胃癌患者MMP-3血清水平及癌组织中VEGF-C、MMP-3的表达
|
摘要
目的：通过检测胃癌患者血清基质金属蛋白酶-3(Matrix metalloproteinases 3,MMP-3)的水平,及其癌组织中血管内皮生长因子-C(Vascular endothelial growth factor C,VEGF-C)、MMP-3的表达,研究它们在胃癌发生发展过程的作用。
方法：选取胃癌患者50例,男34例,女16例,病例为2008年10月至2009年4月在齐鲁医院普外科住院手术的患者,手术后病理证实为胃癌,收集癌组织,同时取距离癌组织边缘5cm以上的胃黏膜作为正常对照,所有标本均行HE染色做病理学检查,且术前未经任何针对胃癌的治疗。上述胃癌患者及对照组(同期健康人30人,均为正常体检者,均无近期手术、创伤及肿瘤等病史)禁饮食10小时后,前者于入院后第2天早上及术后第7天早上采集空腹外周静脉血5m1,后者于清晨采集空腹外周静脉血5ml。所采血液标本凝血后分离血清液,迅速储存于-80℃冰箱冷藏备用。运用ELISA方法检测胃癌患者术前与术后血清中MMP-3的水平变化及正常健康人血清中MMP-3的水平,检测过程严格按照试剂说明书进行。同时应用免疫组织化学方法检测胃癌患者手术标本(癌组织、距癌边缘>5cm胃粘膜)中VEGF-C、MMP-3的表达。
结果：胃癌患者术前血清MMP-3水平明显高于正常对照者(30.96±9.75ng/ml vs 14.43±4.82ng/ml,P<0.05)；胃癌患者术前血清MMP-3水平明显高于术后1周血清MMP-3水平(30.96±9.75ng/ml vs 16.29±5.92ng/ml,P<0.05)；而术后1周血清MMP-3水平与正常对照者无显著性差异(P>0.05)。浸润达到或超过浆膜层的患者术前血清MMP-3水平明显高于未达浆膜层者(32.60±10.05ng/ml vs24.43±4.56ng/ml,P<0.05)；有淋巴结转移者,术前血清MMP-3水平明显高于无淋巴结转移者(32.11±9.79ng/ml vs 22.55±3.41ng/ml,P<0.05)；Ⅲ／Ⅳ期胃癌术前血清MMP-3水平明显高于分期为I／II期者(34.26±9.30ng/ml vs 25.10±7.71ng/ml,P<0.05)；而术前血清MMP-3水平与胃癌患者性别、年龄、肿瘤大小、部位、分化程度无明显相关性(P>0.05)。在胃癌组织中,MMP-3主要定位于胃癌细胞细胞浆内和(或)细胞膜上,阳性率为68%(34／50例),癌旁组织中可见弱阳性染色,阳性率为20%(10／50例),绝大部分为阴性表达,胃癌组织中MMP-3的表达明显高于癌旁组织中MMP-3表达(P<0.05)；胃癌组织中MMP-3的表达与胃癌患者淋巴结转移及TNM分期有关(P<0.05),而与患者性别、年龄、肿瘤大小、部位、分化程度,浸润深度无明显相关性(P>0.05)。胃癌组织MMP-3表达为++／+++的患者术前血清MMP-3水平明显高于MMP-3表达为-／+者(P<0.05)。在胃癌组织中,VEGF-C主要定位于胃癌细胞细胞浆内,阳性率为50%(25／50例),癌旁组织中均为阴性表达,胃癌组织中VEGF-C的表达与胃癌患者浸润深度及淋巴结转移有关(P<0.05),而与患者性别、年龄、肿瘤大小、部位、分化程度,TNM分期无明显相关性(P>0.05)。胃癌组织中MMP-3与VEGF-C的表达成正相关(rs=0.360,P<0.05)。
结论：VEGF-C、MMP-3在胃癌侵袭转移中起到了重要作用；联合检测VEGF-C与MMP-3的表达,特别是检测术前术后血清中MMP-3水平对胃癌早期预测及判断胃癌预后具有一定的临床意义。
Objective:To investigate the serum level of MMP-3 and the expressions of VEGF-C and MMP-3 in gastric cancer to study their role in the process of gastric cancer.
Methods:First,we selected 50 cases of gastric cancer patients,34 cases of males,16 cases of females, that were operated in the department of general surgery in Qilu Hospital from October 2008 to April 2009.A11 Specimens were confirmed by pathology. And we collected tumor tissues and the gastric mucosa from 5 centimeters above the edge of carcinoma.All specimens underwent pathological examination by HE staining. None of them was done any pre-operative treatment for gastric cancer. And we selected 30 healthy people over the same period as the control group. Five milliliters of peripheral venous blood was collected in the morning after fasting. Clotting of blood samples were taken after the separation of serum fluid and rapidly stored in-80℃refrigerator spare. ELISA used to detect the preoperative, the postoperative and the normal group's serum levels of MMP-3.The immunohistochemical method was used to analyze the expression of VEGF-C and MMP-3 in 50 resected specimens.(tumor tissues and the normal control group).
Results:The preoperative serum level of MMP-3(30.96±9.75ng/ml) was significantly higher than that of postoperative group(16.29±5.92ng/ml)and control group (14.43±4.82ng/ml)(P<0.05).The postoperative serum level of MMP-3 after one week and normal controls had no significant difference (P>0.05). The preoperative serum level of MMP-3 of patients whose neoplasms infiltrating meet or exceed the serosa layer was significantly higher than those below the serosa layer (32.60±10.05ng/ml vs 24.43±4.56ng/ml, P＜0.05)., The serum MMP-3 levels of patients with lymph node metastasis was significantly higher than those without lymph node metastasis (32.11±9.79ng/ml vs 22.55±3.41ng/ml, P＜0.05); And preoperative serum MMP-3 level was closely related with TNM stage(34.26±9.30ng/ml vs 25.10±7.71ng/ml, P＜0.05).But the preoperative serum level of MMP-3 in patients with gastric cancer had no significant correlation with sex, age, tumor size, location and degree of differentiation (P>0.05). In gastric cancer, MMP-3 mainly localizes in the cytoplasm of gastric cancer cells and (or) cell membrane, the positive rate was 68% (34/50 cases); but the adjacent normal tissues was seen weak positive staining;the positive rate was 20%(10/50 cases). The expression of MMP-3 of gastric cancer tissues was significantly higher than that in adjacent tissues (P＜0.05). The positive expression of MMP-3 was closely related with TNM stage of gastric cancer, lymph node metastasis (P＜0.05);while had no significant correlation with sex, age, tumor size, location, differentiation and invasion depth (P>0.05). The preoperative serum level of MMP-3 showed consistency with expression of MMP-3 in gastric cancer(P＜0.05). In gastric cancer, VEGF-C mainly localizes in the cytoplasm of gastric cancer cells; the positive rate was 50% (25/50 cases);while the adjacent tissues was negative expression. The positive expression of VEGF-C was closely related with the degree of gastric cancer invasion and lymph node metastasis (P＜0.05),while had no significant correlation with sex, age, tumor size, location, degree of differentiation and TNM staging (P> 0.05). The expression of VEGF-C was positively correlated with that of MMP-3(rs=0.360, P＜0.05).
Conclusion:VEGF-C and MMP-3 have an important role in tumor invasion and metastasis. The detection of preoperative and postoperative serum levels of MMP-3 may have important clinical significance in predicting invasion and metastasis of gastric cancer, also in determining prognosis of gastric cancer.
方法：选取胃癌患者50例,男34例,女16例,病例为2008年10月至2009年4月在齐鲁医院普外科住院手术的患者,手术后病理证实为胃癌,收集癌组织,同时取距离癌组织边缘5cm以上的胃黏膜作为正常对照,所有标本均行HE染色做病理学检查,且术前未经任何针对胃癌的治疗。上述胃癌患者及对照组(同期健康人30人,均为正常体检者,均无近期手术、创伤及肿瘤等病史)禁饮食10小时后,前者于入院后第2天早上及术后第7天早上采集空腹外周静脉血5m1,后者于清晨采集空腹外周静脉血5ml。所采血液标本凝血后分离血清液,迅速储存于-80℃冰箱冷藏备用。运用ELISA方法检测胃癌患者术前与术后血清中MMP-3的水平变化及正常健康人血清中MMP-3的水平,检测过程严格按照试剂说明书进行。同时应用免疫组织化学方法检测胃癌患者手术标本(癌组织、距癌边缘>5cm胃粘膜)中VEGF-C、MMP-3的表达。
结果：胃癌患者术前血清MMP-3水平明显高于正常对照者(30.96±9.75ng/ml vs 14.43±4.82ng/ml,P<0.05)；胃癌患者术前血清MMP-3水平明显高于术后1周血清MMP-3水平(30.96±9.75ng/ml vs 16.29±5.92ng/ml,P<0.05)；而术后1周血清MMP-3水平与正常对照者无显著性差异(P>0.05)。浸润达到或超过浆膜层的患者术前血清MMP-3水平明显高于未达浆膜层者(32.60±10.05ng/ml vs24.43±4.56ng/ml,P<0.05)；有淋巴结转移者,术前血清MMP-3水平明显高于无淋巴结转移者(32.11±9.79ng/ml vs 22.55±3.41ng/ml,P<0.05)；Ⅲ／Ⅳ期胃癌术前血清MMP-3水平明显高于分期为I／II期者(34.26±9.30ng/ml vs 25.10±7.71ng/ml,P<0.05)；而术前血清MMP-3水平与胃癌患者性别、年龄、肿瘤大小、部位、分化程度无明显相关性(P>0.05)。在胃癌组织中,MMP-3主要定位于胃癌细胞细胞浆内和(或)细胞膜上,阳性率为68%(34／50例),癌旁组织中可见弱阳性染色,阳性率为20%(10／50例),绝大部分为阴性表达,胃癌组织中MMP-3的表达明显高于癌旁组织中MMP-3表达(P<0.05)；胃癌组织中MMP-3的表达与胃癌患者淋巴结转移及TNM分期有关(P<0.05),而与患者性别、年龄、肿瘤大小、部位、分化程度,浸润深度无明显相关性(P>0.05)。胃癌组织MMP-3表达为++／+++的患者术前血清MMP-3水平明显高于MMP-3表达为-／+者(P<0.05)。在胃癌组织中,VEGF-C主要定位于胃癌细胞细胞浆内,阳性率为50%(25／50例),癌旁组织中均为阴性表达,胃癌组织中VEGF-C的表达与胃癌患者浸润深度及淋巴结转移有关(P<0.05),而与患者性别、年龄、肿瘤大小、部位、分化程度,TNM分期无明显相关性(P>0.05)。胃癌组织中MMP-3与VEGF-C的表达成正相关(rs=0.360,P<0.05)。
结论：VEGF-C、MMP-3在胃癌侵袭转移中起到了重要作用；联合检测VEGF-C与MMP-3的表达,特别是检测术前术后血清中MMP-3水平对胃癌早期预测及判断胃癌预后具有一定的临床意义。
Objective:To investigate the serum level of MMP-3 and the expressions of VEGF-C and MMP-3 in gastric cancer to study their role in the process of gastric cancer.
Methods:First,we selected 50 cases of gastric cancer patients,34 cases of males,16 cases of females, that were operated in the department of general surgery in Qilu Hospital from October 2008 to April 2009.A11 Specimens were confirmed by pathology. And we collected tumor tissues and the gastric mucosa from 5 centimeters above the edge of carcinoma.All specimens underwent pathological examination by HE staining. None of them was done any pre-operative treatment for gastric cancer. And we selected 30 healthy people over the same period as the control group. Five milliliters of peripheral venous blood was collected in the morning after fasting. Clotting of blood samples were taken after the separation of serum fluid and rapidly stored in-80℃refrigerator spare. ELISA used to detect the preoperative, the postoperative and the normal group's serum levels of MMP-3.The immunohistochemical method was used to analyze the expression of VEGF-C and MMP-3 in 50 resected specimens.(tumor tissues and the normal control group).
Results:The preoperative serum level of MMP-3(30.96±9.75ng/ml) was significantly higher than that of postoperative group(16.29±5.92ng/ml)and control group (14.43±4.82ng/ml)(P<0.05).The postoperative serum level of MMP-3 after one week and normal controls had no significant difference (P>0.05). The preoperative serum level of MMP-3 of patients whose neoplasms infiltrating meet or exceed the serosa layer was significantly higher than those below the serosa layer (32.60±10.05ng/ml vs 24.43±4.56ng/ml, P＜0.05)., The serum MMP-3 levels of patients with lymph node metastasis was significantly higher than those without lymph node metastasis (32.11±9.79ng/ml vs 22.55±3.41ng/ml, P＜0.05); And preoperative serum MMP-3 level was closely related with TNM stage(34.26±9.30ng/ml vs 25.10±7.71ng/ml, P＜0.05).But the preoperative serum level of MMP-3 in patients with gastric cancer had no significant correlation with sex, age, tumor size, location and degree of differentiation (P>0.05). In gastric cancer, MMP-3 mainly localizes in the cytoplasm of gastric cancer cells and (or) cell membrane, the positive rate was 68% (34/50 cases); but the adjacent normal tissues was seen weak positive staining;the positive rate was 20%(10/50 cases). The expression of MMP-3 of gastric cancer tissues was significantly higher than that in adjacent tissues (P＜0.05). The positive expression of MMP-3 was closely related with TNM stage of gastric cancer, lymph node metastasis (P＜0.05);while had no significant correlation with sex, age, tumor size, location, differentiation and invasion depth (P>0.05). The preoperative serum level of MMP-3 showed consistency with expression of MMP-3 in gastric cancer(P＜0.05). In gastric cancer, VEGF-C mainly localizes in the cytoplasm of gastric cancer cells; the positive rate was 50% (25/50 cases);while the adjacent tissues was negative expression. The positive expression of VEGF-C was closely related with the degree of gastric cancer invasion and lymph node metastasis (P＜0.05),while had no significant correlation with sex, age, tumor size, location, degree of differentiation and TNM staging (P> 0.05). The expression of VEGF-C was positively correlated with that of MMP-3(rs=0.360, P＜0.05).
Conclusion:VEGF-C and MMP-3 have an important role in tumor invasion and metastasis. The detection of preoperative and postoperative serum levels of MMP-3 may have important clinical significance in predicting invasion and metastasis of gastric cancer, also in determining prognosis of gastric cancer.
引文
[1]高玉堂.1990-1992年中国恶性肿瘤三年抽样调查的意义及评价[J].中华肿瘤杂志,2000,22(3)：263-264.
[2]吴在德,吴肇汉.外科学[M].第六版.北京：人民卫生出版社,2005,460-461.
[3]Yoo WH,Jung YJ,Kim TD,et al. Gbexatemesilate inhibits colon cancer growth,invasion,and metastasis by reducing matrix metalloproteinases and angiogenesis[J].Clin Cancer Res,2004; 10:4517-4526.
[4]Garzetti GG,Ciavattini A,Lucarini G,etal.Expression of Vascular endothelial growth factor related to 72-kilodalton metalloproteinases immunostaining in patients with serous ovarian tumors[J].Caner,1999;85:2219-2225.
[5]马望前,陈丽荣,赵昌峻,等.CD44V5与胃癌生物学行为的关系[J].实用肿瘤杂志,2003,18：386-389.
[6]Thome RF,Meldrum CJ, Agrez MV Adhesion molecules and metastasis. Life Sci.1995; 7:32-37.
[7]WANG Yuanyu, YE Zaiyuan, ZHAO Zhongsheng. Progression of molecular markers related with invasion and metastases in gastric carcinoma. International Journal of Pathology and Clinical Medicin.2006,26:309-312.
[8]陈意生,史景泉.肿瘤分子细胞生物学[M].北京：北京人民军医出版社,2002,50-79.
[9]ZHAO Yun-Ge,Orbit ANWAR. Extra Cellular Matrix and Matrix Metalloproteinases Prog[J].Biochem.Biophys,1999,26(3):223-228.
[10]Kleiner DE,Stetler-Stevenson WG.Matrix metalloproteinases and metastasis[J]. Cancer Chemother Pharmacol,1999,43(Suppl):42-51.
[11]高进等,粘附和抗粘附与癌细胞侵袭[M].上海：国内外医学进展。1993,72-76.
[12]Muhammad WS.Anti-angiogenesis therapy in pancreatic carcinoma[J].JOP,2006,7 (2):163-173.
[13]胡晓慧,沈飞,董宁征,等.抗人基质金属蛋白酶-2的单抗制备及功能研究 [J].中国病理生理杂志,2005,21(5)：876-881.
[14]Mercapide J,Lopez De Cicco R,Castresana JS,et al.Stromelysin-1/matrix metalloproteinase-3 (MMP-3) expression accounts for invasive propertiesof human astrocytoma cell lines[J].Int J Cancer,2003,106(5):676-682.
[15]Zucker S,Vacirca J.Role of matrix metalloproteinases(MMPs) in colorectal cancer[J].Cancer Metastasis Rev,2004,23(1-2):101-117.
[16]张军勇,张忠明,马富,等.胃癌组织中基质分解素-1基因表达的研究[J].华北国防医药,2002,14(1)：11-12.
[17]Matrisian LM, Bowden GT. Stromelysin/transin and tumor progression[J]. Semin Cancer Biol,1990,1:107-115.
[18]Brown PD, Bloxidge RE, Stuart NSA, et al. Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma[J]. J Natl Cancer Inst,1993,85:574-578.
[19]Murray GI,Duncan ME,Arbuckle E,et al.Matrix metalloproteinases and their inhibitors in gastric cancer[J].Gut,1998,43(6):791-797.
[20]邹赛英.VEGF、MMP-3在胃印戒细胞癌中的表达与浸润转移的关系[J].诊断病理学杂志,2003,10：111-112.
[21]黄钢丁,姜海行,覃山羽,等.胃癌组织MMP-3及MMP-13蛋白的表达[J].广东医学,2007,28(10)：1631-1633.
[22]Braundmeier AG,Nowak RA.Cytokines regulate matrix metalloproteinases in human uterine endometrial fibroblast cells through a mechanism that does not involve increases in extracellular matrix metalloproteinase inducer[J].Am J ReprodImmunol,2006,56(3):201-214.
[23]周文鹏,樊青霞,范魁生,等.胃癌患者血清MMP-3水平的临床研究[J].中国实用医药,2008：3(24)：44-46.
[24]Joukov V,Pajusola K,Kaipainen A,et al.A novel vascular endothelial growth factor,VEGF-C,is a ligand for the Flt-4(VEGFR-3)and KDR(VEGFR-2) receptor tyrosine kinases[J].The EMBO Joumal,1996,15(2):290-298.
[25]Lee J,Gray A,Yuan J,et al.Vascular endothelial growth factor-related protein:A ligand and specific activator of the tyrosine kinase receptor Flt4[J].Proc.NatlSci USA,1996,93(5):1988-1992.
[26]Joukov V,Kaipainen A,Jeltsch M,etal.Vascular Endothelial Growth Factors VEGF-B and VEGF-C[J]. Journal of Cellular Physiology,1997,173(2):211-215.
[27]李秋梨,陈福进,血管内皮生长因子-C、D与肿瘤淋巴道转移研究进展[J].癌症,2002,21(6)：696-700.
[28]DenekampJ.Angiogenesis,neovascular proliferation and vascular Pathophysiology as targets for cancer therapy[J].Br J Radiol,1993,66 (783):181-196.
[29]Ogawa E,Takenaka K,Yanagihara K, et al. Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients[J].Br J Cancer.2004:91:498-503.
[30]Nishida N,Yano H,KomaiK,et al. Vascular endothelial growthfactor C and vascular endothelial growth factor receptor 2 are related closely to the prognosisof patients with ovarian carcinoma[J].Cancer,2004:101:1364-1374.
[31]Yonemura Y Endo Y Tabatu K,et al. Role of VEGF-C and VEGF-D in lymphan-giogenesis in gastric cancer[J].Int J Clin Oncol,2005:10(5):318-327.
[31]Skobe M,Hawighorst T, Jackson DG,et al.Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis[J].Nat Med,2001:7(2):192-198.
[33]Achen MG,Mccoll BK,Stacker SA.Focus on Iymphangiogenesis in tumor metastasis[J].Cancer Cell,2005,7(2):121-127.
[34]Mccarter MD,Clarke JH,Harken AH.Lymphangiogenesis is pivotal to the trials of a successful cancermetastasis[J].Surgery,2004,135(2):121-124.
[35]Onogawa S,Kitadai Y,Tanaka S,et al.Regulation of vascular endothelial growth factor(VEGF)-C and VEGF-D expression by the organ microenvironment in human colon carcinoma[J].Eur J Cancer,2004,40(10):1604-1609.
[36]YonemuraY,EndoY,Fujita H,et al.Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer[J]. Clinical Cancer Research,1999,5(7):1823-1829.
[37]Kabashima A,Maehara Y,Kakeji Y,et al.Overexpression of vascular endothe lial growth factor C is related to lymphogenous metastasis in early gastric carc inoma[J].Oncology,2001,60(2):146-150.
[38]Pepper MS,Mandriota SJ,Jeltsch M,et al. Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity[J].J Cell Physiol,1998,177(3):439-452.
[39]Valtola R,Salven P,Heikkila P,et al.VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer[J].Am J Pathol,1999,154(5):1381-1390.
[1]Joukov V,Pajusola K,Kaipainen A,et al.A novel vascular endothelial growth factor,VEGF-C,is a ligand for the Flt-4(VEGFR-3)and KDR(VEGFR-2) receptor tyrosine kinases[J].The EMBO Joumal,1996,15(2):290-298.
[2]Lee J,Gray A,Yuan J,et al.Vascular endothelial growth factor-related protein:A ligand and specific activator of the tyrosine kinase receptor Flt4[J].Proc.NatlSci USA,1996,93(5):1988-1992.
[3]Joukov V,Kaipainen A,Jeltsch M,etal.Vascular Endothelial Growth Factors VEGF-B and VEGF-C[J]. Journal of Cellular Physiology,1997,173(2):211-215.
[4]李秋梨,陈福进,血管内皮生长因子-C、D与肿瘤淋巴道转移研究进展[J].癌症,2002,21(6)：696-700.
[5]Denekamp J.Angiogenesis,neovascular proliferation and vascular Pathophysiology as targets for cancer therapy[J].Br J Radiol,1993,66 (783):181-196.
[6]Yeo KT, Wang HH, Nagy JA, et al. Vascular permeability factor (vascular Endothelial growth factor) in guinea pig and human tumor and inflammatory effusions[J].Cancer Res,1993,53(12):2912-2918.
[7]Zagzag D.Angiogenic growth factors in neural embryogenesis and neoplasia[J].Am J Pathol,1995,146(2):293-309.
[8]Collins PD, Connolly DT, Williams TJ.Characterization of the increase in vascular permeability induced by vascular permeability factor in vivo[J].Br J Pharmacol,1993,109(1):195-199.
[9]Enholm B,Paavonen K,Ristimaki A,etal.Comparison of VEGF, EGF-B,VEGF-C and Ang-1 mRNA regulation by serum,growth factors,oncoproteins and hypoxia[J].O ncogene,1997,14(20):2475-2483.
[10]Veikkola T,Jussila L,Makinen T,et al.Singalling via vascular endothelial growth factor receptor is sufficient for Lympfaniogenesis intransgenic micel[J].EMBO J,2001,20(6);1223-1231.
[11]Saaristo A,Tammela T, Timonen J,et al.Vascular endothelial growth Factor-C gene therapy restores lymphatic flow across incision wounds[J].FASEB J,2004,18(14);1707-1709.
[12]Oh SJ,Jeltsch MM,Birkenhager R,et al.VEGF and VEGF-C:Specific In duction of Angiogenesis and Lymphangiogenesis in the Differentiated Avian Chorioa llantoic Membrane[J].Development Biology,1997,188(1):96-109.
[13]Paavonen K,Puolakkainen P,Jussila L,et al.Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing [J].Am J Pathol,2000,156(5):5738-5743.
[14]Lymboussaki A, Partanen TA, Olofsson B, et al. Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors[J].Am J Pathol,1998,153(2):395-403.
[15]Jeltsh M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic Vessels in VEGF-C Transgenic Mice[J].Science,1997,276(5317)1423-1425.
[16]Iwasaki T,Hamano T,Ogato A, et al.Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma[J].Br J Haematol, 2002,116(4):796-802.
[17]Cao Y,Linden P, Farnebo J,et al.Vascular endothelial growth factor C induces angiogenesis in vivo[J].Proc Natl Acad Sci U SA,1998,95(24):14389-14394.
[18]Ajisaka H,Yonemura Y,Miwa K.Correlation of lymph node metastasis and expression of matrix metalloproteinase-7 in patients with gastric cancer[J].Hepatogastroenterology,2004,51(57):900-905.
[19]Skobe M,Hawighorst T,Jackson DG et al.Induction of tumor lymph an giogenesis by VEGF-C promotes breast cancer metastasis[J].Nature Medicin e,2001,7(2):192-198.
[20]Karpanen T,Egeblad N,Karkkainen MJ,et al.Vacular endothelial factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth[J].Ca nc er Research,2001,61(5):1786-1790.
[21]Lin M, Lin HZ, Ma SP, et al. Vascular endothelial growth factor-A and-C: expression and correlations with lymphatic metastasis and prognosis in colorectal cancer. Med Oncol,2010.
[22]Cross MJ, Dixelius J,Matsumoto T,et al.VEGF-receptor signal transduction [J].Trends BiochemSci,2003,28(9):488-494.
[23]Valtola R, Salven P, Heikkila P,et al.VEGFR-3 and Its Ligand VEGF-C Are Associated with Angiogenesis in Breast Cancer[J].Am J Pathol,1999,154(5):1381-1390.
[24]Gitay GH,Halaban R,Neufeld G.Human melanma cell but not normal melanocytes express vascular endothelial growth factor receptors[J]. Biochem Biophys Res Commun,1993,190(3):702-708.
[25]Sasaki R.Microvessel count and vascular endothelial growth factor in renal cell carcinoma [J]. Nippon Hittyokika Gakkai Zasski,1996,87(8):1032-1040.
[26]Baker EA,Bergin FG,Leaper DJ.Plasminogen activator system,vascular endothelial growth factor and colorector cancer progression[J]. Mol Pathol,2000, 53(6):307-312.
[27]Fujisawat T, Watanabe J, Kamata Y,et al. Effect of p53 gene transfection on vascular endothelial growth factor expression in endometrial cancer cells [J].Exp MolPathol,2003,74:276-281.
[28]He XW, Liu T, Xiao Y, et al. Vascular endothelial growth factor-C siRNA delivered via calcium carbonate nanoparticle effectively inhibits lymphangiogenesis and growth of colorectal cancer in vivo[J]. Cancer Biother Radiopharm, 2009,24:249-259.
[29]Weng D E, Weiss P, Kellackey C, et al.Angiozyme pharmacokinetic and safety results:a phase Ⅰ/Ⅱ study in patients with refractory solid tumours [M].USA:ProcAmSoc Clin Oncol,2001:99.
[30]Olson TA.Targeting the tumor vasculature; inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate[J].Cancer,1997,73(6),865-870.
[31]Qi JH, Ebrahem Q, Nina M, et al.A novel function for tissue inhibitor of metalloproteinases-3(TIMP3):inhibitionof angiogenesis by blockage of VEGF binding to VEGF receptor-2[J].Nature Med,2003,9(4):407-415.
[32]Yagi Y,Fushida S,Fujita H,et al.Anti-VEGF therapy for peritoneal dissemination model of gastric cancer considering of pharmacokinetics[J].Gan To Kagaku Ryoho,2008,35(12):2005-2008.
[33]Mori A, Arii S, Furutani M, et al. Soluble Fit-1 gene therapyfor peritoneal metastases using HVJ-cationic liposomes[J]. Gene Ther, 2000,7(12):1027-1033.
[34]Ray J M,Stevenson W G. The role of matrix metalloproteinase and their inhibitors in tumor invasion,metastasis and angiogensis[J]. Eur Resir J,1994,7(11):2062.
[35]Koger M, Tschesche H. Cloning expression and action of atruncated 92 Kdage latinase minienzyme[J].Gene,1997,196:175.
[36]金钫,段银钟.基质金属蛋白酶与骨改建[J].牙体牙髓牙周病学杂志.2000,10(4)：232.
[37]PrestonA.MatrixM etaloproteinases[J].Cal Biochem,2002,2:1-20.
[38]Stemlicht MD,Bissel MJ,Werb Z.The Matrix Metaloproteinase Stromelysin-1 acts As a Natural Mammary Tumor Promoter[J].Oncogene,2000,19:1102-1113.
[39]Ye S,Eriksson P,Hamsten A,et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression[J].J Biol Chem,1996,271(2):13055-13060.
[40]Hinoda Y, Okayama N, Takano N, et al.Association of functional polymorphisms of matrix metalloproteinase (MMP)-1 and MMP-3 genes with colorectal cancer[J].Int J Cancer,2002,102(5):526-529.
[41]方淑梅,金霞,李琰,等.基质金属蛋白酶3基因多态性与非小细胞肺癌遗传易感性及淋巴结转移的关系[J].癌症,2005.24(3)：305-310.
[42]Ghilardi G, Biondi ML,Caputo M,et al.A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility.Clin Cancer Res,2002,8:3820-3823.
[43]张莉,秦北宁,任爱琴,等.大肠癌患者基质分解素-1(MMP-3)基因表达增强[J].世界华人消化杂志,2001,9(10)：1210-1212.
[44]Mercapide J,Lopez De Cicco R,Castresana JS,et al.Stromelysin-1/matrix metalloproteinase-3 (MMP-3) expression accounts for invasive propertiesof human astrocytoma cell lines[J].Int J Cancer,2003,106(5):676-682.
[45]Zucker S,Vacirca J.Role of matrix metalloproteinases(MMPs) in colorectal cancer[J].Cancer Metastasis Rev,2004,23(1-2):101-117.
[46]张军勇,张忠明,马富,等.胃癌组织中基质分解素-1基因表达的研究[J].华北国防医药,2002,14(1)：11-12.
[47]Matrisian LM, Bowden GT. Stromelysin/transin and tumor progression[J]. Semin Cancer Biol,1990,1:107-115.
[48]Brown PD, Bloxidge RE, Stuart NSA, et al. Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma[J]. J Natl Cancer Inst,1993,85:574-578.
[49]Murray GI,Duncan ME,Arbuckle E,et al.Matrix metalloproteinases and their inhibitors in gastric cancer[J].Gut,1998,43(6):791-797.
[50]邹赛英.’VEGF、MMP-3在胃印戒细胞癌中的表达与浸润转移的关系[J].诊断病理学杂志,2003,10：111-112.
[51]黄钢丁,姜海行,覃山羽,等.胃癌组织MMP-3及MMP-13蛋白的表达[J].广东医学,2007,28(10)：1631-1633.
[52]Bramhall SR, Hallissey MT, Whiting J, et al.Marimastat as maintenance therapy for patients with advanced gastric cancer:a randomized trial [J]. Br J Cancer,2002,86 (12):1864-1870.
[53]RosemurgyA, Harris J, LanglebenA, et al.Marimastat in Patients with advanced Pancreatic cancer:adose-finding study[J]. AmJ Clin Oncol,1999,23(3):247-252.
[54]Primrose JN,Bleiberg N, Daniel F, et al. Marimastat in recurrent colorectal cancer, exploratory evaluation of biological activity by measurement of carcinoembryonic antigen[J].Br J Cancer,1999,79(4):509-514.
[55]Tiemey GM, Gdfih NR,Stuart RC, et al.A pilot study of the safety and effects of the matrix metalloproteinaseinhibitor Marimastat in gastric cancer[J].EurJ Cancer,1999 35(4):563-568.
[56]Chamichael J,Lederman J, Woll PJ, et al.Phase I B study of concurrent Admininistration of marimastat and gemcitabine in nonresectable Pancreatic cancer[J].Proc Am soc Clin oncol,1998,17:232-237.
[57]Muhammad WS.Anti-angiogenesis therapy in pancreatic carcinoma[J].JOP,2006,7 (2):163-173.
[58]胡晓慧,沈飞,董宁征,等.抗人基质金属蛋白酶-2的单抗制备及功能研究[J].中国病理生理杂志,2005,21(5)：876-881.
[59]Li Wei-fang,Shi Cheng-zhang.Expression of MK,CD105 and VEGF in colorectal carcinoma and its clinical significance [J].The Practical Journal of Cancer,2006,21(1):20-23.
[60]Valtola R,Salven P,Heikkila P,et al.VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer[J].Am J Pathol,1999,154(5):1381-1 390.
[2]吴在德,吴肇汉.外科学[M].第六版.北京：人民卫生出版社,2005,460-461.
[3]Yoo WH,Jung YJ,Kim TD,et al. Gbexatemesilate inhibits colon cancer growth,invasion,and metastasis by reducing matrix metalloproteinases and angiogenesis[J].Clin Cancer Res,2004; 10:4517-4526.
[4]Garzetti GG,Ciavattini A,Lucarini G,etal.Expression of Vascular endothelial growth factor related to 72-kilodalton metalloproteinases immunostaining in patients with serous ovarian tumors[J].Caner,1999;85:2219-2225.
[5]马望前,陈丽荣,赵昌峻,等.CD44V5与胃癌生物学行为的关系[J].实用肿瘤杂志,2003,18：386-389.
[6]Thome RF,Meldrum CJ, Agrez MV Adhesion molecules and metastasis. Life Sci.1995; 7:32-37.
[7]WANG Yuanyu, YE Zaiyuan, ZHAO Zhongsheng. Progression of molecular markers related with invasion and metastases in gastric carcinoma. International Journal of Pathology and Clinical Medicin.2006,26:309-312.
[8]陈意生,史景泉.肿瘤分子细胞生物学[M].北京：北京人民军医出版社,2002,50-79.
[9]ZHAO Yun-Ge,Orbit ANWAR. Extra Cellular Matrix and Matrix Metalloproteinases Prog[J].Biochem.Biophys,1999,26(3):223-228.
[10]Kleiner DE,Stetler-Stevenson WG.Matrix metalloproteinases and metastasis[J]. Cancer Chemother Pharmacol,1999,43(Suppl):42-51.
[11]高进等,粘附和抗粘附与癌细胞侵袭[M].上海：国内外医学进展。1993,72-76.
[12]Muhammad WS.Anti-angiogenesis therapy in pancreatic carcinoma[J].JOP,2006,7 (2):163-173.
[13]胡晓慧,沈飞,董宁征,等.抗人基质金属蛋白酶-2的单抗制备及功能研究 [J].中国病理生理杂志,2005,21(5)：876-881.
[14]Mercapide J,Lopez De Cicco R,Castresana JS,et al.Stromelysin-1/matrix metalloproteinase-3 (MMP-3) expression accounts for invasive propertiesof human astrocytoma cell lines[J].Int J Cancer,2003,106(5):676-682.
[15]Zucker S,Vacirca J.Role of matrix metalloproteinases(MMPs) in colorectal cancer[J].Cancer Metastasis Rev,2004,23(1-2):101-117.
[16]张军勇,张忠明,马富,等.胃癌组织中基质分解素-1基因表达的研究[J].华北国防医药,2002,14(1)：11-12.
[17]Matrisian LM, Bowden GT. Stromelysin/transin and tumor progression[J]. Semin Cancer Biol,1990,1:107-115.
[18]Brown PD, Bloxidge RE, Stuart NSA, et al. Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma[J]. J Natl Cancer Inst,1993,85:574-578.
[19]Murray GI,Duncan ME,Arbuckle E,et al.Matrix metalloproteinases and their inhibitors in gastric cancer[J].Gut,1998,43(6):791-797.
[20]邹赛英.VEGF、MMP-3在胃印戒细胞癌中的表达与浸润转移的关系[J].诊断病理学杂志,2003,10：111-112.
[21]黄钢丁,姜海行,覃山羽,等.胃癌组织MMP-3及MMP-13蛋白的表达[J].广东医学,2007,28(10)：1631-1633.
[22]Braundmeier AG,Nowak RA.Cytokines regulate matrix metalloproteinases in human uterine endometrial fibroblast cells through a mechanism that does not involve increases in extracellular matrix metalloproteinase inducer[J].Am J ReprodImmunol,2006,56(3):201-214.
[23]周文鹏,樊青霞,范魁生,等.胃癌患者血清MMP-3水平的临床研究[J].中国实用医药,2008：3(24)：44-46.
[24]Joukov V,Pajusola K,Kaipainen A,et al.A novel vascular endothelial growth factor,VEGF-C,is a ligand for the Flt-4(VEGFR-3)and KDR(VEGFR-2) receptor tyrosine kinases[J].The EMBO Joumal,1996,15(2):290-298.
[25]Lee J,Gray A,Yuan J,et al.Vascular endothelial growth factor-related protein:A ligand and specific activator of the tyrosine kinase receptor Flt4[J].Proc.NatlSci USA,1996,93(5):1988-1992.
[26]Joukov V,Kaipainen A,Jeltsch M,etal.Vascular Endothelial Growth Factors VEGF-B and VEGF-C[J]. Journal of Cellular Physiology,1997,173(2):211-215.
[27]李秋梨,陈福进,血管内皮生长因子-C、D与肿瘤淋巴道转移研究进展[J].癌症,2002,21(6)：696-700.
[28]DenekampJ.Angiogenesis,neovascular proliferation and vascular Pathophysiology as targets for cancer therapy[J].Br J Radiol,1993,66 (783):181-196.
[29]Ogawa E,Takenaka K,Yanagihara K, et al. Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients[J].Br J Cancer.2004:91:498-503.
[30]Nishida N,Yano H,KomaiK,et al. Vascular endothelial growthfactor C and vascular endothelial growth factor receptor 2 are related closely to the prognosisof patients with ovarian carcinoma[J].Cancer,2004:101:1364-1374.
[31]Yonemura Y Endo Y Tabatu K,et al. Role of VEGF-C and VEGF-D in lymphan-giogenesis in gastric cancer[J].Int J Clin Oncol,2005:10(5):318-327.
[31]Skobe M,Hawighorst T, Jackson DG,et al.Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis[J].Nat Med,2001:7(2):192-198.
[33]Achen MG,Mccoll BK,Stacker SA.Focus on Iymphangiogenesis in tumor metastasis[J].Cancer Cell,2005,7(2):121-127.
[34]Mccarter MD,Clarke JH,Harken AH.Lymphangiogenesis is pivotal to the trials of a successful cancermetastasis[J].Surgery,2004,135(2):121-124.
[35]Onogawa S,Kitadai Y,Tanaka S,et al.Regulation of vascular endothelial growth factor(VEGF)-C and VEGF-D expression by the organ microenvironment in human colon carcinoma[J].Eur J Cancer,2004,40(10):1604-1609.
[36]YonemuraY,EndoY,Fujita H,et al.Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer[J]. Clinical Cancer Research,1999,5(7):1823-1829.
[37]Kabashima A,Maehara Y,Kakeji Y,et al.Overexpression of vascular endothe lial growth factor C is related to lymphogenous metastasis in early gastric carc inoma[J].Oncology,2001,60(2):146-150.
[38]Pepper MS,Mandriota SJ,Jeltsch M,et al. Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity[J].J Cell Physiol,1998,177(3):439-452.
[39]Valtola R,Salven P,Heikkila P,et al.VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer[J].Am J Pathol,1999,154(5):1381-1390.
[1]Joukov V,Pajusola K,Kaipainen A,et al.A novel vascular endothelial growth factor,VEGF-C,is a ligand for the Flt-4(VEGFR-3)and KDR(VEGFR-2) receptor tyrosine kinases[J].The EMBO Joumal,1996,15(2):290-298.
[2]Lee J,Gray A,Yuan J,et al.Vascular endothelial growth factor-related protein:A ligand and specific activator of the tyrosine kinase receptor Flt4[J].Proc.NatlSci USA,1996,93(5):1988-1992.
[3]Joukov V,Kaipainen A,Jeltsch M,etal.Vascular Endothelial Growth Factors VEGF-B and VEGF-C[J]. Journal of Cellular Physiology,1997,173(2):211-215.
[4]李秋梨,陈福进,血管内皮生长因子-C、D与肿瘤淋巴道转移研究进展[J].癌症,2002,21(6)：696-700.
[5]Denekamp J.Angiogenesis,neovascular proliferation and vascular Pathophysiology as targets for cancer therapy[J].Br J Radiol,1993,66 (783):181-196.
[6]Yeo KT, Wang HH, Nagy JA, et al. Vascular permeability factor (vascular Endothelial growth factor) in guinea pig and human tumor and inflammatory effusions[J].Cancer Res,1993,53(12):2912-2918.
[7]Zagzag D.Angiogenic growth factors in neural embryogenesis and neoplasia[J].Am J Pathol,1995,146(2):293-309.
[8]Collins PD, Connolly DT, Williams TJ.Characterization of the increase in vascular permeability induced by vascular permeability factor in vivo[J].Br J Pharmacol,1993,109(1):195-199.
[9]Enholm B,Paavonen K,Ristimaki A,etal.Comparison of VEGF, EGF-B,VEGF-C and Ang-1 mRNA regulation by serum,growth factors,oncoproteins and hypoxia[J].O ncogene,1997,14(20):2475-2483.
[10]Veikkola T,Jussila L,Makinen T,et al.Singalling via vascular endothelial growth factor receptor is sufficient for Lympfaniogenesis intransgenic micel[J].EMBO J,2001,20(6);1223-1231.
[11]Saaristo A,Tammela T, Timonen J,et al.Vascular endothelial growth Factor-C gene therapy restores lymphatic flow across incision wounds[J].FASEB J,2004,18(14);1707-1709.
[12]Oh SJ,Jeltsch MM,Birkenhager R,et al.VEGF and VEGF-C:Specific In duction of Angiogenesis and Lymphangiogenesis in the Differentiated Avian Chorioa llantoic Membrane[J].Development Biology,1997,188(1):96-109.
[13]Paavonen K,Puolakkainen P,Jussila L,et al.Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing [J].Am J Pathol,2000,156(5):5738-5743.
[14]Lymboussaki A, Partanen TA, Olofsson B, et al. Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors[J].Am J Pathol,1998,153(2):395-403.
[15]Jeltsh M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic Vessels in VEGF-C Transgenic Mice[J].Science,1997,276(5317)1423-1425.
[16]Iwasaki T,Hamano T,Ogato A, et al.Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma[J].Br J Haematol, 2002,116(4):796-802.
[17]Cao Y,Linden P, Farnebo J,et al.Vascular endothelial growth factor C induces angiogenesis in vivo[J].Proc Natl Acad Sci U SA,1998,95(24):14389-14394.
[18]Ajisaka H,Yonemura Y,Miwa K.Correlation of lymph node metastasis and expression of matrix metalloproteinase-7 in patients with gastric cancer[J].Hepatogastroenterology,2004,51(57):900-905.
[19]Skobe M,Hawighorst T,Jackson DG et al.Induction of tumor lymph an giogenesis by VEGF-C promotes breast cancer metastasis[J].Nature Medicin e,2001,7(2):192-198.
[20]Karpanen T,Egeblad N,Karkkainen MJ,et al.Vacular endothelial factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth[J].Ca nc er Research,2001,61(5):1786-1790.
[21]Lin M, Lin HZ, Ma SP, et al. Vascular endothelial growth factor-A and-C: expression and correlations with lymphatic metastasis and prognosis in colorectal cancer. Med Oncol,2010.
[22]Cross MJ, Dixelius J,Matsumoto T,et al.VEGF-receptor signal transduction [J].Trends BiochemSci,2003,28(9):488-494.
[23]Valtola R, Salven P, Heikkila P,et al.VEGFR-3 and Its Ligand VEGF-C Are Associated with Angiogenesis in Breast Cancer[J].Am J Pathol,1999,154(5):1381-1390.
[24]Gitay GH,Halaban R,Neufeld G.Human melanma cell but not normal melanocytes express vascular endothelial growth factor receptors[J]. Biochem Biophys Res Commun,1993,190(3):702-708.
[25]Sasaki R.Microvessel count and vascular endothelial growth factor in renal cell carcinoma [J]. Nippon Hittyokika Gakkai Zasski,1996,87(8):1032-1040.
[26]Baker EA,Bergin FG,Leaper DJ.Plasminogen activator system,vascular endothelial growth factor and colorector cancer progression[J]. Mol Pathol,2000, 53(6):307-312.
[27]Fujisawat T, Watanabe J, Kamata Y,et al. Effect of p53 gene transfection on vascular endothelial growth factor expression in endometrial cancer cells [J].Exp MolPathol,2003,74:276-281.
[28]He XW, Liu T, Xiao Y, et al. Vascular endothelial growth factor-C siRNA delivered via calcium carbonate nanoparticle effectively inhibits lymphangiogenesis and growth of colorectal cancer in vivo[J]. Cancer Biother Radiopharm, 2009,24:249-259.
[29]Weng D E, Weiss P, Kellackey C, et al.Angiozyme pharmacokinetic and safety results:a phase Ⅰ/Ⅱ study in patients with refractory solid tumours [M].USA:ProcAmSoc Clin Oncol,2001:99.
[30]Olson TA.Targeting the tumor vasculature; inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate[J].Cancer,1997,73(6),865-870.
[31]Qi JH, Ebrahem Q, Nina M, et al.A novel function for tissue inhibitor of metalloproteinases-3(TIMP3):inhibitionof angiogenesis by blockage of VEGF binding to VEGF receptor-2[J].Nature Med,2003,9(4):407-415.
[32]Yagi Y,Fushida S,Fujita H,et al.Anti-VEGF therapy for peritoneal dissemination model of gastric cancer considering of pharmacokinetics[J].Gan To Kagaku Ryoho,2008,35(12):2005-2008.
[33]Mori A, Arii S, Furutani M, et al. Soluble Fit-1 gene therapyfor peritoneal metastases using HVJ-cationic liposomes[J]. Gene Ther, 2000,7(12):1027-1033.
[34]Ray J M,Stevenson W G. The role of matrix metalloproteinase and their inhibitors in tumor invasion,metastasis and angiogensis[J]. Eur Resir J,1994,7(11):2062.
[35]Koger M, Tschesche H. Cloning expression and action of atruncated 92 Kdage latinase minienzyme[J].Gene,1997,196:175.
[36]金钫,段银钟.基质金属蛋白酶与骨改建[J].牙体牙髓牙周病学杂志.2000,10(4)：232.
[37]PrestonA.MatrixM etaloproteinases[J].Cal Biochem,2002,2:1-20.
[38]Stemlicht MD,Bissel MJ,Werb Z.The Matrix Metaloproteinase Stromelysin-1 acts As a Natural Mammary Tumor Promoter[J].Oncogene,2000,19:1102-1113.
[39]Ye S,Eriksson P,Hamsten A,et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression[J].J Biol Chem,1996,271(2):13055-13060.
[40]Hinoda Y, Okayama N, Takano N, et al.Association of functional polymorphisms of matrix metalloproteinase (MMP)-1 and MMP-3 genes with colorectal cancer[J].Int J Cancer,2002,102(5):526-529.
[41]方淑梅,金霞,李琰,等.基质金属蛋白酶3基因多态性与非小细胞肺癌遗传易感性及淋巴结转移的关系[J].癌症,2005.24(3)：305-310.
[42]Ghilardi G, Biondi ML,Caputo M,et al.A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility.Clin Cancer Res,2002,8:3820-3823.
[43]张莉,秦北宁,任爱琴,等.大肠癌患者基质分解素-1(MMP-3)基因表达增强[J].世界华人消化杂志,2001,9(10)：1210-1212.
[44]Mercapide J,Lopez De Cicco R,Castresana JS,et al.Stromelysin-1/matrix metalloproteinase-3 (MMP-3) expression accounts for invasive propertiesof human astrocytoma cell lines[J].Int J Cancer,2003,106(5):676-682.
[45]Zucker S,Vacirca J.Role of matrix metalloproteinases(MMPs) in colorectal cancer[J].Cancer Metastasis Rev,2004,23(1-2):101-117.
[46]张军勇,张忠明,马富,等.胃癌组织中基质分解素-1基因表达的研究[J].华北国防医药,2002,14(1)：11-12.
[47]Matrisian LM, Bowden GT. Stromelysin/transin and tumor progression[J]. Semin Cancer Biol,1990,1:107-115.
[48]Brown PD, Bloxidge RE, Stuart NSA, et al. Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma[J]. J Natl Cancer Inst,1993,85:574-578.
[49]Murray GI,Duncan ME,Arbuckle E,et al.Matrix metalloproteinases and their inhibitors in gastric cancer[J].Gut,1998,43(6):791-797.
[50]邹赛英.’VEGF、MMP-3在胃印戒细胞癌中的表达与浸润转移的关系[J].诊断病理学杂志,2003,10：111-112.
[51]黄钢丁,姜海行,覃山羽,等.胃癌组织MMP-3及MMP-13蛋白的表达[J].广东医学,2007,28(10)：1631-1633.
[52]Bramhall SR, Hallissey MT, Whiting J, et al.Marimastat as maintenance therapy for patients with advanced gastric cancer:a randomized trial [J]. Br J Cancer,2002,86 (12):1864-1870.
[53]RosemurgyA, Harris J, LanglebenA, et al.Marimastat in Patients with advanced Pancreatic cancer:adose-finding study[J]. AmJ Clin Oncol,1999,23(3):247-252.
[54]Primrose JN,Bleiberg N, Daniel F, et al. Marimastat in recurrent colorectal cancer, exploratory evaluation of biological activity by measurement of carcinoembryonic antigen[J].Br J Cancer,1999,79(4):509-514.
[55]Tiemey GM, Gdfih NR,Stuart RC, et al.A pilot study of the safety and effects of the matrix metalloproteinaseinhibitor Marimastat in gastric cancer[J].EurJ Cancer,1999 35(4):563-568.
[56]Chamichael J,Lederman J, Woll PJ, et al.Phase I B study of concurrent Admininistration of marimastat and gemcitabine in nonresectable Pancreatic cancer[J].Proc Am soc Clin oncol,1998,17:232-237.
[57]Muhammad WS.Anti-angiogenesis therapy in pancreatic carcinoma[J].JOP,2006,7 (2):163-173.
[58]胡晓慧,沈飞,董宁征,等.抗人基质金属蛋白酶-2的单抗制备及功能研究[J].中国病理生理杂志,2005,21(5)：876-881.
[59]Li Wei-fang,Shi Cheng-zhang.Expression of MK,CD105 and VEGF in colorectal carcinoma and its clinical significance [J].The Practical Journal of Cancer,2006,21(1):20-23.
[60]Valtola R,Salven P,Heikkila P,et al.VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer[J].Am J Pathol,1999,154(5):1381-1 390.