uPA-uPAR系统在肿瘤评估与治疗中的研究进展

尿激酶型纤溶酶原激活剂-尿激酶型纤溶酶原激活剂受体(uPA-uPAR)系统是一种细胞外蛋白水解酶系统,该系统可激活纤溶酶,进而引发一系列蛋白水解级联反应,在肿瘤细胞的侵袭与转移中发挥重要作用。这为uPA-uPAR系统各组分成为多种恶性肿瘤的潜在预后生物标志物和治疗靶点提供了可能,本文主要介绍了近年来基于uPA-uPAR系统的恶性肿瘤诊断、治疗及预后评价策略。     

uPA、uPAR及PAI-1在结肠癌侵袭和转移中的作用及其相关性

目的：对尿激酶型纤溶酶原激活物（uPA）及其受体uPAR和血浆纤溶醇原激活物抑制因子PAI-1在结肠癌侵袭和转移中的作用及其相关性进行研究。方法：选择临床病理资料完整的结肠癌蜡块标本156例,正常结肠黏膜标本50例作对照。采用sP免疫组化方法检测uPA、uPAR及PAI-1在其中的表达。结果：uPA及uPAR在结肠癌组织中高表达,并随病理分级的降低、淋巴转移的产生、临床分期的提高而明显增高（P均〈0．05）。PAI-1在结肠癌组织中高表达,并随分级的降低、淋巴结转移的产生、临床分期的提高而明显增高（P均〈0．05）。结肠癌中uPA、uPAR及PAI-1的表达呈正相关（P〈0．01）。结论：uPA、uPAR及PAI-1对结肠癌的侵袭和转移起重要的促进作用并在结肠癌的侵袭和转移相互促进,相互协调,关系密切。uPA、uPAR及PAI-1各自都可以成为结肠癌诊断和预后估计的指标．并目有可能成为结肠痛基因治疗的新靶点。     

ELAM －1在肿瘤靶向治疗中的应用进展

E选择素（Endothelial leukocyte adhesion molecule －1,ELAM－1）是细胞黏附分子家族中的一类,研究表明,ELAM－1与其配体sLe（ x）和sLe（ a）的相互作用,在肿瘤远处转移的过程中扮演着重要的角色。近年来,将ELAM－1运用于肿瘤靶向治疗的研究,逐渐成为一个新的热点。众多研究成果表明,通过对ELAM－1生物学作用的调控,如ELAM－1及其配体抑制剂、单克隆抗体、靶向基因,以及其他介导等路径阻断疗法等,从而抑制或阻断肿瘤的远处转移,达到治疗肿瘤、改善预后的目的。因此,ELAM－1有望在肿瘤靶向治疗方面发挥重要作用。本文就ELAM－1在肿瘤相关靶向治疗中的应用价值做一综述。     

子宫内膜腺癌组织中尿激酶型纤溶酶原激活系统的表达及其临床意义

目的：研究尿激酶型纤溶酶原激活系统在子宫内膜腺癌的发生、发展及浸润转移中的规律及其对临床的指导意义。方法：应用免疫组织化学方法测定24例正常子宫内膜、30例子宫内膜增生过长及62例子宫内膜腺癌组中uPA、uPAR、PAI-1的表达,并分析与良恶性、临床分期、组织学分级、基层浸润深度及淋巴结转移的关系。结果：uPA、uPAR、PAI-1在子宫内膜腺癌组中的表达较正常子宫内膜组和子宫内膜增生过长组中的表达显著升高（P均〈0．05）,而正常子宫内膜组和子宫内膜增生过长组中的表达无显著性差异（P〉0．05）。uPA、uPAR、PAI-1的高表达与肿瘤分化、临床分期、肌层浸润深度和淋巴结转移有关（P〈0．05）。结论：uPA、uPAR、PAI-1的表达与子宫内膜腺癌的发生、发展及浸润转移密切相关,可作为判断预后的重要指标。     

子宫内膜腺癌组织中尿激酶型纤溶酶原激活系统的表达及其临床意

研究尿激酶型纤溶酶原激活系统在子宫内膜腺癌的发生、发展及浸润转移中的规律及其对临床的指导意义.应用免疫组织化学方法测定24例正常子宫内膜、30例子宫内膜增生过长及62例子宫内膜腺癌组中uPA、uPAR、PAI-1的表达,并分析与良恶性、临床分期、组织学分级、基层浸润深度及淋巴结转移的关系. uPA、uPAR、PAI-1在子宫内膜腺癌组中的表达较正常子宫内膜组和子宫内膜增生过长组中的表达显著升高（P均<0.05）,而正常子宫内膜组和子宫内膜增生过长组中的表达无显著性差异（P >0.05）.uPA、uPAR、PAI-1的高表达与肿瘤分化、临床分期、肌层浸润深度和淋巴结转移有关(P <0.05).uPA、uPAR、PAI-1的表达与子宫内膜腺癌的发生、发展及浸润转移密切相关,可作为判断预后的重要指标.     

靶向血管治疗肿瘤的研究进展

靶向血管治疗肿瘤已有３０年的历史,近１０年来有突飞猛进的发展。一、肿瘤区血管的发生及特点肿瘤的生长依赖血管供氧、营养及排泄废物,其发生和发展可分为两期：（１）无血管期：肿瘤细胞处于休眠状态;（２）有血管期：肿瘤细胞分裂生长。１－促使肿瘤由无血管期向有血管期转变的因素：（１）微环境的改变：缺氧,缺营养,ｐＨ变酸性,ＮＯ升高等。已证明缺氧可上调促血管内皮生长因子（ＶＥＧＦ）、血小板衍生生长因子（ＰＤＧＦ）、胰岛素样生长因子（ＩＧＦⅡ）及血管产生素受体（Ｔｉｅ）的表达。（２）基因的改变：有关的基因有…     

头颈部肿瘤靶向治疗的研究进展

近年来,放疗、化疗及手术联合治疗成为了头颈部鳞癌的主要治疗手段。然而,由放化疗带来的毒性作用不可避免地影响了治疗的依从性。分子靶向治疗作为一种新的生物治疗模式,在治疗头颈部肿瘤方面具有毒性作用小的特点,越来越受到关注。头颈部肿瘤的靶向治疗药物主要包括西妥昔单抗和贝伐单抗等,目前西妥昔单抗等靶向治疗药物已被FDA批准用于头颈部鳞癌的治疗。本文以西妥昔单抗和贝伐单抗为主,同时介绍一些正处于研究中的靶向治疗药物,探讨靶向药物在头颈部肿瘤治疗中的应用和进展。     

u-PA、PAI-1在肺癌中的表达及与淋巴结转移的相关关系

目的研究肺癌转移与u－PA，PAI－1的关系。方法对u－PA，PAI－1单克隆抗体，采用ABC法，对22例Ⅰ～Ⅲa期肺癌术前患者肿瘤中心，边缘，正常肺组织进行免疫组化染色。结果u－PA，PAI－1显色主要分布在肿瘤细胞的胞浆，胞膜，间质细胞，肌细胞，部分肺组织内的吞噬细胞，N0与N2两组相比，N2比N0高表达u－PA（P＜0，05），N2比N0低表达PAI-1（P＜0．01），即在LNM-者，其PAI-1高表达，u－PA低表达，LNA 者与LNM-者相比，其u－PA高表达，PAI－1低表达。结论说明基质降解酶U－PA及其抑制剂PAI－1在肺癌转移过程中起着重要的作用。     

血液系统肿瘤的抗体靶向治疗

靶向治疗因其对肿瘤细胞的特异性杀伤可以克服血液肿瘤传统治疗方式选择性差、毒性反应严重及耐药性等缺点,已成为近年来研究的热点.许多单克隆抗体已应用于临床,文章对血液肿瘤的抗体靶向治疗方式及其机制和进展做一综述.     

肿瘤靶向治疗现状和发展前景

近年来,随着分子生物学技术的提高,以及从细胞受体和增殖调控的分子水平对肿瘤发病机制的进一步认识,人们开始进行以细胞受体、关键基因和调控分子为靶点的治疗,亦称之为靶向治疗（targeted therapy）。     

子宫内膜腺癌组织中尿激酶型纤溶酶原激活系统的表达及其临床意义

目的:研究尿激酶型纤溶酶原激活系统在子宫内膜腺癌的发生、发展及浸润转移中的规律及其对临床的指导意义.方法:应用免疫组织化学方法测定24例正常子宫内膜、30例子宫内膜增生过长及62例子宫内膜腺癌组中uPA、uPAR、PAI-1的表达,并分析与良恶性、临床分期、组织学分级、基层浸润深度及淋巴结转移的关系.结果:uPA、uPAR、PAI-1在子宫内膜腺癌组中的表达较正常子宫内膜组和子宫内膜增生过长组中的表达显著升高(P均<0.05),而正常子宫内膜组和子宫内膜增生过长组中的表达无显著性差异(P>0.05).uPA、uPAR、PAI-1的高表达与肿瘤分化、临床分期、肌层浸润深度和淋巴结转移有关(P<0.05).结论:uPA、uPAR、PAI-1的表达与子宫内膜腺癌的发生、发展及浸润转移密切相关,可作为判断预后的重要指标.     

The urokinase-type plasminogen activator system in resected non-small-cell lung cancer

Background:Urokinase-type plasminogen activator (uPA), itsreceptor (uPAR) and plasminogen activator inhibitors (PAI-1 and PAI-2), allplay important roles in tumour invasion and metastasis. The tumour levels ofthe components of the urokinase-type plasminogen activator system (uPA-system)may help to identify individuals with a poor prognosis in postoperativenon-small-cell lung cancer (NSCLC) patients. Patients and methods:The levels of uPA, uPAR PAI-1 and PAI-2 weremeasured by enzyme-linked immunosorbent assay (ELISA) in triton-extracts,prepared from 88 NSCLC tissues (stage I–IIIa) and 74 normal lung tissuesfrom the same patients. Results:The expression levels of uPA, uPAR, PAI-1 and PAI-2 weresignificantly higher in tumour tissues as compared to their normal equivalents(all, P < 0.0001). Significant relations were found between genderand uPA (P = 0.04) or uPAR (P < 0.001), and between PAI-2and pathological stage (P = 0.03). For none of the studied factorsof the uPA-system a significant relation with survival was found, neither inall patients, nor in the subgroups of patients with squamous-cell lungcarcinoma or adenocarcinoma. Conclusions:The expression levels of the components of theuPA-system were higher in NSCLC tissue as compared to normal lung tissue, butthere were no significant relationships between their levels and survival.     

Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients

The plasma urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator receptor (uPAR) levels were measured in healthy volunteers and breast cancer patients. In pre-menopause healthy females, blood was sampled weekly during one menstruation cycle and menstruation phases (follicular, ovulatory, luteal) were determined by FSH/LH levels. uPA, PAI-1, and uPAR levels were at the nadir during ovulatory phase. uPA level was highest at follicular phase while PAI-1 level was highest at luteal phase. In comparison between pre- and post-menopause states, uPA and uPAR levels were higher in post-menopause state while PAI-1 level was higher in pre-menopause state. In breast cancer patients, uPA, PAI-1, and uPAR positive rates were low when we use the menopause-state-unmatched cut-off points. As we adjusted the cut-off points by menopause states, the PAI-1 positivity increased mainly in post-menopause cancer patients. These findings suggest that there is a minor but possible sequential change of these molecules during menstruation cycle which might blur the pathological positivity in pre-menopause cancer patients. The pathological elevation of PAI-1 was well detected in post-menopause cancer patients, but this elevation did not correlate with tumor burden such as number of metastatic sites or metastatic location. In conclusion, adjustment of physiological changes of uPA, PAI-1, and uPAR is required in determining pathological elevation of the plasma levels in cancer patients, especially in females.This revised version was published online in October 2005 with corrections to the Cover Date.     

Correlation of tissue and blood plasminogen activation system in breast cancer

The plasminogen activation system plays a crucial role during cancer invasion and metastasis. In the solid tumor, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and uPA receptor (uPAR) are considered as prognostic factors. In this study, we have investigated whether secretion of the uPA, PAI-1 and uPAR from the primary breast cancer tissue can be detected in the blood of the patients using the ELISA assay. We have found that the plasminogen activation system (uPA, PAI-1, uPAR) of tumor tissue is activated from the early stage of breast cancer. However, only a number of metastatic lymph nodes was a prognostic factor in multivariate analysis for relapse. The blood level of the plasminogen activation system correlated with that of tissue in an order of uPAR (r²=0.61; P=0.001), uPA (r²=0.35; P=0.001) and PAI-1 (r²=0.11; P=0.001). We conclude that the total uPAR level of cancer tissue can be substituted by that which is detected in the blood for further clinical applications.     

血浆uPA、PAI-1浓度与食管鳞状细胞癌临床病理因素的相关性

目的:探讨血浆尿激酶型纤溶酶原激活物(urokinase-type plasminogen activator,uPA)、纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor type-1,PAI-1)浓度作为食管鳞状细胞癌预后指标的可能性。方法:收集20例健康人、54例食管鳞状细胞癌患者(手术前、后)及14例术后复发转移患者血浆标本,采用ELISA法测定其血浆uPA、PAI-1浓度,并分析血浆uPA、PAI-1浓度与食管鳞状细胞癌患者临床病理特征的关系。结果:健康人群血浆uPA、PAI-1浓度显著低于食管鳞状细胞癌患者手术前及手术后血浆uPA、PAI-1浓度(P<0.05)。食管鳞状细胞癌患者手术前血浆uPA、PAI-1浓度显著高于术后血浆uPA、PAI-1浓度(P<0.05),显著低于术后复发转移患者血浆uPA、PAI-1浓度(P<0.05)。食管鳞状细胞癌患者血浆uPA、PAI-1浓度与年龄、性别无关,不同性别及年龄组间差异无显著性(P>0.05)。与临床分期有关,临床分期越晚,浓度越高(P<0.05)。与组织分化程度有关,分化程度越低,浓度越高(P<0.05)。与有无淋巴结转移有关,有淋巴结转移组显著高于无淋巴结转移组(P<0.05)。结论:uPA、PAI-1在食管鳞状细胞癌进展过程中发挥重要作用,血浆浓度可作为食管鳞状细胞癌的预后判断指标,浓度升高提示预后不良。     

uPA、PAI-1在食管癌发生、发展不同阶段的表达及意义

目的:探讨尿激酶型纤溶酶原激活物(uPA)、纤溶酶原激活物抑制剂-1(PAI-1)在食管癌发生、发展中的作用及意义。方法:采用免疫组织化学SP法检测正常食管黏膜上皮组织(18例)、食管黏膜上皮不典型增生组织(23例)及食管癌组织(68例)中uPA、PAI-1蛋白的表达,并分析其和食管癌临床病理特征的关系。结果:uPA蛋白在正常食管黏膜上皮组织、食管黏膜上皮不典型增生组织及食管癌组织中的阳性率分别为27.8%、39.1%、70.6%,三者间有显著性差异(P<0.05);PAI-1蛋白在正常食管黏膜上皮组织、食管黏膜上皮不典型增生组织及食管癌组织中的阳性率分别为22.2%、34.8%、64.7%,三者间有显著性差异(P<0.05)。uPA、PAI-1蛋白表达与年龄、性别、病理类型无关(P>0.05),在临床病理Ⅰ-Ⅱ期和Ⅲ-Ⅳ期间有升高的趋势,但差异无统计学意义(P>0.05),与分化程度和淋巴结有无转移有关(P<0.05)。结论:uPA、PAI-1蛋白在食管癌发生、发展不同阶段的表达呈进行性上升的趋势,可能与食管癌的发生、发展相关,过度表达提示预后不良。     

uPA系统对乳腺癌的影响及在预后与治疗方面的研究进展

恶性肿瘤的侵袭及转移需要细胞外基质的降解,涉及到很多蛋白水解酶类,其中包括尿激酶型纤溶酶原激活物(uPA)系统.uPA系统不仅促进肿瘤的侵袭及转移,还参与癌细胞增殖与肿瘤血管形成.本文对uPA系统在乳腺癌中的作用,临床预后价值,以及目前靶向治疗的最新进展作一综述.     

原发性肝癌介入治疗对尿激酶型纤溶酶原激活剂及其受体表达的影响

  目的 探索原发性肝癌介入治疗前后尿激酶型纤溶酶原激活剂（urokinase plasminogen activator, uPA）及其受体（urokinase plasminogen activator receptor, uPAR）表达的变化，分析uPA及uPAR在人类原发性肝癌发生发展中的作用，并为uPA及uPAR表达水平对介入治疗原发性肝癌的效果评价价值提供可靠的理论依据。方法 对48例已确诊的原发性肝癌患者在介入治疗前后分别取静脉血、癌组织和肝正常区组织标本，应用ELISA、RT-PCR方法，分别检测介入治疗前后uPA／uPAR在血清、肝癌组织与正常肝组织中的表达变化。结果 介入治疗前uPA／uPAR 在血清内的表达量明显高于对照组，两组间的差异有统计学意义（P＜0.01）；肝癌组织中uPA／uPAR mRNA明显高于正常区肝组织，两组间的差异有统计学意义（P＜0.01），且介入治疗后肝癌组织中uPA／uPAR mRNA的表达量较治疗前明显降低，两组间的差异有统计学意义（P＜0.05），但未降至正常。结论 uPA／uPAR 的过量表达与原发性肝癌的发生有关，uPA／uPAR的mRNA表达水平对介入治疗原发性肝癌的效果评价有一定的参考价值。     

Evolving role of uPA/uPAR system in human cancers

Recent advancements in cancer research have led to some major breakthroughs; however, the impact on overall cancer-related death rate remains unacceptable, suggesting that further insight into tumor markers and development of targeted therapies is urgently needed. The urokinase plasminogen activator (uPA) system represents a family of serine proteases that are involved in the degradation of basement membrane and the extracellular matrix, leading to tumor cell invasion and metastasis. In this review, we have provided an overview of emerging data, from basic research as well as clinical studies, highlighting the evolving role of uPA/uPAR system in tumor progression. It is currently believed that the expression and activation of uPA plays an important role in tumorigenicity, and high endogenous levels of uPA and uPAR are associated with advanced metastatic cancers. The endogenous inhibitors of this system, PAI-1 and PAI-2, regulate uPA-uPAR activity by either direct inhibition or affecting cell surface expression and internalization. PAI-1's role in cancers is rather unusual; on one hand, it inhibits uPA-uPAR leading to inhibition of invasion and metastasis and on the other it has been reported to facilitate tumor growth and angiogenesis. Individual components of uPA/uPAR system are reported to be differentially expressed in cancer tissues compared to normal tissues and, thus, have the potential to be developed as prognostic and/or therapeutic targets. Therefore, this system represents a highly attractive target that warrants further in-depth studies. Such studies are likely to contribute towards the development of molecularly-driven targeted therapies in the near future.