uPA、PAI-1在乳腺癌组织中的表达及其与临床病理因素及预后的关系
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摘要
目的:通过检测乳腺癌组织中uPA、PAI-1的表达,探讨其与肿瘤大小、临床分期、腋窝淋巴结转移数目、肿瘤组织学分级、ER、PR、c-erbB2、骨髓微转移及预后的关系,并探讨uPA与PAI-1之间的相互关系。探寻可靠的生物学指标,判断乳腺癌患者的预后,指导个体化治疗。
方法:选择2002年10月至2003年10月在河北医科大学第四医院外一科住院治疗的原发性乳腺癌患者50例,均为女性,为实验组。另取我院同期10例乳腺增生、纤维腺瘤等良性乳腺疾病作对照。采用免疫组化SP法检测乳腺癌组织及对照组良性乳腺疾病组织中uPA、PAI-1的表达情况,结合临床病理因素、骨髓微转移情况及随访结果对数据进行统计处理。
结果:50例乳腺癌患者癌组织中uPA表达阳性率为92.0%。与同期10例良性乳腺疾病对照组组织中uPA阳性率10.0%相比,癌组织中的uPA表达增强,P=0.001。癌组织中uPA表达随肿瘤的增大而增高(P=0.001);淋巴结转移阳性的患者癌组织uPA表达强度高(P=0.001);组织学分级高的患者癌组织uPA表达强度高(P=0.023);临床分期晚的患者癌组织uPA表达强度高(P=0.040)。乳腺癌组织ER蛋白表达阴性组中肿瘤组织中uPA表达强度较ER蛋白表达阳性组高(P=0.040);乳腺癌组织PR蛋白表达阴性组中肿瘤组织中uPA表达强度较PR蛋白表达阳性组高(P=0.040);乳腺癌组织c-erbB2蛋白过表达组中肿瘤组织中uPA表达强度较c-erbB2蛋白低表达组高(P=0.021);乳腺癌患者癌组织uPA表达强度高者易发生骨髓微转移(P=0.002),乳腺癌患者癌组织uPA表达强度高者易发生远处转移,预后较差(P=0.001)。50例乳腺癌患者癌组织中PAI-1表达阳性率为82.0%。与同期10例良性乳腺疾病对照组组织中PAI-1阳性率10.0%相比,癌组织中的PAI-1表达增强,P=0.001。癌组织中PAI-1表达随肿瘤的增大而增高(P=0.001);淋巴结转移阳性的患者癌组织PAI-1表达强度高(P=0.001);组织学分级高的患者癌组织PAI-1表达强度高(P=0.002);临床分期晚的患者癌组织PAI-1表达强度高(P=0.042)。乳腺癌组织ER蛋白表达阴性组中肿瘤组织中PAI-1表达强度较ER蛋白表达阳性组高(P=0.002);乳腺癌组织PR蛋白表达阴性组中肿瘤组织中PAI-1表达强度较PR蛋白表达阳性组高(P=0.023);乳腺癌组织c-erbB2蛋白表达阳性组中肿瘤组织中PAI-1表达强度较c-erbB2蛋白表达阴性组高(P=0.014);乳腺癌患者癌组织PAI-1表达强度高者易发生骨髓微转移(P=0.012),乳腺癌患者癌组织PAI-1表达强度高者易发生远处转移,预后较差(P=0.004)。乳腺癌组织中的uPA与PAI-1的表达呈正相关(r=0.664, P=0.000)。
结论:乳腺癌组织uPA、PAI-1表达与肿瘤大小成正相关,肿瘤越大,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与患者的临床分期成正相关,临床分期越晚,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与腋窝淋巴结转移数目成正相关,转移数目越多,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与肿瘤组织学分级成正相关,组织学分级越高,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与肿瘤组织中ER、PR表达情况成负相关,与肿瘤组织中c-erbB2表达情况成正相关; uPA、PAI-1高表达者发生骨髓微转移及远处转移机会高、预后差,uPA、PAI-1检测可以作为判断乳腺癌预后的指标之一。uPA与PAI-1的表达成正相关,两者之间存在协同作用。
Objective: To detect the uPA and PAI-1 in breast cancer tissue, investigate the relationships between uPA /PAI-1 and clinical pathology factors such as the size of the tumor、clinical stage、the number of metastasis in axillary nodes、tumor histology grade、ER、PR、c-erbB2、bone marrow micro-metastasis(BMM) and prognosis of the patients, also discuss the relationship between uPA and PAI-1. In order to get reliable biological parameter to judge the prognosis of the patients with breast cancer, and to direct individualized treatment.
Methods: To choose 50 women patients with primarily breast cancer as experimentation group, who got hospitalization in the 1st surgery department of the 4th hospital of Hebei Medical University between the Oct. 2002 and Oct. 2003. In the same time, choose another 10 patients with innocence disease of breast as contrast. Use immunohistochemistry to detect the uPA and PAI-1 in breast cancer tissue and the contrast group, combine the results to the clinical pathology factors and the follow-up, then statistics the data.
Results: About 92.0% positive expression rate of uPA in the malignant group was found, which was defined statistical significance, compared to the innocence group with 10.0% positive expression rate (χ~2=28.360, P=0.001). The expression of uPA was more greatly increased in patients with T2、3 (>2cm) tumors than T1(≤2 cm) (χ~2=13.570, P=0.001) and with clinical stageⅡ、Ⅲ、Ⅳthan stage I (χ~2=8.336, P=0.040). The axillary nodes metastasis positive group had much higher expression of uPA than the negative ones (χ~2=17.381, P=0.001). The expression of uPA in the breast cancer with grade I was lower than that of grade II or III (χ~2=7.585, P =0.023). The ER、PR positive group had much lower expression of uPA than the negative group (χ~2=4.222, P =0.040;χ~2=4.218, P=0.040; respectively), while the c-erbB2 positive group has much higher rate (χ~2=5.329, P=0.021). The high positive expression group of uPA had much higher rate of positive micro-metastasis in bone marrow (χ~2=9.979, P=0.001). There was the correlation between uPA and the distant metastasis or poor prognosis (χ~2=18.752, P=0.001). About 82.0% positive expression rate of PAI-1 in the malignant group was found, which was defined statistical significance, compared to the innocence group with 10.0% positive expression rate (χ~2=17.286, P=0.001). The expression of PAI-1 was more greatly increased in patients with T2、3 (>2cm) tumors than T1(≤2 cm) (χ~2=16.118, P=0.001) and with clinaical stageⅡ、Ⅲ、Ⅳthan stage I (χ~2=8.213, P=0.042). The axillary nodes metastasis positive group has much higher expression of uPA than the negative ones (χ~2=15.353, P=0.001). The expression of uPA in the breast cancer with grade I was lower than that of grade II or III (χ~2=12.482, P=0.002). The ER、PR positive group had much lower expression of uPA than the negative group (χ~2=9.790, P=0.002;χ~2=5.145, P=0.023; respectively), while the c-erbB2 positive group has much higher rate (χ~2=5.992, P=0.014). The high positive expression group of PAI-1 had much higher rate of positive micro-metastasis in bone marrow (χ~2=6.349, P=0.012). There was the correlation between the patients with positive expression of PAI-1 and the distant metastasis or poor prognosis (χ~2=8.470, P=0.004). uPA and PAI-1 had positive relationship with each other(r=0.664, P=0.000).
Conclusion: uPA and PAI-1 in breast cancer tissue have relationship with the size of the tumor、the clinical stage、the axillary nodes metastasis、the histology grade of the tumor、the ER、PR、c-erbB2 and the BMM. The most important is that uPA、PAI-1 have positive relationship with each other, the patients with positive expression of uPA、PAI-1 have more chances with distant metastasis and poor prognosis. The detection of uPA、PAI-1 could be as targets to predict the prognosis of breast cancer.
方法:选择2002年10月至2003年10月在河北医科大学第四医院外一科住院治疗的原发性乳腺癌患者50例,均为女性,为实验组。另取我院同期10例乳腺增生、纤维腺瘤等良性乳腺疾病作对照。采用免疫组化SP法检测乳腺癌组织及对照组良性乳腺疾病组织中uPA、PAI-1的表达情况,结合临床病理因素、骨髓微转移情况及随访结果对数据进行统计处理。
结果:50例乳腺癌患者癌组织中uPA表达阳性率为92.0%。与同期10例良性乳腺疾病对照组组织中uPA阳性率10.0%相比,癌组织中的uPA表达增强,P=0.001。癌组织中uPA表达随肿瘤的增大而增高(P=0.001);淋巴结转移阳性的患者癌组织uPA表达强度高(P=0.001);组织学分级高的患者癌组织uPA表达强度高(P=0.023);临床分期晚的患者癌组织uPA表达强度高(P=0.040)。乳腺癌组织ER蛋白表达阴性组中肿瘤组织中uPA表达强度较ER蛋白表达阳性组高(P=0.040);乳腺癌组织PR蛋白表达阴性组中肿瘤组织中uPA表达强度较PR蛋白表达阳性组高(P=0.040);乳腺癌组织c-erbB2蛋白过表达组中肿瘤组织中uPA表达强度较c-erbB2蛋白低表达组高(P=0.021);乳腺癌患者癌组织uPA表达强度高者易发生骨髓微转移(P=0.002),乳腺癌患者癌组织uPA表达强度高者易发生远处转移,预后较差(P=0.001)。50例乳腺癌患者癌组织中PAI-1表达阳性率为82.0%。与同期10例良性乳腺疾病对照组组织中PAI-1阳性率10.0%相比,癌组织中的PAI-1表达增强,P=0.001。癌组织中PAI-1表达随肿瘤的增大而增高(P=0.001);淋巴结转移阳性的患者癌组织PAI-1表达强度高(P=0.001);组织学分级高的患者癌组织PAI-1表达强度高(P=0.002);临床分期晚的患者癌组织PAI-1表达强度高(P=0.042)。乳腺癌组织ER蛋白表达阴性组中肿瘤组织中PAI-1表达强度较ER蛋白表达阳性组高(P=0.002);乳腺癌组织PR蛋白表达阴性组中肿瘤组织中PAI-1表达强度较PR蛋白表达阳性组高(P=0.023);乳腺癌组织c-erbB2蛋白表达阳性组中肿瘤组织中PAI-1表达强度较c-erbB2蛋白表达阴性组高(P=0.014);乳腺癌患者癌组织PAI-1表达强度高者易发生骨髓微转移(P=0.012),乳腺癌患者癌组织PAI-1表达强度高者易发生远处转移,预后较差(P=0.004)。乳腺癌组织中的uPA与PAI-1的表达呈正相关(r=0.664, P=0.000)。
结论:乳腺癌组织uPA、PAI-1表达与肿瘤大小成正相关,肿瘤越大,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与患者的临床分期成正相关,临床分期越晚,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与腋窝淋巴结转移数目成正相关,转移数目越多,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与肿瘤组织学分级成正相关,组织学分级越高,uPA、PAI-1表达强度越高;乳腺癌组织uPA、PAI-1表达与肿瘤组织中ER、PR表达情况成负相关,与肿瘤组织中c-erbB2表达情况成正相关; uPA、PAI-1高表达者发生骨髓微转移及远处转移机会高、预后差,uPA、PAI-1检测可以作为判断乳腺癌预后的指标之一。uPA与PAI-1的表达成正相关,两者之间存在协同作用。
Objective: To detect the uPA and PAI-1 in breast cancer tissue, investigate the relationships between uPA /PAI-1 and clinical pathology factors such as the size of the tumor、clinical stage、the number of metastasis in axillary nodes、tumor histology grade、ER、PR、c-erbB2、bone marrow micro-metastasis(BMM) and prognosis of the patients, also discuss the relationship between uPA and PAI-1. In order to get reliable biological parameter to judge the prognosis of the patients with breast cancer, and to direct individualized treatment.
Methods: To choose 50 women patients with primarily breast cancer as experimentation group, who got hospitalization in the 1st surgery department of the 4th hospital of Hebei Medical University between the Oct. 2002 and Oct. 2003. In the same time, choose another 10 patients with innocence disease of breast as contrast. Use immunohistochemistry to detect the uPA and PAI-1 in breast cancer tissue and the contrast group, combine the results to the clinical pathology factors and the follow-up, then statistics the data.
Results: About 92.0% positive expression rate of uPA in the malignant group was found, which was defined statistical significance, compared to the innocence group with 10.0% positive expression rate (χ~2=28.360, P=0.001). The expression of uPA was more greatly increased in patients with T2、3 (>2cm) tumors than T1(≤2 cm) (χ~2=13.570, P=0.001) and with clinical stageⅡ、Ⅲ、Ⅳthan stage I (χ~2=8.336, P=0.040). The axillary nodes metastasis positive group had much higher expression of uPA than the negative ones (χ~2=17.381, P=0.001). The expression of uPA in the breast cancer with grade I was lower than that of grade II or III (χ~2=7.585, P =0.023). The ER、PR positive group had much lower expression of uPA than the negative group (χ~2=4.222, P =0.040;χ~2=4.218, P=0.040; respectively), while the c-erbB2 positive group has much higher rate (χ~2=5.329, P=0.021). The high positive expression group of uPA had much higher rate of positive micro-metastasis in bone marrow (χ~2=9.979, P=0.001). There was the correlation between uPA and the distant metastasis or poor prognosis (χ~2=18.752, P=0.001). About 82.0% positive expression rate of PAI-1 in the malignant group was found, which was defined statistical significance, compared to the innocence group with 10.0% positive expression rate (χ~2=17.286, P=0.001). The expression of PAI-1 was more greatly increased in patients with T2、3 (>2cm) tumors than T1(≤2 cm) (χ~2=16.118, P=0.001) and with clinaical stageⅡ、Ⅲ、Ⅳthan stage I (χ~2=8.213, P=0.042). The axillary nodes metastasis positive group has much higher expression of uPA than the negative ones (χ~2=15.353, P=0.001). The expression of uPA in the breast cancer with grade I was lower than that of grade II or III (χ~2=12.482, P=0.002). The ER、PR positive group had much lower expression of uPA than the negative group (χ~2=9.790, P=0.002;χ~2=5.145, P=0.023; respectively), while the c-erbB2 positive group has much higher rate (χ~2=5.992, P=0.014). The high positive expression group of PAI-1 had much higher rate of positive micro-metastasis in bone marrow (χ~2=6.349, P=0.012). There was the correlation between the patients with positive expression of PAI-1 and the distant metastasis or poor prognosis (χ~2=8.470, P=0.004). uPA and PAI-1 had positive relationship with each other(r=0.664, P=0.000).
Conclusion: uPA and PAI-1 in breast cancer tissue have relationship with the size of the tumor、the clinical stage、the axillary nodes metastasis、the histology grade of the tumor、the ER、PR、c-erbB2 and the BMM. The most important is that uPA、PAI-1 have positive relationship with each other, the patients with positive expression of uPA、PAI-1 have more chances with distant metastasis and poor prognosis. The detection of uPA、PAI-1 could be as targets to predict the prognosis of breast cancer.
引文
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33. Volm M, Mattem J, Koomagi R. Relationship of urokinase and urokinase receptor in non-small cell lung cancer to proliferation, angiogenesis, metastasis and patients survival. Oncol Rep, 1999, 6(3):611-615
34. Herszenyi L, Farinati F, Plebani M, et al. The role of cathepsins and the plasminogen activator/inhibitor system in colorectal cancer. Orv Hetil, 1999, 140(33):1833-1836
35. Stephan B, Florian D, Bj?rn N, et al. A Pooled Analysis ofBone Marrow Micrometastasis in Breast Cancer [J]. N Engl J Med, 2005, 353(8):793-802
36. 刘运江,刘现义,刘巍,hMAM 检测乳腺癌骨髓微转移及其意义。中国肿瘤临床,2006, 33(10):549-552
37. 张文敏,黄纲雄,黄爱民,等,uPA 和 PAI-1 在人脑胶质瘤的表达及其与肿瘤血管生成的关系。解剖学研究,2005, 27(1):15-17
38. Gottfried K, Michael Un, Astrid P, et al. Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clinical Cancer Res, 2001, 6(7):1743-1749
39. Schmitt M, Harbeck N, Thomssen C, et al. Clinical impact of the plasminogen activation system in tumor ivasion and metastasis: prognostic relevance and target for therapy [J]. Thromb Haemost, 1997, 78 (1) :285
40. Jan Grondahi-Hansen, Sier CF, Stephens R, et al. The level of urokinase-type plasminogen activator receptor is increased in semu of ovarian cancer patients [J]. Cancer Res, 1993, 53:2513
41. David R, Stein metzer T, Arvan M, et al. Synthetic urokinase inhibitors as potential antitumor drugs [J]. Int J Cancer, 1992, 50:208
42. Pyke C, Kristensen P, Ralfkiaer E, et al. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in thetumor stroma [J]. Cancer Res, 1991, 51 (15) : 4067-4071
1 Tecimer C, Doering DL, Goldsmith LJ, et al. Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type I in endometrial cancer [J]. Gynecol Onco, 2001, 80(1): 48-55
2 Schenk-Braat EA, Morser J, Rijken DC, et al. Identification of the epi-dermal growth factor-like domains ofthrombomodulin essential for the acceleration of thrombin-mediated inactivation of single-chain urokinase-type plasminogen activator [J]. Eur J Biochem, 2001, 268(21):5562-5569
3 Ikeda Y, Ikata T, Mishiro T, et al. Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase [J]. J Med Invest, 2000, 47(1-2):61-75
4 Bdeir K, Kuo A, Sachais BS, et al. The kringle stabilizes urokinase binding to the urokinase receptor [J]. Blood, 2003, 102(10): 3600-3608
5 Alfano D, Franco P, Vocca I, et al. The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis [J]. Thromb Hae-most, 2005, 93(2): 205-211
6 Hilal G, Martel-Pelletier J, Pelletier JP, et al. Abnormal regulation of urokinase plasminogen activator by insulin-like growth factor I in human osteoarthritis subchond ralosteoblasts [J]. Arthritis Rheum, 1999, 42(10):2112-2122
7 Mikolajczyk SD, Millar LS, Kumar A, et al. Prostatic human kallikrein2 inactivates and complexes with plasminogen activator inhibitor-1. Int J Cancer, 1999, 81(3): 438-442
8 Wind T, Jensen MA, et al. Epitope mapping for four monoclonal antibodies against human plasminogen activator inhibitor type-1 [J]. Eur J Biochem, 2001, 268(4):1095-1106
9 Yu W, Kim J, Ossowski L, et al. Reduction in surface urokinase receptor forces malignant cells into a protractedstate of dormancy [J]. J Cell Biol, 1997, 137(3):767-777
10 Gutierrez LS, Schulman A, Brito-Robinson T, et al. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1 [J]. Cancer Res, 2000, 60(20):5839-5847
11 Stefansson S, Petitclerc E, Wong M K, et al. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1 [J]. J BiolChem, 2001, 276(11):8135-8141
12 Isogai C, Laug WE, Shimada H, et al. Plasminogen activator inhibitor-1 promotes angiogensis by stimulating endothelial cell migration toward fibronectin [J]. Cancer Res, 2001, 61 (14): 5587 -5594
13 Dumler l, Petri T, Schleuning WD, et al. Induction of c-fos gene expression by urokinase-type plasminogen activator in human ovarian cancer cells. FEBS Lett, 1994, 343:103-106
14 G Jayarama Bhat, Jagadambika J Gunaje, Steven I, et al. The American Physiological Society, 1999, L301-309
15 Liotta LA, et al. Tumor invasion and metastases-role of the extracellular matrix: Rhoads Memorial Award lecture [J]. Cancer Res, 1986, 46(1):1-7
16 Ellenrieder V, Adeler G, Gress TM,et al.Invasion and metastasis in pancreatic cancer [J]. Ann Oncol, 1999, 10(suppl 4):41
17 Andreasen PA, Egelund R, Petersen HH, et al. The plasminogen activation system in tumor growth, invasion,and metastasis [J]. Cell Mol Life Sci, 2000, 57:25
18 Andreasen PA, Kjoler L, Christen L, et al. The urokinase-type plasminogen activator system in cancer metastasis: A review [J]. Int J Cancer, 1997, 7221-7227
19 Huang S, New L, Pan ZX, et al. Urokinase plasminogen activator/ urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p382 mitogenactivated protein kinase activity [J]. J Biol Chem, 2000, 275:12266-12274
20 Pepper MS, Sappino AP, Sticklin R, et al. Upregulation of urokinase receptor expression on migrating endothelial cells [J]. J Cell Biol, 1993, 122:673-680
21 Dear AE, Medcalf RL, et al. The urokinase-type plasminogen activator receptor is a pleiotropic melocule [J]. Eur J Biochem, 1998, 252:185-193
22 Lyu MA, Chor YK, Park BN, et al. Over-expression of urokinase receptor in human epidermoid-carcinoma cell line(Hep 3) increases tumorigenicity on chorio-allantoic membrane and in severe combined-immunodeficient mice [J] .Int J Cancer, 1998, 77:257-264
23 Schmitt M, Harbeck N, Thomssen C, et al. Clinical impact of the plasminogen activation system in tumor ivasion and metastasis prognostic relevance and target for therapy [J]. Thromb Haemost, 1997, 78(1):285-292
24 Jan Grondahi-Hansen, Sier CF, Stephens R, et al. The level of urokinase-type plasminogen activator receptor isincreased in semu of ovarian cancer patients [J]. Cancer Res, 1993, 53:2513-2521
25 David R, Stein metzer T, Arvan M, et al. Synthetic urokinase inhibitors as potential antitumor drugs [J]. Int J Cancer, 1992, 50:208-215
26 Pyke C, Kristensen P, Ralfkiaer E, et al. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma [J]. Cancer Res, 1991, 51(15): 4067-4071
27 Quax PH, van Leeawen RT, Verspaget HV, et al. Protein and messenger RNA levels of plasminogen activators and inhibitors analyzed in 22 human tumor cellline. Cancer Res, 1990, 50:1488-1495
28 Liu G, Shuman MA Cohen RL, et al. Co expression of urokinase, urokinase receptor and Pal-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer, 1995, 60:501-506
29 Achbarou A, Kaiser S, Tremblay G, et a1. Urokinase over production results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res, 1994, 54:2372-2377
30 Schmalfeldt B, Kuhn W, Reuning U, et a1. Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator . its receptor and inhibitors types 1 and 2. Cancer Res, 1995, 55:3958-3963
31 Gandolfo GM, Conyi L, Vercillo M, et al. Fibrinolysiscomponents as prognostic markers in breast cancer and colorectal carcinoma. Anticancer Res, 1996, 16(4B):2155-2161
32 Festuccia C, Dolo V, Gueerra F, et al. Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells [J]. Clin Exp Metastasis, 1998, 16(6):513-528
33 Mc William N, Robbie L, Booth N, et al. Plasminogen activator in acute myeloid leukaemic marrows: u-PA in contrast to t-PA in normal marrow [J]. Br J Haematol, 1998, 101(4):626-631
34 Zhang H, Morisaki T, Matsunaga H, et al. Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs [J]. Clin Exp Metastasis, 2000, 18:343-352
35 Rowland-Goldsmith MA, Maruyama H, Matsuda K, et al. Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer metastasis[J].Mol Cancer Ther, 2002, 1:161-167
36 Farina AR, Tacconelli A, Cappabbianca L, et al. Inhibition of Human MDA- MB- 231breast cancer cell invasion by matrix metallo-proteinase 3 involves degradation of plasminogen [J]. Eur J Biochem, 2002, 269:4476-4483
37 Liu S, Aaronson H, Mitola DJ, et al. Potent antitumor activity of a urokinase-activated engineered anthrax toxin [J].Proc Natl Acad Sci USA, 2003, 100(2):657-662
38 Jankun J, Keck RW, Skrzypczak-Jankun E, et al. Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combine- immunodeficient mice [J]. Cancer Res, 1997, 57(4):559-563
39 Li Y, Rizvi SM, Ranson M, et al. 213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model [J]. Br J Cancer, 2002, 86(7): 1197-1203
40 Kobayashi H, Sugino D, She MY, et al. A bifunctional hybrid molecule of the amino-terminal fragment of urokinase and domainⅡof bikunin efficiently inhibits tumor cell invasion and metastasis [J]. Eur J Biochem, 1998, 253(3):817-826
41 Osswski L, Payne HR, Wilson EL, et al. Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the mude mice. Cancer Res, 1991, 51:274-280
2. Ellenrieder V, Adeler G, Gress TM, et al.Invasion and metastasis in pancreatic cancer [J]. Ann Oncol, 1999, 10(suppl 4):41
3. Andreasen PA, Egelund R, Petersen HH, et al. The plasminogen activation system in tumor growth, invasion, and metastasis [J]. Cell Mol Life Sci, 2000, 57:25
4. Andreasen PA, Kjoler L, Christen L, et al. The urokinase-type plasminogen activator system in cancer metastasis: A review [J]. Int J Cancer, 1997, 7221-7227
5. Huang S, New L, Pan ZX, et al. Urokinase plasminogen activator/ urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p382 mitogenactivated protein kinase activity [J]. J Biol Chem, 2000, 275:12266-12274
6. Pepper MS, Sappino AP, Sticklin R, et al. Upregulation of urokinase receptor expression on migrating endothelial cells [J]. J Cell Biol, 1993, 122:673-680
7. Dear AE, Medcalf RL, et al. The urokinase-type plasminogen activator receptor is a pleiotropic melocule [J]. Eur J Biochem, 1998, 252:185-193
8. Lyu MA, Chor YK, Park BN, et al. Over-expression of urokinase receptor in human epidermoid-carcinoma cell line (Hep 3) increases tumorigenicity on chorio-allantoic membrane and in severe combined-immunodeficient mice [J]. Int J Cancer, 1998, 77:257-264
9. Tecimer C, Doering DL, Goldsmith LJ, et al. Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type I in endometrial cancer [J]. Gynecol Onco, 2001, 80(1): 48-55
10. Schenk-Braat EA, Morser J, Rijken DC, et al. Identification of the epi-dermal growth factor-like domains of thrombomodulin essential for the acceleration of thrombin-mediated inactivation of single-chain urokinase-type plasminogen activator [J]. Eur J Biochem, 2001, 268(21):5562-5569
11. Ikeda Y, Ikata T, Mishiro T, et al. Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase [J]. J Med Invest, 2000, 47(1-2):61-75
12. Bdeir K, Kuo A, Sachais BS, et al. The kringle stabilizes urokinase binding to the urokinase receptor [J]. Blood, 2003, 102(10): 3600-3608
13. Alfano D, Franco P, Vocca I, et al. The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis [J]. Thromb Hae-most, 2005, 93(2): 205-211
14. Hilal G, Martel-Pelletier J, Pelletier JP, et al. Abnormal regulation of urokinase plasminogen activator by insulin-like growth factor I in human osteoarthritis subchond ralosteoblasts [J]. Arthritis Rheum, 1999, 42(10): 2112-2122
15. Mikolajczyk SD, Millar LS, Kumar A, et al. Prostatic human kallikrein 2 in activates and complexes with plasminogen activator inhibitor-1. Int J Cancer, 1999, 81(3): 438-442
16. Wind T, Jensen MA, et al. Epitope mapping for four monoclonal antibodies against human plasminogen activator inhibitor type-1 [J]. Eur J Biochem, 2001, 268(4):1095-1106
17. Yu W, Kim J, Ossowski L, et al. Reduction in surface urokinase receptor forces malignant cells into a protracted state of dormancy [J]. J Cell Biol, 1997, 137(3):767-777
18. Cao Y, Veitonmaki N, Keough K, et al. Elevated levels of urine angiostatin and Plasrninoge/Plasmin in cancer patients. Int J Mol Med, 2000, 5(5):547-551
19. 肖继平,张广德,夏广华,等,尿激酶型纤溶酶原激活的过度表达。实用癌症杂志,1999, 14(4):261-262
20. de Bruin PA, Griffioen G, Verspaget HW, et al. Plasminogenactivators and tumor development in the human colon:activity levels in normal mucosa, adenmatous polyps, and adenoearcinomas. Cancer Res, 1987, 47(17):4654-657
21. 刘大林,陈国玉,夏建国,等,尿激酶型纤溶酶原激活物与胃癌侵袭及转移关系的研究。南京医科大学学报,2001, 21(5):393-395
22. 步星耀,章翔,陈恩志,等,uPA 与胶质瘤的侵袭及预后的关系。肿瘤,1999, 19(4):223-225
23. 李鹏,高亚,李恭才,等,尿激酶型纤溶酶原激活因子及其受体在神经母细胞瘤中的表达及其意义。中华实验外科杂志,2002, 19(2):137-138
24. Gandolfo GM, Conyi L, Vercillo M, et al. Fibrinolysis components as prognostic markers in breast cancer and colorectal carcinoma. Anticancer Res, 1996, 16(4B): 2155-2161
25. Festuccia C, Dolo V, Gueerra F, et al. Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells [J]. Clin Exp Metastasis, 1998, 16(6):513-528
26. Mc William N, Robbie L, Booth N, et al. Plasminogen activator in acute myeloid leukaemic marrows: u-PA in contrast to t-PA in normal marrow [J]. Br J Haematol, 1998, 101 (4):626-631
27. Liu G, Shuman MA Cohen RL, et al. Co expression of urokinase,urokinase receptor and Pal-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int JCancer, 1995, 60:501-506
28. Achbarou A, Kaiser S, Tremblay G, et a1. Urokinase over production results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res, 1994, 54:2372-2377
29. 陈淑勤,黄培生,李一伟,等,尿激酶型纤溶原激活物在鼻咽癌的表达及临床意义。福建医科大学学报,2002, 36(1):36-35
30. 杨进益,李韶,周荣祥,等,尿激酶型纤溶原激活物及其受体在膀肤移行细胞癌中表达的意义。中华泌尿外科杂志,2000, 21(8):465-466
31. Brunner G, Reimbold K, M Eeissauer A, et al. Sulfated glycosaminoglycans enhance tumor cell invasion in vitro by stimulating plasrninogenactivation. Exp Cell Res, 1998, 239(2):301-310
32. 周晓武,王元和,欧阳吕玺,等,尿激酶型纤溶原激活物 mRNA 表达与胃癌侵袭及转移的关系。中国普通外科杂志,2000, 9(4):315-317
33. Volm M, Mattem J, Koomagi R. Relationship of urokinase and urokinase receptor in non-small cell lung cancer to proliferation, angiogenesis, metastasis and patients survival. Oncol Rep, 1999, 6(3):611-615
34. Herszenyi L, Farinati F, Plebani M, et al. The role of cathepsins and the plasminogen activator/inhibitor system in colorectal cancer. Orv Hetil, 1999, 140(33):1833-1836
35. Stephan B, Florian D, Bj?rn N, et al. A Pooled Analysis ofBone Marrow Micrometastasis in Breast Cancer [J]. N Engl J Med, 2005, 353(8):793-802
36. 刘运江,刘现义,刘巍,hMAM 检测乳腺癌骨髓微转移及其意义。中国肿瘤临床,2006, 33(10):549-552
37. 张文敏,黄纲雄,黄爱民,等,uPA 和 PAI-1 在人脑胶质瘤的表达及其与肿瘤血管生成的关系。解剖学研究,2005, 27(1):15-17
38. Gottfried K, Michael Un, Astrid P, et al. Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clinical Cancer Res, 2001, 6(7):1743-1749
39. Schmitt M, Harbeck N, Thomssen C, et al. Clinical impact of the plasminogen activation system in tumor ivasion and metastasis: prognostic relevance and target for therapy [J]. Thromb Haemost, 1997, 78 (1) :285
40. Jan Grondahi-Hansen, Sier CF, Stephens R, et al. The level of urokinase-type plasminogen activator receptor is increased in semu of ovarian cancer patients [J]. Cancer Res, 1993, 53:2513
41. David R, Stein metzer T, Arvan M, et al. Synthetic urokinase inhibitors as potential antitumor drugs [J]. Int J Cancer, 1992, 50:208
42. Pyke C, Kristensen P, Ralfkiaer E, et al. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in thetumor stroma [J]. Cancer Res, 1991, 51 (15) : 4067-4071
1 Tecimer C, Doering DL, Goldsmith LJ, et al. Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type I in endometrial cancer [J]. Gynecol Onco, 2001, 80(1): 48-55
2 Schenk-Braat EA, Morser J, Rijken DC, et al. Identification of the epi-dermal growth factor-like domains ofthrombomodulin essential for the acceleration of thrombin-mediated inactivation of single-chain urokinase-type plasminogen activator [J]. Eur J Biochem, 2001, 268(21):5562-5569
3 Ikeda Y, Ikata T, Mishiro T, et al. Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase [J]. J Med Invest, 2000, 47(1-2):61-75
4 Bdeir K, Kuo A, Sachais BS, et al. The kringle stabilizes urokinase binding to the urokinase receptor [J]. Blood, 2003, 102(10): 3600-3608
5 Alfano D, Franco P, Vocca I, et al. The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis [J]. Thromb Hae-most, 2005, 93(2): 205-211
6 Hilal G, Martel-Pelletier J, Pelletier JP, et al. Abnormal regulation of urokinase plasminogen activator by insulin-like growth factor I in human osteoarthritis subchond ralosteoblasts [J]. Arthritis Rheum, 1999, 42(10):2112-2122
7 Mikolajczyk SD, Millar LS, Kumar A, et al. Prostatic human kallikrein2 inactivates and complexes with plasminogen activator inhibitor-1. Int J Cancer, 1999, 81(3): 438-442
8 Wind T, Jensen MA, et al. Epitope mapping for four monoclonal antibodies against human plasminogen activator inhibitor type-1 [J]. Eur J Biochem, 2001, 268(4):1095-1106
9 Yu W, Kim J, Ossowski L, et al. Reduction in surface urokinase receptor forces malignant cells into a protractedstate of dormancy [J]. J Cell Biol, 1997, 137(3):767-777
10 Gutierrez LS, Schulman A, Brito-Robinson T, et al. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1 [J]. Cancer Res, 2000, 60(20):5839-5847
11 Stefansson S, Petitclerc E, Wong M K, et al. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1 [J]. J BiolChem, 2001, 276(11):8135-8141
12 Isogai C, Laug WE, Shimada H, et al. Plasminogen activator inhibitor-1 promotes angiogensis by stimulating endothelial cell migration toward fibronectin [J]. Cancer Res, 2001, 61 (14): 5587 -5594
13 Dumler l, Petri T, Schleuning WD, et al. Induction of c-fos gene expression by urokinase-type plasminogen activator in human ovarian cancer cells. FEBS Lett, 1994, 343:103-106
14 G Jayarama Bhat, Jagadambika J Gunaje, Steven I, et al. The American Physiological Society, 1999, L301-309
15 Liotta LA, et al. Tumor invasion and metastases-role of the extracellular matrix: Rhoads Memorial Award lecture [J]. Cancer Res, 1986, 46(1):1-7
16 Ellenrieder V, Adeler G, Gress TM,et al.Invasion and metastasis in pancreatic cancer [J]. Ann Oncol, 1999, 10(suppl 4):41
17 Andreasen PA, Egelund R, Petersen HH, et al. The plasminogen activation system in tumor growth, invasion,and metastasis [J]. Cell Mol Life Sci, 2000, 57:25
18 Andreasen PA, Kjoler L, Christen L, et al. The urokinase-type plasminogen activator system in cancer metastasis: A review [J]. Int J Cancer, 1997, 7221-7227
19 Huang S, New L, Pan ZX, et al. Urokinase plasminogen activator/ urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p382 mitogenactivated protein kinase activity [J]. J Biol Chem, 2000, 275:12266-12274
20 Pepper MS, Sappino AP, Sticklin R, et al. Upregulation of urokinase receptor expression on migrating endothelial cells [J]. J Cell Biol, 1993, 122:673-680
21 Dear AE, Medcalf RL, et al. The urokinase-type plasminogen activator receptor is a pleiotropic melocule [J]. Eur J Biochem, 1998, 252:185-193
22 Lyu MA, Chor YK, Park BN, et al. Over-expression of urokinase receptor in human epidermoid-carcinoma cell line(Hep 3) increases tumorigenicity on chorio-allantoic membrane and in severe combined-immunodeficient mice [J] .Int J Cancer, 1998, 77:257-264
23 Schmitt M, Harbeck N, Thomssen C, et al. Clinical impact of the plasminogen activation system in tumor ivasion and metastasis prognostic relevance and target for therapy [J]. Thromb Haemost, 1997, 78(1):285-292
24 Jan Grondahi-Hansen, Sier CF, Stephens R, et al. The level of urokinase-type plasminogen activator receptor isincreased in semu of ovarian cancer patients [J]. Cancer Res, 1993, 53:2513-2521
25 David R, Stein metzer T, Arvan M, et al. Synthetic urokinase inhibitors as potential antitumor drugs [J]. Int J Cancer, 1992, 50:208-215
26 Pyke C, Kristensen P, Ralfkiaer E, et al. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma [J]. Cancer Res, 1991, 51(15): 4067-4071
27 Quax PH, van Leeawen RT, Verspaget HV, et al. Protein and messenger RNA levels of plasminogen activators and inhibitors analyzed in 22 human tumor cellline. Cancer Res, 1990, 50:1488-1495
28 Liu G, Shuman MA Cohen RL, et al. Co expression of urokinase, urokinase receptor and Pal-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer, 1995, 60:501-506
29 Achbarou A, Kaiser S, Tremblay G, et a1. Urokinase over production results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res, 1994, 54:2372-2377
30 Schmalfeldt B, Kuhn W, Reuning U, et a1. Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator . its receptor and inhibitors types 1 and 2. Cancer Res, 1995, 55:3958-3963
31 Gandolfo GM, Conyi L, Vercillo M, et al. Fibrinolysiscomponents as prognostic markers in breast cancer and colorectal carcinoma. Anticancer Res, 1996, 16(4B):2155-2161
32 Festuccia C, Dolo V, Gueerra F, et al. Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells [J]. Clin Exp Metastasis, 1998, 16(6):513-528
33 Mc William N, Robbie L, Booth N, et al. Plasminogen activator in acute myeloid leukaemic marrows: u-PA in contrast to t-PA in normal marrow [J]. Br J Haematol, 1998, 101(4):626-631
34 Zhang H, Morisaki T, Matsunaga H, et al. Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs [J]. Clin Exp Metastasis, 2000, 18:343-352
35 Rowland-Goldsmith MA, Maruyama H, Matsuda K, et al. Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer metastasis[J].Mol Cancer Ther, 2002, 1:161-167
36 Farina AR, Tacconelli A, Cappabbianca L, et al. Inhibition of Human MDA- MB- 231breast cancer cell invasion by matrix metallo-proteinase 3 involves degradation of plasminogen [J]. Eur J Biochem, 2002, 269:4476-4483
37 Liu S, Aaronson H, Mitola DJ, et al. Potent antitumor activity of a urokinase-activated engineered anthrax toxin [J].Proc Natl Acad Sci USA, 2003, 100(2):657-662
38 Jankun J, Keck RW, Skrzypczak-Jankun E, et al. Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combine- immunodeficient mice [J]. Cancer Res, 1997, 57(4):559-563
39 Li Y, Rizvi SM, Ranson M, et al. 213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model [J]. Br J Cancer, 2002, 86(7): 1197-1203
40 Kobayashi H, Sugino D, She MY, et al. A bifunctional hybrid molecule of the amino-terminal fragment of urokinase and domainⅡof bikunin efficiently inhibits tumor cell invasion and metastasis [J]. Eur J Biochem, 1998, 253(3):817-826
41 Osswski L, Payne HR, Wilson EL, et al. Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the mude mice. Cancer Res, 1991, 51:274-280