应用组织芯片技术对基质金属蛋白酶7（MMP-7），基质金属蛋白酶9（MMP-9）与人结直肠癌腹腔转移的相关性研究
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摘要
目的:研究基质金属蛋白酶7(MMP-7),基质金属蛋白酶9(MMP-9)在人结直肠癌(colorectal carcinoma,CRC)中的表达情况,以探讨其在人结直肠癌腹腔转移中的相关作用,为其在人结直肠癌腹腔转移相关预测及监测诊断性研究以及抗人结直肠癌药物的治疗性研究提供理论基础,并初步探讨组织芯片免疫组织化学在人结直肠癌相关指标检测中的应用。
人结直肠癌是常见的消化道恶性肿瘤,尽管对其采取了以手术为主的综合性治疗,但因缺乏有效的早期诊断标准及抗转移治疗靶点,患者预后仍不佳。因此,深入研究控制人结直肠癌发生发展过程的关键基因的表达变化及其作用,将为其早期诊断预后判断和抗转移治疗提供理论依据。
基质金属蛋白酶7(MMP-7)和金属蛋白酶9(MMP-9)对细胞外基质成分具有广泛的降解作用,与多数肿瘤的侵袭转移密切相关。但有关其协同表达及其意义的研究国外报道较少,国内还未见报道。
组织芯片(tissue chip)又称组织微阵列(tissue microarrays, T MA),是将数十至上千个小组织整齐地排放在一张载玻片上而制成的组织切片。1998年,Kononen等首次提出了组织芯片的概念,并制作了乳腺癌的组织微阵列,应用荧光原位杂交、免疫组织化学和mRNA原位杂交技术研究了6种基因及其表达产物的表达状态,不但发现这些指标与乳腺癌的预后密切相关,而且与大组织的检测结果完全一致。组织芯片的诞生为医学病理学提供了一种高通量、大样本以及快速的分子水平的分析工具。此以后,组织芯片技术得到了迅速发展。国内外发表的组织芯片技术相关报道已有近千篇。这样用同一套组织芯片即可迅速的对上百种生物分子标记(如抗原,DNA和RNA)进行分析、检测。因此组织芯片技术是建立疾病,特别是肿瘤的生物分子文库的强有力的工具。
为此,本实验拟应用组织芯片技术,采用免疫组织化学方法对12例正常大肠黏膜,50例伴有腹腔转移腺癌组织,48例无腹腔转移腺癌组织的MMP-7,MMP-9的表达进行检测,旨在探讨MMP-7,MMP-9对大肠癌发生和腹腔转移的影响及其机制。
方法:本实验分为三部分。
1收集河北医科大学附属第四病院外二科2006-2007年住院病人98例CRC原发灶和12例正常大肠黏膜的石蜡标本,使用组织阵列仪(personaltis suear rayer)制作成组织芯片(也称组织微阵列,tissue microarray)共3块。
2采用抗生物素蛋白一过氧化酶(SP)法,对组织芯片进行免疫组织化学染色,并评估MMP-7,MMP-9的表达情况。寻找与CRC腹腔转移密切相关肿瘤标记物。
3用SPSS10.0统计软件包进行统计分析,以P<0.05为差异显著,P<0.01为差异非常显著。比较有腹腔转移腺癌与无腹腔转移腺癌之间MMP-7,MMP-9的表达差异。
结果:
1制备了组织芯片蜡块3块,每个蜡块可切片成70-100张组织芯片玻片,供免疫组织化学检测及今后研究使用。在制片、染色过程中组织芯片上有部分组织块出现移位或脱失,可供统计分析的有96例。
2 MMP-7,MMP-9在伴有腹腔转移CRC的阳性表达率分别为68%和78%,明显高于与无腹腔转移CRC表达率39.5%和33.3% (P<0.01)
结论:
1采用石蜡标本制作组织芯片,结合免疫组织化学方法,可以大规模、快速、高效地检测MMP-7,MMP-9在CRC中表达。
2有腹腔转移CRC中MMP-7,MMP-9的表达明显高于腹腔转移,提示高表达MMP-7,MMP-9的CRC更容易发生腹腔转移。
Objective:
To observe the expressions o f Matrix Metalloproteinase 7 , Matrix Metalloproteinase 9 in human Colorectal Carcinoma,and explore the correlation between MMP-7,MMP-9 and abdominal cavity metastasis in humanColorectal Carcinoma using tissue microarray. The aim of these studies is to provide further rationale basis for MMPs family members in diagnostic study of prediction and monitoring of metastasis correlated with Colorectal Carcinoma and in remedial study of anti- Colorectal Carcinoma drugs. The other aim of these studies is to explore the application of Microarray immunohistochernical technique in the detection of the index correlated with Colorectal Carcinoma.
Colorectal carcinoma (CRC) is one of the most common malignancies in digestive tracts. Although comprehensive therapies have been used, the prognosis of CRC is still poor, which is possibly due to the lack of early effective diagnosis and effective targets of anti-metastasis. Therefore, further exploring the alterations of key genes related to development and progression of CRC will be considered useful.
Degradating almost all components of extracellular matrix, matrix metalloproteinase-7 (MMP-7) and matrix metalloproteinase-9 (MMP-9) are hence considered to be related to invasion/metastasis of malignancies.
Tissue chip, also called tissue microarray (TMA), can sample up to 1000 cylindrical tissue specimens on one glass slide. In 1998, Kononen first described this high-throughput technique and constructed a breast cancer tissue microarray. Six gene amplifications were detected by fluorescence in situ hybridization, immunohistochemistry and mRNA ISH. The results confirmed these makers were related to the prognosis of breast cancer and agreed with published results. Tissue
Microarrays provide a high-throughout molecularte chnique for pathology.An umber of diffrerent applications of tissue microarrays have been described in recent publications. Because a large number of nearly identical sections can be obtained from a single MTTB, these sections could be useful for large scale interlaboratory quality control studies. Tissue microarrays can be used for educational purposes as well as to improve quality control and standardization of staining methods and interpretation. Tissue microarrays have become one of the most promising tools for the molecular and anatomic pathologist and will have many applications in cancer research, as well as in other fields of pathology.
In order to investigate the impact of MMP-7 and MMP-9 on development and progression of CRC, we first constructed the tissue microarrays of CRC including 12 cases common intestinal mucosa, 50 cases adenocarcinoma with abdominal cavity metastasis and 48 cases without abdominal cavity metastasis, then detected MMP-7 and MMP-9 protein expressions by immunohistochemistry.
Methods:
This experiment includes three parts:
1 Collect 110 cases of paraffin-embeddeds pecimen stored in the 4th hospital of HEBEI medical university, including 12 cases common intestinal mucosa, 50 cases adenocarcinoma with abdominal cavity metastasis and 48 cases without abdominal cavity metastasis.Then construct tissue microarrays using personaltis suear rayer.
2 To evaluate the expression of MMP7, MMP9 using S-P method of IHC (immunohistochemistry).
3 With SPSS10.0, to compare the differences of the expression between adenocarcinoma with abdominal cavity metastasis and without abdominal cavity metastasis; to evaluate the relationship of markers' expression and abdominal cavity metastasis in CRC.
Results:
1 Succeed in constructing three blocks of tissue microarray of CRC and 96 cases of data are eligible for analysis.
2 The expression rate of MMP7 and MMP9 were much higher in adenocarcinoma with abdominal cavity metastasis (68%, 78%) than those without abdominal cavity metastasis (39.5%, 33.3%) (P<0.01)
Conclusion:
1 Tissue microarray can provide a large scale of immunohi-stochemistry evaluation of MMP7 and MMP9 expression in CRC of in a short period with efficiency.
2 The expression rate of MMP7 and MMP9 were much higher in adenocarcinoma with abdominal cavity metastasis than those without abdominal cavity metastasis. It seems that the case with high expression of MMP7 and MMP9 has the liability of abdominal cavity metastasis in CRC.
人结直肠癌是常见的消化道恶性肿瘤,尽管对其采取了以手术为主的综合性治疗,但因缺乏有效的早期诊断标准及抗转移治疗靶点,患者预后仍不佳。因此,深入研究控制人结直肠癌发生发展过程的关键基因的表达变化及其作用,将为其早期诊断预后判断和抗转移治疗提供理论依据。
基质金属蛋白酶7(MMP-7)和金属蛋白酶9(MMP-9)对细胞外基质成分具有广泛的降解作用,与多数肿瘤的侵袭转移密切相关。但有关其协同表达及其意义的研究国外报道较少,国内还未见报道。
组织芯片(tissue chip)又称组织微阵列(tissue microarrays, T MA),是将数十至上千个小组织整齐地排放在一张载玻片上而制成的组织切片。1998年,Kononen等首次提出了组织芯片的概念,并制作了乳腺癌的组织微阵列,应用荧光原位杂交、免疫组织化学和mRNA原位杂交技术研究了6种基因及其表达产物的表达状态,不但发现这些指标与乳腺癌的预后密切相关,而且与大组织的检测结果完全一致。组织芯片的诞生为医学病理学提供了一种高通量、大样本以及快速的分子水平的分析工具。此以后,组织芯片技术得到了迅速发展。国内外发表的组织芯片技术相关报道已有近千篇。这样用同一套组织芯片即可迅速的对上百种生物分子标记(如抗原,DNA和RNA)进行分析、检测。因此组织芯片技术是建立疾病,特别是肿瘤的生物分子文库的强有力的工具。
为此,本实验拟应用组织芯片技术,采用免疫组织化学方法对12例正常大肠黏膜,50例伴有腹腔转移腺癌组织,48例无腹腔转移腺癌组织的MMP-7,MMP-9的表达进行检测,旨在探讨MMP-7,MMP-9对大肠癌发生和腹腔转移的影响及其机制。
方法:本实验分为三部分。
1收集河北医科大学附属第四病院外二科2006-2007年住院病人98例CRC原发灶和12例正常大肠黏膜的石蜡标本,使用组织阵列仪(personaltis suear rayer)制作成组织芯片(也称组织微阵列,tissue microarray)共3块。
2采用抗生物素蛋白一过氧化酶(SP)法,对组织芯片进行免疫组织化学染色,并评估MMP-7,MMP-9的表达情况。寻找与CRC腹腔转移密切相关肿瘤标记物。
3用SPSS10.0统计软件包进行统计分析,以P<0.05为差异显著,P<0.01为差异非常显著。比较有腹腔转移腺癌与无腹腔转移腺癌之间MMP-7,MMP-9的表达差异。
结果:
1制备了组织芯片蜡块3块,每个蜡块可切片成70-100张组织芯片玻片,供免疫组织化学检测及今后研究使用。在制片、染色过程中组织芯片上有部分组织块出现移位或脱失,可供统计分析的有96例。
2 MMP-7,MMP-9在伴有腹腔转移CRC的阳性表达率分别为68%和78%,明显高于与无腹腔转移CRC表达率39.5%和33.3% (P<0.01)
结论:
1采用石蜡标本制作组织芯片,结合免疫组织化学方法,可以大规模、快速、高效地检测MMP-7,MMP-9在CRC中表达。
2有腹腔转移CRC中MMP-7,MMP-9的表达明显高于腹腔转移,提示高表达MMP-7,MMP-9的CRC更容易发生腹腔转移。
Objective:
To observe the expressions o f Matrix Metalloproteinase 7 , Matrix Metalloproteinase 9 in human Colorectal Carcinoma,and explore the correlation between MMP-7,MMP-9 and abdominal cavity metastasis in humanColorectal Carcinoma using tissue microarray. The aim of these studies is to provide further rationale basis for MMPs family members in diagnostic study of prediction and monitoring of metastasis correlated with Colorectal Carcinoma and in remedial study of anti- Colorectal Carcinoma drugs. The other aim of these studies is to explore the application of Microarray immunohistochernical technique in the detection of the index correlated with Colorectal Carcinoma.
Colorectal carcinoma (CRC) is one of the most common malignancies in digestive tracts. Although comprehensive therapies have been used, the prognosis of CRC is still poor, which is possibly due to the lack of early effective diagnosis and effective targets of anti-metastasis. Therefore, further exploring the alterations of key genes related to development and progression of CRC will be considered useful.
Degradating almost all components of extracellular matrix, matrix metalloproteinase-7 (MMP-7) and matrix metalloproteinase-9 (MMP-9) are hence considered to be related to invasion/metastasis of malignancies.
Tissue chip, also called tissue microarray (TMA), can sample up to 1000 cylindrical tissue specimens on one glass slide. In 1998, Kononen first described this high-throughput technique and constructed a breast cancer tissue microarray. Six gene amplifications were detected by fluorescence in situ hybridization, immunohistochemistry and mRNA ISH. The results confirmed these makers were related to the prognosis of breast cancer and agreed with published results. Tissue
Microarrays provide a high-throughout molecularte chnique for pathology.An umber of diffrerent applications of tissue microarrays have been described in recent publications. Because a large number of nearly identical sections can be obtained from a single MTTB, these sections could be useful for large scale interlaboratory quality control studies. Tissue microarrays can be used for educational purposes as well as to improve quality control and standardization of staining methods and interpretation. Tissue microarrays have become one of the most promising tools for the molecular and anatomic pathologist and will have many applications in cancer research, as well as in other fields of pathology.
In order to investigate the impact of MMP-7 and MMP-9 on development and progression of CRC, we first constructed the tissue microarrays of CRC including 12 cases common intestinal mucosa, 50 cases adenocarcinoma with abdominal cavity metastasis and 48 cases without abdominal cavity metastasis, then detected MMP-7 and MMP-9 protein expressions by immunohistochemistry.
Methods:
This experiment includes three parts:
1 Collect 110 cases of paraffin-embeddeds pecimen stored in the 4th hospital of HEBEI medical university, including 12 cases common intestinal mucosa, 50 cases adenocarcinoma with abdominal cavity metastasis and 48 cases without abdominal cavity metastasis.Then construct tissue microarrays using personaltis suear rayer.
2 To evaluate the expression of MMP7, MMP9 using S-P method of IHC (immunohistochemistry).
3 With SPSS10.0, to compare the differences of the expression between adenocarcinoma with abdominal cavity metastasis and without abdominal cavity metastasis; to evaluate the relationship of markers' expression and abdominal cavity metastasis in CRC.
Results:
1 Succeed in constructing three blocks of tissue microarray of CRC and 96 cases of data are eligible for analysis.
2 The expression rate of MMP7 and MMP9 were much higher in adenocarcinoma with abdominal cavity metastasis (68%, 78%) than those without abdominal cavity metastasis (39.5%, 33.3%) (P<0.01)
Conclusion:
1 Tissue microarray can provide a large scale of immunohi-stochemistry evaluation of MMP7 and MMP9 expression in CRC of in a short period with efficiency.
2 The expression rate of MMP7 and MMP9 were much higher in adenocarcinoma with abdominal cavity metastasis than those without abdominal cavity metastasis. It seems that the case with high expression of MMP7 and MMP9 has the liability of abdominal cavity metastasis in CRC.
引文
1 Sappino AP, Schurch W, Gabbiani G: Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of pHenotypic modulations. Lab Invest 1990, 63:144-161
2 van den Hooff A: Stromal involvement in malignant growth. Adv Cancer Res 1988, 50:159-96
3 Varani J: Interaction of tumor cells with the extracellular matrix. Revis Biol Celular 1987, 12:1-113
4 Garbett EA ,Reed MV ,Brown NJ, et al. Proteolysis in human breast and colorectal cancer. Br J Cancer, 1999;81(2):287-293
5 Behrens P, Mathiak M, Mangold E, et al. Stromal expression of invasionpromoting, matrix-degrading proteases MMP-1and -9 and the Ets 1 transcription factor in HNPCC carcinomas and sporadic colorectal cancers. Int J Cancer 2003, 107:183-188
6 Garbett EA, Reed MW, Brown NJ. Proteolysis in colorectal cancer. Mol Pathol 1999, 52:140-145.
7 Islekel H, Oktay G, Terzi C, et al. Matrix metalloproteinase-9,-3 and tissue inhibitor of matrix metalloproteinase-1 in colorectal cancer: relationship to clinicopathological variables. Cell Biochem Funct 2006 in press
8 Karakiulakis G, Papanikolaou C, Jankovic SM, et al. Increased type IV collagendegrading activity in metastases originating from primary tumors of the human colon. Invasion Metastasis 1997, 17:158-168
9 Langenskiold M, Holmdahl L, Falk P, et al. Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
10 Liabakk NB, Talbot I, Smith RA, et al.Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res1996, 56:190-196
11 Luo HZ, Zhou ZG, Yang L, et al.Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol 2005, 35:739-744
12 Parsons SL, Watson SA, Collins HM, et al.Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy.Br J Cancer 1998, 78:1495-1502
13 Roeb E, Arndt M, Jansen B, et al. Simultaneous determination of matrix metalloproteinase (MMP)-7, MMP- 1, -3, and -13 gene expression by multiplex PCR in colorectal carcinomas. Int J Colorectal Dis 2004, 19:518-524
14 Saitoh Y, Yanai H, Higaki S, et al.Relationship between matrix metalloproteinase-7 and pit pattern in early stage colorectal cancer. Gastrointest Endosc 2004, 59:385-392
15 Zeng ZS, Shu WP, Cohen AM, et al.Matrix metalloproteinase-7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases. Clin Cancer Res 2002, 8:144-148
16 Baker EA, Bergin FG, Leaper DJ. Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging. Br J Surg 2000, 87:1215-1221
17 李莉, 张声, 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: 305
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20 Masaki T, Matsuoka H, Sugiyama M, et al.Matrilysin (MMP-7) as a significant determinant of malignant potentialof early invasive colorectal carcinomas. Br J Cancer 2001, 84:1317-1321
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1 Sappino AP, Schurch W, Gabbiani G. Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of pHenotypic modulations. Lab Invest 1990, 63:144-161
2 van den Hooff A. Stromal involvement in malignant growth. Adv Cancer Res 1988, 50:159-96
3 Varani J. Interaction of tumor cells with the extracellular matrix. Revis Biol Celular 1987, 12:1-113
4 Chakraborti S, Mandal M, Das S, et al. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 2003, 253:269-285
5 Momohara S, Okamoto H, Komiya K, et al.Matrix metalloproteinase 28/epilysin expression in cartilage from patients with rheumatoid arthritis and osteoarthritis: comment on the article by Kevorkian et al. Arthritis Rheum 2004, 50:131-141
6 Stetler-Stevenson WG, Hewitt R, Corcoran M.Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic. Semin Cancer Biol 1996, 7:147-154
7 Lukashev ME, Werb Z. ECM signalling: orchestrating cell behaviour and misbehaviour. Trends Cell Biol 1998, 8:437-441
8 Garbett EA ,Reed MV ,Brown NJ ,et al. Proteolysis in human breast and colorectal cancer. Br J Cancer, 1999;81(2):287-293
9 Behrens P, Mathiak M, Mangold E, et al.Stromal expression of invasionpromoting, matrix-degrading proteases MMP-1 and -9 and the Ets 1 transcription factor in HNPCC carcinomas and sporadic colorectal cancers. Int J Cancer 2003, 107:183-188
10 Chan CC, Menges M, Orzechowski HD, et al.Increased matrix metalloproteinase 2 concentration and transcript expression in advanced colorectal carcinomas. Int J Colorectal Dis 2001, 16:133-140
11 Garbett EA, Reed MW, Brown NJ: Proteolysis in colorectal cancer. Mol Pathol 1999, 52:140-145
12 Islekel H, Oktay G, Terzi C, et al.Matrix metalloproteinase-9,-3 and tissue inhibitor of matrixmetalloproteinase-1 in colorectal cancer: relationship to clinicopathological variables. Cell Biochem Funct 2006 in press
13 Karakiulakis G, Papanikolaou C, Jankovic SM, et al.Increased type IV collagendegrading activity in metastases originating from primary tumors of the human colon. Invasion Metastasis 1997,17:158-168
14 Langenskiold M, Holmdahl L, Falk P, et al.Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
15 Liabakk NB, Talbot I, Smith RA, et al.Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res1996, 56:190-196
16 Luo HZ, Zhou ZG, Yang L, et al.Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol 2005, 35:739-744
17 Parsons SL, Watson SA, Collins HM, et al.Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy. Br J Cancer 1998, 78:1495-1502
18 Roeb E, Arndt M, Jansen B, et al. Simultaneous determination of matrix metalloproteinase (MMP)-7, MMP- 1, -3, and -13 gene expression by multiplex PCR in colorectal carcinomas. Int J Colorectal Dis 2004, 19:518-524
19 Saitoh Y, Yanai H, Higaki S, et al. Relationship between matrix metalloproteinase-7 and pit pattern in early stagecolorectal cancer. Gastrointest Endosc 2004, 59:385-392
20 Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase- 7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases. Clin Cancer Res 2002, 8:144-148
21 Baker EA, Bergin FG, Leaper DJ. Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging. Br J Surg 2000, 87:1215-1221
22 Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase-7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases. Clin Cancer Res 2002, 8:144-148
23 Langenskiold M, Holmdahl L, Falk P, et al. Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
24 Murray GI, Duncan ME, O'Neil P, et al. Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nat Med 1996, 2:461-462
25 Baker EA, Bergin FG, Leaper DJ. Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging. Br J Surg 2000, 87:1215-1221
26 Mukai M, Sadahiro S, Tokunaga N, et al. The expression of MMP-2 and TIMP-2 in patients with colorectal adenocarcinoma invaded to the submucosal and proper muscle layer. Oncol Rep, 1998;5:335~340
27 Levy AT, Cioce V, Sobel ME, et al. Increased expression of the Mr 72,000 type collagenase in human colonic adenocarcinoma. Cancer Res, 1991;51:439~444;
28 Ring P, Johansson K, Hoyhtya M, et al.Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer – a predictor of tumour stage. Br J Cancer 1997, 76:805-811
29 Takeha S, Fujiyama Y, Bamba T, et al.Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/ inflammatory aspect. Jpn J Cancer Res 1997, 88:72-81
30 Islekel H, Oktay G, Terzi C, et al.Matrix metalloproteinase-9,-3 and tissue inhibitor of matrix metalloproteinase-1 in colorectal cancer: relationship to clinicopathological variables. Cell Biochem Funct 2006 in press
31 Adachi Y, Mori M, Kuroiwa S, et al. Histopathological evaluation of survival time in patients with colorectal carcinoma. J Surg Oncol 1989, 42:219-224
32 Luo HZ, Zhou ZG, Yang L, et al.Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol 2005, 35:739-744
33 Masaki T, Matsuoka H, Sugiyama M, et al.Matrilysin (MMP-7) as a significant determinant of malignant potential of early invasive colorectal carcinomas. Br J Cancer 2001,84:1317-1321
34 Ogawa M, Ikeuchi K, Watanabe M, et al. Expression of matrix metalloproteinase 7, laminin and type IV collagen-associated liver metasta sis in human colorectal cancer: immunohistochemical approach. Hepatogastroenterology 2005, 52: 875-880
35 Koumura H, Sugiyama Y, Kunieda K, et al. Significance in gene expression of matrix metalloproteinase-9, urokinase-type plasminogen activator and tissue inhibitor of metalloproteinase for metastases of gastric and/or colo-rectal cancer Gan To Kagaku Ryoho, 1997 ;24 (Suppl):324~331
36 Islekel H, Oktay G, Terzi C, et al. Matrix metalloproteinase-9,-3 and tissue inhibitor of matrix metalloproteinase-1 in colorectal cancer: relationship to clinic opathological variables. Cell Biochem Funct 2006 in press
37 Ala-Aho, Risto, Johansson Nina, et al. Expression of collagenase-3 (MMP-13) enhances invasion of human fibrosarcoma HT-1080 cells. Int J Cancer, 2002; 97(3): 283-9
38 Leeman MF, McKay JA, Murray GI. Matrix metalloproteinase 13 activity is associated with poor prognosis in colorectal cancer. J Clin Pathol 2002, 55: 758-762
39 Chan C, Menges M, Orzechowski HD, et al.Increased matrix metalloproteinase 2 concentration and transcript expression in advanced colorectal carcinomas. Int J Colorectal Dis 2001, 16:133-140
40 Langenskiold M, Holmdahl L, Falk P, et al. Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
41 Ring P, Johansson K, Hoyhtya M, et al. Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer – a predictor of tumour stage. Br J Cancer 1997, 76: 805-811
42 Patterson BC, Sang QA. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem 1997, 272: 28823-28825
43 O'Reilly MS, Wiederschain D, Stetler-Stevenson WG, et al.Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J Biol Chem 1999, 274: 29568-29571
44 Vincenti MP, et al. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods-Mol-Biol, 2001, 151: 121-48
45 Bigg H F, Morrison C J, Butler G S, et al. Tissue inhibitor of metalloproteinases-4 inhibits but does not support the activation of gelatinase A via efficient inhibition of membrane type 1-matrix metalloproteinase. Cancer-Res, 2001; 61(9): 3610-8
46 Doglas DA, Shi YE, Sang QA. J Prot Chem, 1997, 16:237-255
47 Yamamoto H, Horiuchi S, Adachi Y, et al.Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer. Carcinogenesis 2004,25:325-332
48 Ala-aho R, Grenman R, Seth P, et al. Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells. Oncogene 2002, 21:1187-1195
49 Sun Y, Cheung JM, Martel-Pelletier J, et al.Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). J Biol Chem 2000, 275:11327-11332
50 Zucker S, Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev 2004, 23:101-117
51 Ogata Y, Matono K, Sasatomi T, et al. The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer. Cancer Chemother PHarmacol 2006, 57: 577-583
52 Drevs J, Zirrgiebel U, Schmidt-Gersbach CI, et al.Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two pHase I trials. Ann Oncol, 2005, 16: 558-565
53 Jubb AM, Hurwitz HI, Bai W, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. Clin Oncol 2006, 24: 217-227
54 Molina JR, Reid JM, Erlichman C, et al. A pHase I and pHarmacokinetic study of the selective, non-peptidic inhibitor of matrix metalloproteinase BAY 12–9566 in combination with etoposide and carboplatin. Anticancer Drugs 2005, 16: 997-1002
55 Posey JA, Ng TC, Yang B, et al. A pHase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma. Clin Cancer Res 2003, 9: 1323-1232
56 Rizvi NA, HumpHrey JS, Ness EA, et al. A pHase I study of oral BMS-275291 a novel nonhydroxamate sheddase- sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res 2004, 10: 1963-1970
57 Guedez L, McMarlin A J, Kingma D W,et al. Tissue inhibitor of metalloproteinase-1 alters the tumorigenicity of Burkitt's lympHoma via divergent effects on tumor growth and angiogenesis. Am-J-Pathol. 2001; 158(4): 1207-1215
2 van den Hooff A: Stromal involvement in malignant growth. Adv Cancer Res 1988, 50:159-96
3 Varani J: Interaction of tumor cells with the extracellular matrix. Revis Biol Celular 1987, 12:1-113
4 Garbett EA ,Reed MV ,Brown NJ, et al. Proteolysis in human breast and colorectal cancer. Br J Cancer, 1999;81(2):287-293
5 Behrens P, Mathiak M, Mangold E, et al. Stromal expression of invasionpromoting, matrix-degrading proteases MMP-1and -9 and the Ets 1 transcription factor in HNPCC carcinomas and sporadic colorectal cancers. Int J Cancer 2003, 107:183-188
6 Garbett EA, Reed MW, Brown NJ. Proteolysis in colorectal cancer. Mol Pathol 1999, 52:140-145.
7 Islekel H, Oktay G, Terzi C, et al. Matrix metalloproteinase-9,-3 and tissue inhibitor of matrix metalloproteinase-1 in colorectal cancer: relationship to clinicopathological variables. Cell Biochem Funct 2006 in press
8 Karakiulakis G, Papanikolaou C, Jankovic SM, et al. Increased type IV collagendegrading activity in metastases originating from primary tumors of the human colon. Invasion Metastasis 1997, 17:158-168
9 Langenskiold M, Holmdahl L, Falk P, et al. Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
10 Liabakk NB, Talbot I, Smith RA, et al.Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res1996, 56:190-196
11 Luo HZ, Zhou ZG, Yang L, et al.Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol 2005, 35:739-744
12 Parsons SL, Watson SA, Collins HM, et al.Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy.Br J Cancer 1998, 78:1495-1502
13 Roeb E, Arndt M, Jansen B, et al. Simultaneous determination of matrix metalloproteinase (MMP)-7, MMP- 1, -3, and -13 gene expression by multiplex PCR in colorectal carcinomas. Int J Colorectal Dis 2004, 19:518-524
14 Saitoh Y, Yanai H, Higaki S, et al.Relationship between matrix metalloproteinase-7 and pit pattern in early stage colorectal cancer. Gastrointest Endosc 2004, 59:385-392
15 Zeng ZS, Shu WP, Cohen AM, et al.Matrix metalloproteinase-7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases. Clin Cancer Res 2002, 8:144-148
16 Baker EA, Bergin FG, Leaper DJ. Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging. Br J Surg 2000, 87:1215-1221
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20 Masaki T, Matsuoka H, Sugiyama M, et al.Matrilysin (MMP-7) as a significant determinant of malignant potentialof early invasive colorectal carcinomas. Br J Cancer 2001, 84:1317-1321
21 Ogawa M, Ikeuchi K, Watanabe M, et al.Expression of matrix metalloproteinase 7, laminin and type IV collagen-associated liver metasta sis in human colorectal cancer: immunohistochemical approach. Hepatogastroenterology 2005, 52:875-880
22 Koumura H, Sugiyama Y, Kunieda K et al. Significance in gene expression of matrix metalloproteinase-9, urokinase-type plasminogen activator and tissue inhibitor of metalloproteinase for metastases of gastric and/or colo-rectal cancer Gan To Kagaku Ryoho, 1997 ;24 (Suppl):324~331
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1 Sappino AP, Schurch W, Gabbiani G. Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of pHenotypic modulations. Lab Invest 1990, 63:144-161
2 van den Hooff A. Stromal involvement in malignant growth. Adv Cancer Res 1988, 50:159-96
3 Varani J. Interaction of tumor cells with the extracellular matrix. Revis Biol Celular 1987, 12:1-113
4 Chakraborti S, Mandal M, Das S, et al. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 2003, 253:269-285
5 Momohara S, Okamoto H, Komiya K, et al.Matrix metalloproteinase 28/epilysin expression in cartilage from patients with rheumatoid arthritis and osteoarthritis: comment on the article by Kevorkian et al. Arthritis Rheum 2004, 50:131-141
6 Stetler-Stevenson WG, Hewitt R, Corcoran M.Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic. Semin Cancer Biol 1996, 7:147-154
7 Lukashev ME, Werb Z. ECM signalling: orchestrating cell behaviour and misbehaviour. Trends Cell Biol 1998, 8:437-441
8 Garbett EA ,Reed MV ,Brown NJ ,et al. Proteolysis in human breast and colorectal cancer. Br J Cancer, 1999;81(2):287-293
9 Behrens P, Mathiak M, Mangold E, et al.Stromal expression of invasionpromoting, matrix-degrading proteases MMP-1 and -9 and the Ets 1 transcription factor in HNPCC carcinomas and sporadic colorectal cancers. Int J Cancer 2003, 107:183-188
10 Chan CC, Menges M, Orzechowski HD, et al.Increased matrix metalloproteinase 2 concentration and transcript expression in advanced colorectal carcinomas. Int J Colorectal Dis 2001, 16:133-140
11 Garbett EA, Reed MW, Brown NJ: Proteolysis in colorectal cancer. Mol Pathol 1999, 52:140-145
12 Islekel H, Oktay G, Terzi C, et al.Matrix metalloproteinase-9,-3 and tissue inhibitor of matrixmetalloproteinase-1 in colorectal cancer: relationship to clinicopathological variables. Cell Biochem Funct 2006 in press
13 Karakiulakis G, Papanikolaou C, Jankovic SM, et al.Increased type IV collagendegrading activity in metastases originating from primary tumors of the human colon. Invasion Metastasis 1997,17:158-168
14 Langenskiold M, Holmdahl L, Falk P, et al.Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
15 Liabakk NB, Talbot I, Smith RA, et al.Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res1996, 56:190-196
16 Luo HZ, Zhou ZG, Yang L, et al.Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol 2005, 35:739-744
17 Parsons SL, Watson SA, Collins HM, et al.Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy. Br J Cancer 1998, 78:1495-1502
18 Roeb E, Arndt M, Jansen B, et al. Simultaneous determination of matrix metalloproteinase (MMP)-7, MMP- 1, -3, and -13 gene expression by multiplex PCR in colorectal carcinomas. Int J Colorectal Dis 2004, 19:518-524
19 Saitoh Y, Yanai H, Higaki S, et al. Relationship between matrix metalloproteinase-7 and pit pattern in early stagecolorectal cancer. Gastrointest Endosc 2004, 59:385-392
20 Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase- 7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases. Clin Cancer Res 2002, 8:144-148
21 Baker EA, Bergin FG, Leaper DJ. Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging. Br J Surg 2000, 87:1215-1221
22 Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase-7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases. Clin Cancer Res 2002, 8:144-148
23 Langenskiold M, Holmdahl L, Falk P, et al. Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
24 Murray GI, Duncan ME, O'Neil P, et al. Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nat Med 1996, 2:461-462
25 Baker EA, Bergin FG, Leaper DJ. Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging. Br J Surg 2000, 87:1215-1221
26 Mukai M, Sadahiro S, Tokunaga N, et al. The expression of MMP-2 and TIMP-2 in patients with colorectal adenocarcinoma invaded to the submucosal and proper muscle layer. Oncol Rep, 1998;5:335~340
27 Levy AT, Cioce V, Sobel ME, et al. Increased expression of the Mr 72,000 type collagenase in human colonic adenocarcinoma. Cancer Res, 1991;51:439~444;
28 Ring P, Johansson K, Hoyhtya M, et al.Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer – a predictor of tumour stage. Br J Cancer 1997, 76:805-811
29 Takeha S, Fujiyama Y, Bamba T, et al.Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/ inflammatory aspect. Jpn J Cancer Res 1997, 88:72-81
30 Islekel H, Oktay G, Terzi C, et al.Matrix metalloproteinase-9,-3 and tissue inhibitor of matrix metalloproteinase-1 in colorectal cancer: relationship to clinicopathological variables. Cell Biochem Funct 2006 in press
31 Adachi Y, Mori M, Kuroiwa S, et al. Histopathological evaluation of survival time in patients with colorectal carcinoma. J Surg Oncol 1989, 42:219-224
32 Luo HZ, Zhou ZG, Yang L, et al.Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol 2005, 35:739-744
33 Masaki T, Matsuoka H, Sugiyama M, et al.Matrilysin (MMP-7) as a significant determinant of malignant potential of early invasive colorectal carcinomas. Br J Cancer 2001,84:1317-1321
34 Ogawa M, Ikeuchi K, Watanabe M, et al. Expression of matrix metalloproteinase 7, laminin and type IV collagen-associated liver metasta sis in human colorectal cancer: immunohistochemical approach. Hepatogastroenterology 2005, 52: 875-880
35 Koumura H, Sugiyama Y, Kunieda K, et al. Significance in gene expression of matrix metalloproteinase-9, urokinase-type plasminogen activator and tissue inhibitor of metalloproteinase for metastases of gastric and/or colo-rectal cancer Gan To Kagaku Ryoho, 1997 ;24 (Suppl):324~331
36 Islekel H, Oktay G, Terzi C, et al. Matrix metalloproteinase-9,-3 and tissue inhibitor of matrix metalloproteinase-1 in colorectal cancer: relationship to clinic opathological variables. Cell Biochem Funct 2006 in press
37 Ala-Aho, Risto, Johansson Nina, et al. Expression of collagenase-3 (MMP-13) enhances invasion of human fibrosarcoma HT-1080 cells. Int J Cancer, 2002; 97(3): 283-9
38 Leeman MF, McKay JA, Murray GI. Matrix metalloproteinase 13 activity is associated with poor prognosis in colorectal cancer. J Clin Pathol 2002, 55: 758-762
39 Chan C, Menges M, Orzechowski HD, et al.Increased matrix metalloproteinase 2 concentration and transcript expression in advanced colorectal carcinomas. Int J Colorectal Dis 2001, 16:133-140
40 Langenskiold M, Holmdahl L, Falk P, et al. Increased plasma MMP-2 protein expression in lympH node-positive patients with colorectal cancer. Int J Colorectal Dis 2005, 20:245-252
41 Ring P, Johansson K, Hoyhtya M, et al. Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer – a predictor of tumour stage. Br J Cancer 1997, 76: 805-811
42 Patterson BC, Sang QA. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem 1997, 272: 28823-28825
43 O'Reilly MS, Wiederschain D, Stetler-Stevenson WG, et al.Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J Biol Chem 1999, 274: 29568-29571
44 Vincenti MP, et al. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods-Mol-Biol, 2001, 151: 121-48
45 Bigg H F, Morrison C J, Butler G S, et al. Tissue inhibitor of metalloproteinases-4 inhibits but does not support the activation of gelatinase A via efficient inhibition of membrane type 1-matrix metalloproteinase. Cancer-Res, 2001; 61(9): 3610-8
46 Doglas DA, Shi YE, Sang QA. J Prot Chem, 1997, 16:237-255
47 Yamamoto H, Horiuchi S, Adachi Y, et al.Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer. Carcinogenesis 2004,25:325-332
48 Ala-aho R, Grenman R, Seth P, et al. Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells. Oncogene 2002, 21:1187-1195
49 Sun Y, Cheung JM, Martel-Pelletier J, et al.Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). J Biol Chem 2000, 275:11327-11332
50 Zucker S, Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev 2004, 23:101-117
51 Ogata Y, Matono K, Sasatomi T, et al. The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer. Cancer Chemother PHarmacol 2006, 57: 577-583
52 Drevs J, Zirrgiebel U, Schmidt-Gersbach CI, et al.Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two pHase I trials. Ann Oncol, 2005, 16: 558-565
53 Jubb AM, Hurwitz HI, Bai W, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. Clin Oncol 2006, 24: 217-227
54 Molina JR, Reid JM, Erlichman C, et al. A pHase I and pHarmacokinetic study of the selective, non-peptidic inhibitor of matrix metalloproteinase BAY 12–9566 in combination with etoposide and carboplatin. Anticancer Drugs 2005, 16: 997-1002
55 Posey JA, Ng TC, Yang B, et al. A pHase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma. Clin Cancer Res 2003, 9: 1323-1232
56 Rizvi NA, HumpHrey JS, Ness EA, et al. A pHase I study of oral BMS-275291 a novel nonhydroxamate sheddase- sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res 2004, 10: 1963-1970
57 Guedez L, McMarlin A J, Kingma D W,et al. Tissue inhibitor of metalloproteinase-1 alters the tumorigenicity of Burkitt's lympHoma via divergent effects on tumor growth and angiogenesis. Am-J-Pathol. 2001; 158(4): 1207-1215