissue microarray profiling of cancer specimens and cell lines : Opportunities and limitations. Lab Invest ,2001 ,81(10) : 133121338.
64 Meinhold2Heerlein I , Stener2Liewen F ,Liewen H , et al. Expression and potential role of Fasassociated phosphatase21 in ovarian cancer. Am J Pathol ,158(4) :133521344.
65 Bubendorf L , Kolmer M , Kononen J , et al. Hormone therapy failure in human prostate cancer :analysis by complementary DNA and tissue microarrays. J Natl Can Inst ,1999 ,91(20) : 175821764.
66 Ekins R , Chu FW. Microarrays :their origins and ap2 plication. Trends in Biotechnol , 1999 , 17 (6) : 2172 218.
67 Wooster R. Cancer classification with DNA microar2 rays is less more ? Trends Genet 2000 ,16 (8) : 3272 329.
68 Moch H , Kononen T ,Kallioiemi OP , et al. Tissue mi2 croarrays : what will they bring to molecular and anatomic pathology ?Adv Anat Pathol , 2001 , 8 (1) :14220.
69 Sallinen SL ,Sallinen PK, Haapasalo HK,et al. Iden2 tification of differentially expressed genes in human gliomas by DNA microarray and tissue chip tech2 niques. Cancer Res ,2000 ,60(23) :661726622.
70 Richter J , Wagner U , Kononen J , high2throughput tissue microarray analysis of cylin E gene amplifica2 tion and ovevexpression in urinary bladder cancer. Am J Pathol ,2000 ,157(3) :7872794.
71 Barlund M , Monni O , Kononen J , et al. Multiple genes at 17q23 undergo amplification and overex2 pression in breast cancer. Cancer Res ,2000 ,60(19) : 53402-5344.
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59 Kallioniemi OP. Biochip technologies in cancer re2 search. Ann Med ,2001 ,33(2) : 1422147.
60 Kononen J , Bubendorf L , Kallioniemi , A , et al.Tissue microarrays for high2throughput molecular profiling of tumor specimens. Nat Med , 1998 ,4(7) : 8442847.
61 Fejzo M , Slamon D. Frozen tumor tissue microarray technology for analysis of tumor RNA , DNA , and proteins. Am J Pathol ,2001 ,59(5) :164521650.
62 Camp R , Charette L , Rimm D. Validation of tissue microarray technology in breast carcinoma. Lab In2 vest ,2000 ,80(12) :194321949.
63 Hoos A , Cordon2Cardo C. Tissue microarray profiling of cancer specimens and cell lines : Opportunities and limitations. Lab Invest ,2001 ,81(10) : 133121338.
64 Meinhold2Heerlein I , Stener2Liewen F ,Liewen H , et al. Expression and potential role of Fasassociated phosphatase21 in ovarian cancer. Am J Pathol ,158(4) :133521344.
65 Bubendorf L , Kolmer M , Kononen J , et al. Hormone therapy failure in human prostate cancer :analysis by complementary DNA and tissue microarrays. J Natl Can Inst ,1999 ,91(20) : 175821764.
66 Ekins R , Chu FW. Microarrays :their origins and ap2 plication. Trends in Biotechnol , 1999 , 17 (6) : 2172 218.
67 Wooster R. Cancer classification with DNA microar2 rays is less more ? Trends Genet 2000 ,16 (8) : 3272 329.
68 Moch H , Kononen T ,Kallioiemi OP , et al. Tissue mi2 croarrays : what will they bring to molecular and anatomic pathology ?Adv Anat Pathol , 2001 , 8 (1) :14220.
69 Sallinen SL ,Sallinen PK, Haapasalo HK,et al. Iden2 tification of differentially expressed genes in human gliomas by DNA microarray and tissue chip tech2 niques. Cancer Res ,2000 ,60(23) :661726622.
70 Richter J , Wagner U , Kononen J , high2throughput tissue microarray analysis of cylin E gene amplifica2 tion and ovevexpression in urinary bladder cancer. Am J Pathol ,2000 ,157(3) :7872794.
71 Barlund M , Monni O , Kononen J , et al. Multiple genes at 17q23 undergo amplification and overex2 pression in breast cancer. Cancer Res ,2000 ,60(19) : 53402-5344.