细胞外基质金属蛋白酶诱导因子与妇科肿瘤

细胞外基质金属蛋白酶诱导因子（EMMPRIN）又称CDl47，广泛地存在于人类各种肿瘤细胞，刺激与肿瘤有关的成纤维细胞和肿瘤细胞自身的基质金属蛋白酶合成增加，在恶性肿瘤的发生、浸润和转移中起重要作用。近年来其在肿瘤的早期发生和浸润及肿瘤抗药性方面的作用已受到重视。EMMPRIN与妇科肿瘤的发展关系密切，现就其与妇科肿瘤的关系及其结构和功能作一综述。     

细胞外基质金属蛋白酶诱导因子对细胞滋养细胞分泌基质金属蛋白酶的调节

胎盘植入和胎盘形成过程中，滋养细胞向母体子宫内膜有节制的浸润是细胞外基质降解和重建的关键步骤，基质金属蛋白酶（matrix metalloproteinases，MMP）在这一过程中发挥重要作用。细胞外基质金属蛋白酶诱导因子（extracellular matrix metalloproteinase inducer，EMMPRIN）是免疫球蛋白超家族的成员之一，能刺激与肿瘤有关的成纤维细胞和肿瘤细胞自身的MMP显著增加。最新的研究发现，在足月妊娠妇女的胎盘和胎膜组织中有高水平的EMMPRIN表达，推测与维持妊娠和发动分娩有关。作为MMP的上调因子EMMPRIN，在妊娠早期胎盘绒毛组织中的表达未见报道。本研究采用高纯度的原代细胞滋养细胞体外培养模型，探讨EMMPRIN在胎盘绒毛组织中的表达变化及其对细胞滋养细胞分泌MMP的调节作用。     

基质金属蛋白酶及其组织抑制物与妇科肿瘤的侵袭和转移

细胞外基质的降解是肿瘤侵袭、转移的重要信号和途径，基质金属蛋白酶（MMPs)是溶解基质的一组重要酶类，金属蛋白酶组织抑制物（TIMPs)是MMPs的特异性抑制物。两者的表达、代谢平衡调节与宫颈癌、卵巢癌、子宫内膜癌浸润转移、生理病理和临床预后有密切关系。MMPs-TIMPs调节失衡、细胞外基质降解，以及基底膜消失，均可促进妇科恶性肿瘤发生浸润转移。MMPs、TIMPs表达量的检测可作为早期诊断、监测妇科恶性肿瘤的理想标志物，并可针对其平衡采取相应的肿瘤治疗措施。     

细胞外基质金属蛋白酶诱导因子、基质金属蛋白酶9及P38丝裂原活化蛋白激酶在子宫内膜异位症中的表达及相关性

目的探讨细胞外基质金属蛋白酶诱导因子(extracellular matrix metalloproteinase inducer,EMMPRIN)、基质金属蛋白酶9(matrix metalloproteinases-9,MMP-9)和P38丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)在子宫内膜异位症(endometriosis,EMs)中的表达及相关性。方法收集2008年5-12月重庆医科大学附属第一医院收治的EMs患者44例(异位内膜44例,在位内膜38例),对照组为同期非EMs患者在位内膜34例。应用免疫组化SABC三步法检测各组织中EMMPRIN、MMP-9、P38及磷酸化P385(p-P38)蛋白的表达,并对各蛋白表达水平进行相关性分析。结果 EMMPRIN、MMP-9、P38、p-P38蛋白在EMs异位内膜表达均高于EMs在位内膜组及对照组在位内膜,差异有统计学意义(P<0.05);Spearman相关分析显示,在EMs异位内膜中各蛋白表达呈正相关(P<0.05)。在EMs异位内膜组中各蛋白表达Ⅲ～Ⅳ期高于Ⅰ～Ⅱ期,差异均有统计学意义(P<0....     

基质金属蛋白酶与宫颈癌

基底膜(BM)、细胞外基质(ECM)的降解是肿瘤侵蚀正常组织和开始转移的信号.基质金属蛋白酶(MMPs)是人体内一组降解ECM的关键酶系,通过探讨MMPs在肿瘤演进中的功能和相互调控及对MMPs与宫颈癌的相关研究,提出检测MMPs将成为宫颈癌预防、早期诊断、判断预后和寻找早期终止疾病方法的新指针.     

基质金属蛋白酶及其组织抑制物与妇科肿瘤的侵袭和转移

细胞外基质的降解是肿瘤侵袭、转移的重要信号和途径,基质金属蛋白酶(MMPs)是溶解基质的一组重要酶类,金属蛋白酶组织抑制物(TIMPs)是MMPs的特异性抑制物.两者的表达、代谢平衡调节与宫颈癌、卵巢癌、子宫内膜癌浸润转移、生理病理和临床预后有密切关系.MMPs-TIMPs调节失衡、细胞外基质降解,以及基底膜消失,均可促进妇科恶性肿瘤发生浸润转移.MMPs、TIMPs表达量的检测可作为早期诊断、监测妇科恶性肿瘤的理想标志物,并可针对其平衡采取相应的肿瘤治疗措施.     

基质金属蛋白酶与宫颈癌

基底膜(BM)、细胞外基质(ECM)的降解是肿瘤侵蚀正常组织和开始转移的信号。基质金属蛋白酶(MMPs)是人体内一组降解ECM的关键酶系，通过探讨MMPs在肿瘤演进中的功能和相互调控及对MMPs与宫颈癌的相关研究，提出检测MMPs将成为宫颈癌预防、早期诊断、判断预后和寻找早期终止疾病方法的新指针。     

基质金属蛋白酶在卵巢癌侵袭转移中的研究进展

侵袭和转移是卵巢癌患者死亡的直接原因,基质金属蛋白酶（MMPs）通过降解细胞外基质（ECM）在卵巢癌侵袭转移中发挥重要作用,深入研究MMPs降解ECM的机制,选择针对MMPs的抑制物来治疗卵巢癌转移是一个很有希望的目标。     

细胞外基质金属蛋白酶诱导因子在绒毛和胎盘组织中的表达

目的 探讨细胞外基质金属蛋白酶诱导因子(EMMPRIN)在绒毛及胎盘组织中的表达以及表达部位。方法 分别取36例妊娠6～9周妇女的早孕绒毛组织、7例因病理指征行中期引产妇女的胎盘组织和11例足月妊娠妇女的胎盘组织,免疫组化方法检测绒毛组织和胎盘组织中EMMPRIN的表达部位变化特点。结果 (1)表达部位：EMMPRIN在早孕绒毛组织、中期和足月妊娠的胎盘组织中均有高度表达。在早孕绒毛组织中的表达部位主要集中在绒毛内细胞滋养细胞、合体滋养细胞及细胞滋养层柱细胞;在中期和足月妊娠的胎盘组织中,主要表达于底蜕膜的绒毛外细胞滋养细胞。(2)表达特点：在早孕绒毛组织中细胞滋养细胞、合体滋养细胞和细胞滋养层柱细胞的。EMMPRIN阳性率随妊娠进展逐渐下降。在妊娠中期的胎盘组织中,细胞滋养细胞、合体滋养细胞和细胞滋养层柱细胞的EMMPRIN阳性率分别为5／7、3／7、5／7;在足月妊娠的胎盘组织中,细胞滋养细胞、合体滋养细胞和细胞滋养层柱细胞的EMMPRIN阳性率分别为73％、18％和82％。在中期和足月妊娠的底蜕膜中的EMMPRIN阳性率较弱,且趋于稳定。而早期妊娠阶段,侵入到底蜕膜的绒毛外细胞滋养细胞中。EMMPRIN阳性表达则随孕周进展逐渐增强。结论 EMMPRIN在妊娠早期与胚胎植入有关,在妊娠的中晚期则可能参与妊娠维持。     

基质金属蛋白酶与早产的关系

由于早产机制未完全阐明,故早产发生率及早产儿发病率和死亡率一直无明显下降,感染和胎膜早破是早产的主要原因,近来研究认为感染和胎膜早破引起的早产和妊娠妇女体内基质金属蛋白酶(MMPs)的含量变化有关,这两种情况引起的早产发生前,母体血、尿及羊水中的MMPs含量将升高,从而降解妊娠组织的细胞外基质(ECM),引起胎膜破裂及宫颈成熟扩张,而导致早产,且测定妊娠妇女体内MMPs的含量变化可进行早产预测以及应用其抑制剂在动物实验中可降低早产的发生率.     

The role of matrix metalloproteinases in tumor invasion and metastasis

The complicated process of invasion and metastasis consists of a long series of sequential and interrelated steps. The outcome of the process is dependent on both: the tumour cells and the properties of tissue microenvironments. Many investigators are interested in the influence of extracellular matrix components on that process. Especially matrix metalloproteinases (MMPs)--family of zinc-dependent enzymes, which take part in the coordination of extracellular matrix synthesis and breakdown seems to play crucial role in this process. A positive correlation between different type of MMPs and specific tumors has been demonstrated in many studies. In this article we summarize the current views on the role of MMPs in cancer invasion and metastasis.     

Functional role of matrix metalloproteinases in ovarian tumor cell plasticity

OBJECTIVE: We previously demonstrated that aggressive ovarian cancer cells are able to display in vitro vasculogenic mimicry, which is reflected by their ability to form vasculogenic-like networks in 3-dimensional cultures and to express vascular cell-associated markers. The goal of this study was to examine the functional role of specific matrix metalloproteinases in the formation of vasculogenic-like networks and extracellular matrix remodeling in vitro. We also investigated the clinical relevance of matrix metalloproteinase-2 and -9 and membrane type 1-matrix metalloproteinase in human ovarian cancers with evidence of tumor cell-lined vasculature. STUDY DESIGN: Ovarian cancer cells (A2780-PAR, SKOV3, and EG) were seeded onto separate 3-dimensional cultures that contained either Matrigel or type I collagen, in the absence of endothelial cells or fibroblasts. These cultures were treated with either chemically modified tetracycline-3 (general matrix metalloproteinase inhibitor), recombinant tissue inhibitor of metalloproteinase-1 or -2, or function-blocking antibodies to matrix metalloproteinase-2 or -9 or membrane type 1-matrix metalloproteinase. In addition, 78 invasive epithelial ovarian cancers were evaluated for expression of matrix metalloproteinase-2 and -9 and membrane type 1-matrix metalloproteinase and correlated with various clinical parameters. RESULTS: The aggressive ovarian cancer cells (SKOV3 and EG) were able to form in vitro vasculogenic-like networks and contract 3-dimensional collagen I gels, whereas the poorly aggressive A2780-PAR cell line did not. Chemically modified tetracycline-3 completely blocked the network formation. Blocking antibodies to matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase inhibited the formation of the vasculogenic-like networks and collagen gel contraction, but the antibody to matrix metalloproteinase-9 had no effect on network formation and minimal effect on gel contraction. Treatment of 3-dimensional cultures with tissue inhibitor of metalloproteinase-2 retarded the network formation and only small, partially developed structures were noted that did not form network connections. Tissue inhibitor of metalloproteinase-1 had no appreciable effect on the extent or efficiency of network formation. Human invasive ovarian cancers with evidence of tumor cell-lined vasculature were significantly more likely to have strong epithelial and stromal matrix metalloproteinase-2 and -9 and membrane type 1-matrix metalloproteinase expression (all probability values were <.05). CONCLUSION: Matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase appear to play a key role in the development of vasculogenic-like networks and matrix remodeling by aggressive ovarian cancer cells. Human ovarian cancers with matrix metalloproteinase overexpression are more likely to have tumor cell-lined vasculature. These results may offer new insights for consideration in ovarian cancer treatment strategies.     

Regulation of matrix metalloproteinases (MMPS) and their inhibitors (TIMPS) during mouse peri-implantation: role of nitric oxide

Nitric oxide (NO) is believed to play pivotal roles in embryo implantation. The purpose of this study was to investigate the effect of NO on matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), as well as the mechanism of NO during mouse implantation. Nitric oxide synthase (NOS) inhibitor, L-NAME was administered with or without sodium nitroprusside (SNP), NO donor, into one uterine horn on day 3 of pregnancy, and the contralateral uterine horn served as the control. We collected the uteri on days 5, 6, and 7 of pregnancy and examined the mRNA expression of MMP-2, -9, and TIMP-1, -2, -3, as well as the activities of MMP-2 and -9 by using in situ hybridization and gelatin zymography, respectively. The results showed that, compared with the control, the expression of MMP-2 and -9 mRNAs was decreased in L-NAME-treated uteri during peri-implantation. Treatment of mice with L-NAME had slight effect on the expression of TIMP-1 mRNA on day 5 of pregnancy, and no effect on TIMP-2 mRNA expression during peri-implantation. However, the expression of TIMP-3 mRNA was increased. The gelatin zymography results indicated that the activity of MMP-9 was decreased during peri-implantation, but the activity of MMP-2 did not change significantly in these time points examined. The L-NAME-mediated effect on MMPs and TIMPs were significantly reversed when SNP was co-administered with L-NAME. These data suggest that inhibition of NO production regulates the gene expression of MMP-2, -9, and TIMP-3, together with the activity of MMP-9 during peri-implantation, which may have serious consequence on embryo implantation.     

妇科肿瘤标志物及其应用

1　肿瘤标志物的概念肿瘤标志物 (ｔｕｍｏｒｍａｒｋｅｒ)是由肿瘤组织产生 ,或与肿瘤相关的物质 ,可从体液 ,主要是血液、尿液或其它分泌物中检测 ,与正常情况或无肿瘤状态有明显之分别。实际上 ,我们尚难给“肿瘤标志物”下一个完整的定义 ,因为科学在不断发展。从广义上 ,可以认为肿瘤标志物意味着负瘤机体的任何确定的变化 ;但在肿瘤中 ,并不是细胞成分 (细胞膜、细胞质和细胞核 )在结构、生物化学或其他都会发生某种变化。“ｔｕｍｏｒｍａｒｋｅｒ”有译标志物及标记物者 ,似以用肿瘤标志物为好 ,因为它不仅仅是个“ｌａｂｅｌｌｅｄ…     

Screening of novel matrix metalloproteinases (MMPs) in human fetal membranes

Objective : Endogenous activation of matrix metalloproteinase (MMP) in human fetal membranes is hypothesized to contribute to membrane weakening leading to early rupture and is also involved in the initiation of labor. Our laboratory and several others have studied the source and action of some of these MMPs. The objective of this study is to document the expression pattern of most of the MMPs cloned and sequenced so far in amniochorion during preterm premature rupture of membranes (pPROM), at term not in labor and during term labor. Materials and Methods : Placentas were collected from women with PROM, term not in labor after C-sections and from women after term vaginal delivery. Membranes were separated from the placenta and a section away from the rupture site was selected. Amniochorion were separated from the placenta. RT-PCR was performed to study the expression pattern of MMP15 (MT2-MMP), MMP16 (MT3-MMP), MMP17 (MT4-MMP), MMP18, MMP20, MMP23, MMP24 (MT5-MMP), MMP25 (MT6-MMP), and MMP 26 using specific primers. Results : A differential pattern of expression was noted for some of the novel MMPs screened in this study in human fetal membranes. mRNA for most of the MMPs were expressed by amniochorion. MMP16 [membrane type metalloproteinase 3], MMP20 [enamelysin], and MMP26 [matrilysin] were not expressed. Conclusion : Amniochorion expresses several of the MMP genes at the time of pPROM, term not in labor and during active labor. We have previously reported the expression pattern of other MMPs and their inhibitors and their potential role in PROM. These findings support our hypothesis that amniochorion has a fully functional MMP system.     

孕产妇血清中MMP-3、TNF-α、IL-10的表达与早产和早产胎膜早破的关系

目的探讨基质金属蛋白酶-3（MMP-3）、肿瘤坏死因子-α（TNF-α）、白细胞介素-10（lL-10）在孕产妇血清中的表达与早产、胎膜早破的关系。方法选择单胎头位初产妇80例作为研究对象,按孕周、胎膜是否破裂和产妇是否临产分为早产临产组（sPTD）、早产胎膜早破组（PPROM）、先兆早产组（TPL）和妊娠28～36＋6周无产兆组（对照组）,每组各20例。用ELISA法检测孕妇血清中MMP-3及TNF-α、lL-10的水平。结果①早产临产组、早产胎膜早破组、先兆早产组和对照组血清中MMP-3的浓度分别为（242.25±72.40）ng/ml、（225.95±85.43）ng/ml、（197.85±57.08）ng/ml、（186.80±54.33）ng/ml;TNF-α的浓度分别为（1332.35±346.65）pg/ml、（1365.00±211.80）pg/ml、（1188.15±269.43）pg/ml、（1061.85±210.02）pg/ml;IL-10的浓度分别为（563.65±116.50）pg/ml、（566.80±123.03）pg/ml、（521.00±105.14）pg/ml、（483.50±119.17）pg/ml;②早产组血清中MMP-3,TNF-α浓度高于对照组,以TNF-α升高更明显（P〈0.01）;而IL-10在前两组中有增高趋势,但与后两组相比差异无统计学意义（P〉0.05）;③血清中MMP-3、TNF-α、IL-10浓度呈两两正相关。结论①孕产妇血清中MMP-3及TNF-α浓度与早产、胎膜早破密切相关;②孕产妇血清中MMP-3、TNF-α及IL-10在临产、胎膜早破中可能起协同作用。     

Extracellular matrix components of the wall of umbilical cord vein and their alterations in pre-eclampsia

Pre-eclampsia--edema, proteinuria, hypertension (EPH-gestosis) is one of the more common complications observed during pregnancy. The umbilical cord vein walls were taken from newborns delivered by healthy mothers (control material) and by mothers with polysymptomatic pre-eclampsia (investigated material). Normal saphenous vein walls were collected from adult subjects undergoing varicose vein surgery. The collagen content was measured by the assay of hydroxyproline. Elastin was determined according to Fastin Elastin Assay and gravimetrically. Glycosaminoglycans content was determined by uronic acids assay. The collagen content decreased in the pre-eclampsia material. The amount of soluble elastin increased in the investigated material. The insoluble elastin content decreased in the umbilical cord veins of newborns delivered by mothers with pre-eclampsia. Reconstructing the umbilical cord vein wall may disturb fetal blood flow and affect the vascular system in adulthood.