【作者】 刘芳；

【导师】 张云汉； 陈奎生；

【作者基本信息】 郑州大学 ， 病理学与病理生理学， 2004， 硕士

【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。更多还原

【Abstract】 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 researchsubject 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更多还原