uPA、P-选择素在乳腺癌组织中的表达及其与浸润、转移关系的研究
|
摘要
目的：
浸润、转移是恶性肿瘤的最本质特征，也是引起恶性肿瘤患者死亡的主要原因之一。肿瘤的浸润转移过程极为复杂，涉及肿瘤细胞与宿主细胞间的一系列相互作用，涉及某些基因的异常表达，并受多种细胞因子的影响和调控。研究表明，肿瘤细胞的浸润与转移必须突破其周围的基质屏障。细胞外基质可分为基底膜和间质组织两类，它们都是由基底物、弹性蛋白和胶原构成的致密网络，在肿瘤的浸润转移中起到屏障作用。原发性肿瘤转变为浸润性肿瘤，直至发生远距离转移，要发生多次的间质和基底膜组织的降解。在此过程中，尿激酶型纤溶酶原激活物(urokinase-type plasminogen activator，uPA)和P-选择素起着十分重要的作用。
肿瘤细胞分泌的尿激酶型纤溶酶原激活物原是单链无活性的，可被血浆中的组织蛋白B激活为双链有活性的uPA，从而激活纤溶酶原转化为纤溶酶，降解大多数的细胞外基质，参与肿瘤的浸润、转移过程；而且uPA自身也具有降解细胞外基质及其基底膜的作用，它还可以通过激活金属蛋白酶参与细胞外基质成份的降解。
肿瘤细胞从原发灶脱离是肿瘤转移的关键条件，而肿瘤细胞与内皮细胞、细
郑州大学2004年学位论文
uPA、P一选择素在乳腺癌组织中的表达及其与浸润、转移关系的研究
胞外基质粘附是肿瘤血行转移不可缺少的环节。选择素(selectin)家族是近年被确
定的一个受体型粘附分子群，包括L一选择素、P一选择素和E一选择素。P一选择素能
介导肿瘤细胞与血小板及血管内皮细胞间的粘附，促进肿瘤细胞的血道转移和扩
散。
研究表明，uPA不但参与了卵巢癌、胃癌、前列腺癌、大肠癌等恶性肿瘤的发
生、发展，更重要的是与这些肿瘤的浸润、转移也有关系;P一选择素在胃癌、肾细
胞癌、肺癌、卵巢癌组织中呈异常表达，而且与这些肿瘤的浸润、转移有关。
关于P一选择素在乳腺癌组织中的异常表达与乳腺癌浸润、转移的关系，以及
uPA与P一选择素在乳腺癌浸润和转移中的相互关系，尚未见报道。为探讨uPA与
P一选择素在乳腺癌浸润、转移中的作用以及u以蛋白和P一选择素蛋白的表达在乳
腺癌发生、发展、浸润及转移过程中的相互关系，本课题采用免疫组化SP法检测
u以蛋白与P--选择素蛋白在乳腺纤维腺瘤、乳腺导管内癌及浸润性导管癌组织中
的表达情况。通过本实验，试图进一步阐明乳腺癌浸润、转移的机制，为临床预
防乳腺癌浸润、转移奠定理论基础。
方法:
采用免疫组织化学SP法，分别检测25例乳腺纤维腺瘤、28例乳腺导管内癌
及50例浸润性导管癌(其中26例伴淋巴结转移)组织中u以蛋白和P一选择素蛋
白的表达情况。
结果:
1.u以蛋白在乳腺纤维腺瘤、乳腺导管内癌、浸润性导管癌组织中的阳性表
达率分别是:20.既(5/25)、53.既(15/28)和88.既(44/50)，三组间两两比较，差
异均有统计学意义(P<0.05)。
2.u以蛋白在乳腺癌无浸润组和浸润组中的阳性表达率分别为:53.既(15/28)
和88，0%(44/50)，两组比较，差异有统计学意义(P<0.05)。
3.u以蛋白在乳腺癌无淋巴结转移组和淋巴结转移组中的阳性表达率分别为
67.3%(35/52)和92.3%(24/26)，两组比较，差异有统计学意义(P<0.05)。
4.卜选择素蛋白在乳腺纤维腺瘤、乳腺导管内癌、浸润性导管癌组织中的阳
性表达率分别是:12.0%(3/25)、39.3%(11/28)和74.0%(37/50)，三组间两两比较，
郑州大学2004年学位论文
uPA、P一选择素在乳腺癌组织中的表达及其与浸润、转移关系的研究
差异均有统计学意义(P<0.05)。
5.P一选择素蛋白在乳腺癌无浸润组和浸润组中的阳性表达率分别为:
39.3%(11/28)和74.0%(37/50)，两组比较，差异有统计学意义(P<0.05)。
6.P一选择素蛋白在乳腺癌无淋巴结转移组和淋巴结转移组中的阳性表达率分
别为50.0%(26/52)和84.6%(22/26)，两组比较，差异有统计学意义(P<0.05)。
7.uPA蛋白与P一选择素蛋白在乳腺癌组织中的阳性表达率有显著相关性(P<
0 .05)。
结论:
1.uPA蛋白和P一选择素蛋白的阳性表达在乳腺纤维腺瘤组织中较低，但在乳
腺导管内癌及浸润性导管癌组织中依次显著增高，提示u以和P一选择素参与了乳
腺癌的发生、发展。u以和P一选择素有望成为乳腺癌的病情监测及早期诊断的生
物学指标。
2.uPA蛋白和P一选择素蛋白的阳性表达与乳腺癌有无浸润和有无淋巴结转移
明显相关，提示u以和P一选择素可作为预测乳腺癌转移和评价预后的指标。
3.uPA蛋白与P一选择素蛋白在乳腺癌组织中的阳性表达有明显的相关性，联
合检测uPA和P一选择素，对探讨乳腺癌的发生、发展、浸润、淋巴结转移及预后
判断可能有更大的意义。
Objective:
Invasion and metastasis are the most fundamental characters of malignant tumor and the main reasons causing patients' death. With a extremely complicated process, invasion and metastasis involve a series of interactions between tumor cells and host cells, involve over expressions of certain genes and are affected and controlled by many cell factors. The research shows that the invasion and metastasis of the tumor cells might break through the matrix around. Extracellular matrix can be classified into basement membrane and stroma tissue. Both of them are made up of basement subtance,
elastic protein and collagen. During the invasion and metastasis of the tumor cells, they can play the role of protective screen. For many times, the degradation of stroma and basement membrane occurs when primary tumor transfers into invasive tumor and even when the far distance metastasis happens. In this process, urokinase-type plasminogen activator(uPA) and P-selectin play a very important role .
Secreted by tumor cells, pro-uPA is inactive with single strand and may be activated into active uPA with double strands by tissue protein B in plasma. Thus, plasminogen is activated into plasmin, and most extracellular matrix are degraded. In summary, uPA participates in the process of tumor invasion and metastasis. Moreover, uPA itself may obtain the function of degradating extracellular matrix and basement membrane. And uPA may take part in the degradation of extracellular matrix elements by activating MMPs.
Aparting from the primary oven is the key condition of tumor metastasis. The adhesion among tumor cells, endothelial cells and extracellular matrix is the necessary step for blood metastasis. In recent years, selectin family has been recognized as Recepter-type adhesion molecule group, including L-selectin, P-selectin and E-selectin. P-selectin may mediate the adhesion among tumor cells, platelets and endothelial cells of blood vessel so as to promote blood metastasis and diffusion of tumor cells.
The research shows that uPA takes part in the pathogenesis and development of ovary carcinoma, carcinoma of stomach, carcinoma of the prostate, carcinoma of large intestine, etc. Furthermore, it has something with the invasion and metastasis of the tumors. P-selectin aberrantly expresses in the tissue of carcinoma of stomach, renal cell carcinoma , carcinoma of the lung , ovary carcinoma and concers the tumor invasion and metastasis.
The relation between over expressions of P-selectin in breast carcinoma and the invasion and metastasis of breast carcinoma and the relation between uPA and P-selectin in the invasion and metastasis of breast carcinoma haven't been reported. This research
subject investigates, through immunohistochemisty SP method, the expressions of uPA protein and P-selectin protein in fibroadenoma, carcinoma in situ and invasive ductal carcinoma tissue, discusses the role that uPA and P-selectin play in invasion and metastasis of breast carcinoma and discusses the correlation between uPA protein expressions and P-selectin protein expressions during the course of pathogenesis, development, invasion and metastasis in breast carcinoma, so as to provide theoretical basis for clinic diagnosis.
Methods:
Respectively investigate, by adopting immunohistochemisty SP method, the expressions of uPA protein and P-selectin protein in tissue of 25 fibroademoma cases,28 cases of carcinoma in situ and 50 cases of invasive ductal carcinoma (22 cases accompany with the lymph node metastasis).
Results:
1 .The rates of positive expressions of uPA protein in the tissue of fibroadenoma, carcinoma in situ and invasive ductal cancer are respectively 20.0%(5/25), 53.6%(15/28) and 88.0%(44/50). The difference of pairwise comparisons out of the three groups have statistical significance (P < 0.05) .
2.The rates of positive expressions of uPA protein in the tissue of non-invasion and invasion are respectively 53. 6%( 15/28) and 88.0%(44/50). The difference in the two groups has statistical significance (P < 0.05) .
3. The ra
浸润、转移是恶性肿瘤的最本质特征，也是引起恶性肿瘤患者死亡的主要原因之一。肿瘤的浸润转移过程极为复杂，涉及肿瘤细胞与宿主细胞间的一系列相互作用，涉及某些基因的异常表达，并受多种细胞因子的影响和调控。研究表明，肿瘤细胞的浸润与转移必须突破其周围的基质屏障。细胞外基质可分为基底膜和间质组织两类，它们都是由基底物、弹性蛋白和胶原构成的致密网络，在肿瘤的浸润转移中起到屏障作用。原发性肿瘤转变为浸润性肿瘤，直至发生远距离转移，要发生多次的间质和基底膜组织的降解。在此过程中，尿激酶型纤溶酶原激活物(urokinase-type plasminogen activator，uPA)和P-选择素起着十分重要的作用。
肿瘤细胞分泌的尿激酶型纤溶酶原激活物原是单链无活性的，可被血浆中的组织蛋白B激活为双链有活性的uPA，从而激活纤溶酶原转化为纤溶酶，降解大多数的细胞外基质，参与肿瘤的浸润、转移过程；而且uPA自身也具有降解细胞外基质及其基底膜的作用，它还可以通过激活金属蛋白酶参与细胞外基质成份的降解。
肿瘤细胞从原发灶脱离是肿瘤转移的关键条件，而肿瘤细胞与内皮细胞、细
郑州大学2004年学位论文
uPA、P一选择素在乳腺癌组织中的表达及其与浸润、转移关系的研究
胞外基质粘附是肿瘤血行转移不可缺少的环节。选择素(selectin)家族是近年被确
定的一个受体型粘附分子群，包括L一选择素、P一选择素和E一选择素。P一选择素能
介导肿瘤细胞与血小板及血管内皮细胞间的粘附，促进肿瘤细胞的血道转移和扩
散。
研究表明，uPA不但参与了卵巢癌、胃癌、前列腺癌、大肠癌等恶性肿瘤的发
生、发展，更重要的是与这些肿瘤的浸润、转移也有关系;P一选择素在胃癌、肾细
胞癌、肺癌、卵巢癌组织中呈异常表达，而且与这些肿瘤的浸润、转移有关。
关于P一选择素在乳腺癌组织中的异常表达与乳腺癌浸润、转移的关系，以及
uPA与P一选择素在乳腺癌浸润和转移中的相互关系，尚未见报道。为探讨uPA与
P一选择素在乳腺癌浸润、转移中的作用以及u以蛋白和P一选择素蛋白的表达在乳
腺癌发生、发展、浸润及转移过程中的相互关系，本课题采用免疫组化SP法检测
u以蛋白与P--选择素蛋白在乳腺纤维腺瘤、乳腺导管内癌及浸润性导管癌组织中
的表达情况。通过本实验，试图进一步阐明乳腺癌浸润、转移的机制，为临床预
防乳腺癌浸润、转移奠定理论基础。
方法:
采用免疫组织化学SP法，分别检测25例乳腺纤维腺瘤、28例乳腺导管内癌
及50例浸润性导管癌(其中26例伴淋巴结转移)组织中u以蛋白和P一选择素蛋
白的表达情况。
结果:
1.u以蛋白在乳腺纤维腺瘤、乳腺导管内癌、浸润性导管癌组织中的阳性表
达率分别是:20.既(5/25)、53.既(15/28)和88.既(44/50)，三组间两两比较，差
异均有统计学意义(P<0.05)。
2.u以蛋白在乳腺癌无浸润组和浸润组中的阳性表达率分别为:53.既(15/28)
和88，0%(44/50)，两组比较，差异有统计学意义(P<0.05)。
3.u以蛋白在乳腺癌无淋巴结转移组和淋巴结转移组中的阳性表达率分别为
67.3%(35/52)和92.3%(24/26)，两组比较，差异有统计学意义(P<0.05)。
4.卜选择素蛋白在乳腺纤维腺瘤、乳腺导管内癌、浸润性导管癌组织中的阳
性表达率分别是:12.0%(3/25)、39.3%(11/28)和74.0%(37/50)，三组间两两比较，
郑州大学2004年学位论文
uPA、P一选择素在乳腺癌组织中的表达及其与浸润、转移关系的研究
差异均有统计学意义(P<0.05)。
5.P一选择素蛋白在乳腺癌无浸润组和浸润组中的阳性表达率分别为:
39.3%(11/28)和74.0%(37/50)，两组比较，差异有统计学意义(P<0.05)。
6.P一选择素蛋白在乳腺癌无淋巴结转移组和淋巴结转移组中的阳性表达率分
别为50.0%(26/52)和84.6%(22/26)，两组比较，差异有统计学意义(P<0.05)。
7.uPA蛋白与P一选择素蛋白在乳腺癌组织中的阳性表达率有显著相关性(P<
0 .05)。
结论:
1.uPA蛋白和P一选择素蛋白的阳性表达在乳腺纤维腺瘤组织中较低，但在乳
腺导管内癌及浸润性导管癌组织中依次显著增高，提示u以和P一选择素参与了乳
腺癌的发生、发展。u以和P一选择素有望成为乳腺癌的病情监测及早期诊断的生
物学指标。
2.uPA蛋白和P一选择素蛋白的阳性表达与乳腺癌有无浸润和有无淋巴结转移
明显相关，提示u以和P一选择素可作为预测乳腺癌转移和评价预后的指标。
3.uPA蛋白与P一选择素蛋白在乳腺癌组织中的阳性表达有明显的相关性，联
合检测uPA和P一选择素，对探讨乳腺癌的发生、发展、浸润、淋巴结转移及预后
判断可能有更大的意义。
Objective:
Invasion and metastasis are the most fundamental characters of malignant tumor and the main reasons causing patients' death. With a extremely complicated process, invasion and metastasis involve a series of interactions between tumor cells and host cells, involve over expressions of certain genes and are affected and controlled by many cell factors. The research shows that the invasion and metastasis of the tumor cells might break through the matrix around. Extracellular matrix can be classified into basement membrane and stroma tissue. Both of them are made up of basement subtance,
elastic protein and collagen. During the invasion and metastasis of the tumor cells, they can play the role of protective screen. For many times, the degradation of stroma and basement membrane occurs when primary tumor transfers into invasive tumor and even when the far distance metastasis happens. In this process, urokinase-type plasminogen activator(uPA) and P-selectin play a very important role .
Secreted by tumor cells, pro-uPA is inactive with single strand and may be activated into active uPA with double strands by tissue protein B in plasma. Thus, plasminogen is activated into plasmin, and most extracellular matrix are degraded. In summary, uPA participates in the process of tumor invasion and metastasis. Moreover, uPA itself may obtain the function of degradating extracellular matrix and basement membrane. And uPA may take part in the degradation of extracellular matrix elements by activating MMPs.
Aparting from the primary oven is the key condition of tumor metastasis. The adhesion among tumor cells, endothelial cells and extracellular matrix is the necessary step for blood metastasis. In recent years, selectin family has been recognized as Recepter-type adhesion molecule group, including L-selectin, P-selectin and E-selectin. P-selectin may mediate the adhesion among tumor cells, platelets and endothelial cells of blood vessel so as to promote blood metastasis and diffusion of tumor cells.
The research shows that uPA takes part in the pathogenesis and development of ovary carcinoma, carcinoma of stomach, carcinoma of the prostate, carcinoma of large intestine, etc. Furthermore, it has something with the invasion and metastasis of the tumors. P-selectin aberrantly expresses in the tissue of carcinoma of stomach, renal cell carcinoma , carcinoma of the lung , ovary carcinoma and concers the tumor invasion and metastasis.
The relation between over expressions of P-selectin in breast carcinoma and the invasion and metastasis of breast carcinoma and the relation between uPA and P-selectin in the invasion and metastasis of breast carcinoma haven't been reported. This research
subject investigates, through immunohistochemisty SP method, the expressions of uPA protein and P-selectin protein in fibroadenoma, carcinoma in situ and invasive ductal carcinoma tissue, discusses the role that uPA and P-selectin play in invasion and metastasis of breast carcinoma and discusses the correlation between uPA protein expressions and P-selectin protein expressions during the course of pathogenesis, development, invasion and metastasis in breast carcinoma, so as to provide theoretical basis for clinic diagnosis.
Methods:
Respectively investigate, by adopting immunohistochemisty SP method, the expressions of uPA protein and P-selectin protein in tissue of 25 fibroademoma cases,28 cases of carcinoma in situ and 50 cases of invasive ductal carcinoma (22 cases accompany with the lymph node metastasis).
Results:
1 .The rates of positive expressions of uPA protein in the tissue of fibroadenoma, carcinoma in situ and invasive ductal cancer are respectively 20.0%(5/25), 53.6%(15/28) and 88.0%(44/50). The difference of pairwise comparisons out of the three groups have statistical significance (P < 0.05) .
2.The rates of positive expressions of uPA protein in the tissue of non-invasion and invasion are respectively 53. 6%( 15/28) and 88.0%(44/50). The difference in the two groups has statistical significance (P < 0.05) .
3. The ra
引文
[1] 李龙山，孙东植，孙抒，等．乳腺癌及其癌前病变中细胞凋亡P53、bcl-2蛋白的表达．中国肿瘤临床，2000，27(5)：329-332
[2] 上海市肿瘤研究所流行病学研究室．1996年上海市区恶性肿瘤发病率．肿瘤，1999，19(2)：封3
[3] 张远鹰，段德生．骨转移癌的分布和发生机制．吉林医学，1987，8(5)：12-14
[4] 汤文浩，李国强，王凤臣，等．食管癌组织中纤溶成份的表达及其意义．中华消化杂志，2000，20(2)：85-88
[5] Johnston G I , Cook R G , Mcever R P. Cloning of GMP-140, a granule membrane protein of platelets and endothelium: sequence similarity to proteins involved in cell adhesion and inflammation.Cell, 1989, 56(6): 1033-1044
[6] Dunlop LC, Skinner MP, Bendall LJ, Favaloro EJ, Castaldi PA, Gorman JJ, Gamble JR, Vadas MA, Berndt MC. Characterization of GMP-140 (P-selectin) as a circulating plasma protein. J Exp Med, 1992, 175(4): 1147-1150
[7] Kim YJ, Borsig L, Varki NM, et al. P-selectin deficiency attenuates tumor growth and metastasis. Proc NatI Acad Sci USA, 1998, 95(16): 9325-9330
[8] Jahkola T, Toivonen T, von Smitten K, et al. Cathe-psin-D, urokinase plasminogen activator and type-1 plasminogen activator inhibitor in early breast cancer: an immunohistochemical study of prognostic value and relations to tenascin-C and other factors. Br J Cancer, 1999, 80 (2): 167-174
[9] Okusa Y, Ichikura T, Mochizuki H. Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma. Cancer, 1999, 85 (5): 1033-1038
[10] Hoffmann G, Pollow K, Weikel W, et al. Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathologieal parameters. Clin Chem Lab. Med, 1999, 37 (1): 47-54
[11] Miyake H, Hara I, Yamanaka K, et al. Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer. Int J Oncol, 1999, 14 (3): 535-541
[12] 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
[13] Volm M, Mattern J, Koomagi R. Relationship of urokinase and urokinase receptor in non-small cell lung cancer to proliferation, angiogenesis, metastasis and patient survival. Oncol Rep, 1999, 6 (3): 611-615
[14] 周同，王玲玲，陈金联，等．P选择素在几种肿瘤中表达的临床意义．上海免疫学杂志，2000，20(4)：236-238
[15] Schadeorf D, Diehl S, Zuberbier T, et al.Quantitative detection of soluble adhesion molecules in sera of melanoma patients correlates with clinical stage.Dermatology, 1996, 192(2): 89-94
[16] Weidner N, Carroll PR, Flax T, et al. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N Engl J Med, 1991, 324(1): 1-18
[17] Liotta LA. Tumor invasion and metastases-role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res, 1986, 46(1): 1-7
[18] Hart DA, Rehemtulla A. Plasminogen activators and their inhibitors: regulators of extracellular proteolysis and cell function. Comp Biochem Physiol B, 1988, 90(4): 691-708
[19] Andreasen PA, Kjoller L, Christensen L, et al.The urokinase-type plasminogen activator system in cancer metastasis.Int J Cancer, 1997, 72 (1): 1-22
[20] Pannell R, Gurewich V. Activation of plasminogen by single-chain urokinase or by two-chain urokinase-a demonstration that single-chain urokinase has a low catalytic activity(pro-urokinase). Blood, 1987, 69(1): 22-26
[21] Appella E, Robinson EA, Ullrich SJ, et al. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem. 1987, 262(10): 4437-4440
[22] Patthy L Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules. Cell, 1985, 41(3): 657-663
[23] Bowen RM, Hoidal JR, Estensen RD. Urokinase-type plasminogen activator in alveolar macrophages and bronchoalveolar lavage fluid from normal and smoke-exposed hamsters and humans. J Lab Clin Med, 1985, 106(6): 667-673
[24] Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Dano K, Appella E, Blasi F. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J, 1990, 9(2): 467-474
[25] Cao Y Veitoumaki N, Keough K, et al. Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients. Int J Mol Med, 2000, 5(5): 547-551
[26] 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
[27] de Bruin PA, Griffioen G, Verspaget HW, et al. Plasminogen activators and tumor development in the human colon: activity levels in normal mucosa, adenmatous polyps, and adenocarcinomas. Cancer Res, 1987, 47(17): 4654-4657
[28] 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
[29] 步星耀，章翔，陈恩志，等．与胶质瘤的侵袭及预后的关系．肿瘤，1999，19(4)：223-225
[30] 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
[31] 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)：36-38
[32] 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胱移行细胞癌中表达的意义．中华泌尿外科杂志，2000，21(8)：465-466
[33] Brunner G, Reimbold K, M Eeissauer A, et al. Sulfated glycosaminoglycans enhance tumor cell invasion in vitro by stimulating plasminogen activation.Exp Cell Res, 1998, 239(2): 301-310
[34] 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
[35] 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
[36] 孙达春，刘文励．恶性肿瘤患者血液中尿激酶型纤溶酶原激活物系统测定的临床意义．临床内科杂志，2000，17(3)：157-158
[37] 陈卫昌，严辉，彭群新，等．胃癌患者血清uPA测定及临床意义．苏州医学院学报，2001，21(4)：440-442
[38] 汤文浩，李国强，王凤臣，等．食管癌组织中纤溶成份的表达及其意义．中华消化杂志，2000，20(2)：85-88
[39] Febreqa E, Casagont F, Merino J, et al. Value of plasma P-selectin for vascular complication in liver transplantation. Clin Transplat, 1996, 10 (2): 261-264
[40] 陈金联，吴云林．选择素与肿瘤转移机制．肿瘤，1996，16(1)：54-56
[41] Lip GY, Blann AD, Zarifis J, Beevers M, Lip PL, Beevers DG. Soluble adhesion molecule P-selectin and endothelial dysfunction in essential hypertension: implications for atherogenesis? A preliminary report. J Hypertens, 1995, 13(12 Pt 2): 1674-1678
[42] Pottratz ST, Hall TD, Scribner WM, et al. P-selectin-mediated attachment of small cell lung carcinoma to endothelial cells. Am J Physiol, 1996; 271 (6): 1918-1923.
[43] Silke A, Zev MS, Mina F, et al. CD_(24), a mucin-type glycoprotein, is a ligand for P-selectin of human tumor cells. Blood, 1997, 89(6): 3385-3395
[44] Mannori G, Crottet P, Cecconi O, et al. Differential colon cancer cell adhesion to E-, P-, and L-selectin: role ofmucin-type glycoprotein. Cancer Res, 1995, 55(19): 4425-4431
[45] 钱思源，王黎娜，刘惠喜．P-选择素在卵巢癌中表达的意义．武警医学，2001，12(9)：520-522
[46] 官成浓，徐军发，银正民．中晚期原发性肝癌患者血浆可溶性P-选择素的测定及临床意义．癌症，2000，19(3)：256-258
[47] 官成浓，银正民，徐军发，血浆可溶性P-选择素的临床意义．实用癌症杂志，2001，16(3)：295-296
[48] 徐军发，唐湘涓，官成浓，等。肺癌患者血浆P-选择素的检测及其临床意义．实用癌症杂志，2000，15(1)：49-50
[49] 刘剑勇，高月芳，覃宇周，等．乳腺癌患者手术前后血浆可溶性P-选择素的检测及意义．中国普外基础与临床杂志，2002，9(2)：121-121
[50] 徐西琳，李清泉，杨炯．P-选择素的表达与肺癌转移的关系。中华结核和呼吸杂志，2000，23(9)：573-573
[51] Schadendorf D, Heidel J, Gawlik C, et al.Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on inttratumoral Vessels. J Natl Cancer Inst, 1995, 87(4): 366-370
[52] 黄耀庭，马天乐．CD62P在结直肠癌患者组织及血浆中的表达．胃肠病学，2000，5(3)：161-163
[2] 上海市肿瘤研究所流行病学研究室．1996年上海市区恶性肿瘤发病率．肿瘤，1999，19(2)：封3
[3] 张远鹰，段德生．骨转移癌的分布和发生机制．吉林医学，1987，8(5)：12-14
[4] 汤文浩，李国强，王凤臣，等．食管癌组织中纤溶成份的表达及其意义．中华消化杂志，2000，20(2)：85-88
[5] Johnston G I , Cook R G , Mcever R P. Cloning of GMP-140, a granule membrane protein of platelets and endothelium: sequence similarity to proteins involved in cell adhesion and inflammation.Cell, 1989, 56(6): 1033-1044
[6] Dunlop LC, Skinner MP, Bendall LJ, Favaloro EJ, Castaldi PA, Gorman JJ, Gamble JR, Vadas MA, Berndt MC. Characterization of GMP-140 (P-selectin) as a circulating plasma protein. J Exp Med, 1992, 175(4): 1147-1150
[7] Kim YJ, Borsig L, Varki NM, et al. P-selectin deficiency attenuates tumor growth and metastasis. Proc NatI Acad Sci USA, 1998, 95(16): 9325-9330
[8] Jahkola T, Toivonen T, von Smitten K, et al. Cathe-psin-D, urokinase plasminogen activator and type-1 plasminogen activator inhibitor in early breast cancer: an immunohistochemical study of prognostic value and relations to tenascin-C and other factors. Br J Cancer, 1999, 80 (2): 167-174
[9] Okusa Y, Ichikura T, Mochizuki H. Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma. Cancer, 1999, 85 (5): 1033-1038
[10] Hoffmann G, Pollow K, Weikel W, et al. Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathologieal parameters. Clin Chem Lab. Med, 1999, 37 (1): 47-54
[11] Miyake H, Hara I, Yamanaka K, et al. Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer. Int J Oncol, 1999, 14 (3): 535-541
[12] 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
[13] Volm M, Mattern J, Koomagi R. Relationship of urokinase and urokinase receptor in non-small cell lung cancer to proliferation, angiogenesis, metastasis and patient survival. Oncol Rep, 1999, 6 (3): 611-615
[14] 周同，王玲玲，陈金联，等．P选择素在几种肿瘤中表达的临床意义．上海免疫学杂志，2000，20(4)：236-238
[15] Schadeorf D, Diehl S, Zuberbier T, et al.Quantitative detection of soluble adhesion molecules in sera of melanoma patients correlates with clinical stage.Dermatology, 1996, 192(2): 89-94
[16] Weidner N, Carroll PR, Flax T, et al. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N Engl J Med, 1991, 324(1): 1-18
[17] Liotta LA. Tumor invasion and metastases-role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res, 1986, 46(1): 1-7
[18] Hart DA, Rehemtulla A. Plasminogen activators and their inhibitors: regulators of extracellular proteolysis and cell function. Comp Biochem Physiol B, 1988, 90(4): 691-708
[19] Andreasen PA, Kjoller L, Christensen L, et al.The urokinase-type plasminogen activator system in cancer metastasis.Int J Cancer, 1997, 72 (1): 1-22
[20] Pannell R, Gurewich V. Activation of plasminogen by single-chain urokinase or by two-chain urokinase-a demonstration that single-chain urokinase has a low catalytic activity(pro-urokinase). Blood, 1987, 69(1): 22-26
[21] Appella E, Robinson EA, Ullrich SJ, et al. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem. 1987, 262(10): 4437-4440
[22] Patthy L Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules. Cell, 1985, 41(3): 657-663
[23] Bowen RM, Hoidal JR, Estensen RD. Urokinase-type plasminogen activator in alveolar macrophages and bronchoalveolar lavage fluid from normal and smoke-exposed hamsters and humans. J Lab Clin Med, 1985, 106(6): 667-673
[24] Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Dano K, Appella E, Blasi F. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J, 1990, 9(2): 467-474
[25] Cao Y Veitoumaki N, Keough K, et al. Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients. Int J Mol Med, 2000, 5(5): 547-551
[26] 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
[27] de Bruin PA, Griffioen G, Verspaget HW, et al. Plasminogen activators and tumor development in the human colon: activity levels in normal mucosa, adenmatous polyps, and adenocarcinomas. Cancer Res, 1987, 47(17): 4654-4657
[28] 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
[29] 步星耀，章翔，陈恩志，等．与胶质瘤的侵袭及预后的关系．肿瘤，1999，19(4)：223-225
[30] 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
[31] 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)：36-38
[32] 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胱移行细胞癌中表达的意义．中华泌尿外科杂志，2000，21(8)：465-466
[33] Brunner G, Reimbold K, M Eeissauer A, et al. Sulfated glycosaminoglycans enhance tumor cell invasion in vitro by stimulating plasminogen activation.Exp Cell Res, 1998, 239(2): 301-310
[34] 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
[35] 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
[36] 孙达春，刘文励．恶性肿瘤患者血液中尿激酶型纤溶酶原激活物系统测定的临床意义．临床内科杂志，2000，17(3)：157-158
[37] 陈卫昌，严辉，彭群新，等．胃癌患者血清uPA测定及临床意义．苏州医学院学报，2001，21(4)：440-442
[38] 汤文浩，李国强，王凤臣，等．食管癌组织中纤溶成份的表达及其意义．中华消化杂志，2000，20(2)：85-88
[39] Febreqa E, Casagont F, Merino J, et al. Value of plasma P-selectin for vascular complication in liver transplantation. Clin Transplat, 1996, 10 (2): 261-264
[40] 陈金联，吴云林．选择素与肿瘤转移机制．肿瘤，1996，16(1)：54-56
[41] Lip GY, Blann AD, Zarifis J, Beevers M, Lip PL, Beevers DG. Soluble adhesion molecule P-selectin and endothelial dysfunction in essential hypertension: implications for atherogenesis? A preliminary report. J Hypertens, 1995, 13(12 Pt 2): 1674-1678
[42] Pottratz ST, Hall TD, Scribner WM, et al. P-selectin-mediated attachment of small cell lung carcinoma to endothelial cells. Am J Physiol, 1996; 271 (6): 1918-1923.
[43] Silke A, Zev MS, Mina F, et al. CD_(24), a mucin-type glycoprotein, is a ligand for P-selectin of human tumor cells. Blood, 1997, 89(6): 3385-3395
[44] Mannori G, Crottet P, Cecconi O, et al. Differential colon cancer cell adhesion to E-, P-, and L-selectin: role ofmucin-type glycoprotein. Cancer Res, 1995, 55(19): 4425-4431
[45] 钱思源，王黎娜，刘惠喜．P-选择素在卵巢癌中表达的意义．武警医学，2001，12(9)：520-522
[46] 官成浓，徐军发，银正民．中晚期原发性肝癌患者血浆可溶性P-选择素的测定及临床意义．癌症，2000，19(3)：256-258
[47] 官成浓，银正民，徐军发，血浆可溶性P-选择素的临床意义．实用癌症杂志，2001，16(3)：295-296
[48] 徐军发，唐湘涓，官成浓，等。肺癌患者血浆P-选择素的检测及其临床意义．实用癌症杂志，2000，15(1)：49-50
[49] 刘剑勇，高月芳，覃宇周，等．乳腺癌患者手术前后血浆可溶性P-选择素的检测及意义．中国普外基础与临床杂志，2002，9(2)：121-121
[50] 徐西琳，李清泉，杨炯．P-选择素的表达与肺癌转移的关系。中华结核和呼吸杂志，2000，23(9)：573-573
[51] Schadendorf D, Heidel J, Gawlik C, et al.Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on inttratumoral Vessels. J Natl Cancer Inst, 1995, 87(4): 366-370
[52] 黄耀庭，马天乐．CD62P在结直肠癌患者组织及血浆中的表达．胃肠病学，2000，5(3)：161-163