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Matrix metalloproteinases and carcinogenesis   总被引:3,自引:0,他引:3  
Rodgers W 《Human pathology》1999,30(4):363-364
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Matrix metalloproteinases in tumour invasion and metastasis.   总被引:47,自引:0,他引:47  
The matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes, which are involved in the degradation of many different components of the extracellular matrix. The MMPs have been classified into different groups including collagenases, gelatinases, stromelysins, and others, particularly membrane-type MMPs, based mainly on the in vitro substrate specificity of individual MMPs. There is increasing evidence to indicate that individual MMPs have important roles in tumour invasion and metastasis. However, the current concept of the role of MMPs in tumour invasion is that they not only have a direct role in tumour invasion by facilitating extracellular matrix degradation, but as a consequence they also have an important role in maintaining the tumour micro-environment and thus promoting tumour growth. Inhibiting the action of MMPs represents a new therapeutic approach for the treatment of individual types of cancer and several broad-spectrum, low-molecular-weight MMP inhibitors are currently being assessed for clinical use. This review examines the role of MMPs in tumour invasion and metastasis, with an emphasis on studies of clinical relevance.  相似文献   

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背景:椎间盘细胞外基质的破坏是椎间盘退变的主要标志,已经证实这与主要基质金属蛋白酶的表达和活性上调有关。然而到目前为止对于基质金属蛋白酶家族的调节几乎没有系统的资料。 目的:全面了解基质金属蛋白酶在椎间盘退变中的表达及作用。 方法:由第一作者用计算机检索中国生物医学全文数据库(SinoMed:2000/2011)和Medline数据库(2000/2011),检索词分别为“基质金属蛋白酶,基质金属蛋白酶组织抑制因子,椎间盘,退行性变,脊柱”和“matrix metalloproteinases,tissue inhibitor of matrix metalloproteinases,disc,degeneration,intervertebral”。共检索到207篇文章,按纳入和排除标准对文献进行筛选,共纳入31篇文章。回顾收录的基质金属蛋白酶相关综述和论文报告,并分析生物学作用及调节的研究进展。 结果与结论:基质金属蛋白酶在椎间盘退变中起着重要作用,已有证据表明基质金属蛋白酶能加速椎间盘细胞外基质的退变进程,并已取得了大量免疫组化证据的支持。  相似文献   

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Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are major regulators of tissue remodelling of the extracellular matrix (ECM) and may also be involved in the control of growth factor availability. We have investigated their production and localization in the developing human gonad during mid-gestation using zymographic techniques and immunohistochemistry. The secretion of MMP-2, MMP-9 and all four TIMP was demonstrated from both testis and ovary, with the predominant gelatinase produced by both being MMP-2. In the testis, MMP-1, MMP-2, MMP-9 and all TIMP family members were localized to the interstitium and to varying degrees within the tubules. MMP-9 and TIMP-4 were abundant in both Sertoli cells and gonocytes and MMP-1 and TIMP-1 were localized in particular to Sertoli cells. In the ovary, all TIMP and MMP-1, MMP-2 and MMP-9 were localized to the oogonium/oocyte cytoplasm with varying intensities and MMP-1, TIMP-2 and TIMP-3 were also detected in the ovarian stroma. This study demonstrates that MMP-1, MMP-2, MMP-9 and all TIMP family members are secreted by the developing ovary and testis and are localized to specific cell and tissue sites. MMP and TIMP are likely to play a role in ECM remodelling during gonadal development and also in the cell and matrix interactions that control a range of cellular functions.  相似文献   

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Matrix metalloproteinases (MMPs) are thought to participate in the pathogenesis of coronary artery disease (CAD), particularly in the occurrence of acute coronary syndrome (ACS). Little is known about human in vivo MMP regulation in CAD. The expression and regulation of MMPs and their tissue inhibitors (TIMPs) were evaluated in premature CAD. The distribution of MMP-3 5A/6A and MMP-9 C/T promoter polymorphisms and MMP-9 A/G exon-6 polymorphism were investigated in 200 consecutive male premature CAD patients (aged < or = 55 years) and 201 age-matched male blood donors. Plasma concentrations/activities of MMP-2 and MMP-9 were also measured, as were plasma concentrations of MMP-3, TIMP-1, and TIMP-2 in 80 patients (49 with ACSs and 31 with stable CAD) and 40 controls. Inflammation markers were also obtained. MMP genetic polymorphism distributions did not vary between patients and controls and did not seem to influence their respective MMP plasma levels. Patients showed increased MMP-9 and TIMP-1 concentrations and decreased TIMP-2 concentration and MMP-2 total activity (all P < or = 0.002). Overall, TIMP-1 correlated with C-reactive protein (CPR) (r = 0.594, P < 0.001) and haptoglobin (r = 0.276, P = 0.005), whereas MMP-2 activity correlated inversely with haptoglobin (r = -0.195, P = 0.032). Blood glucose correlated positively with TIMP-1 concentration (r = 0.711, P < 0.001) and negatively with MMP-2 activity (r = -0.250, P = 0.006). In conclusion, MMP and TIMP plasma levels in premature CAD are linked to clinical presentation and markers of inflammation and metabolic disorders rather than to genetic polymorphisms.  相似文献   

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The timely breakdown of the extracellular matrix (ECM) is essential in many physiological and biological processes. The matrix-degradation process involves tissue remodeling and immune/inflammatory reactions that occur in the stroma. Thus, the proteolytic and destructive potential of the matrix metalloproteinase (MMP) family is a major concern in several pathological conditions involving ECM degradation. This review details the structures and functions of MMPs and presents an overview of the interaction of MMPs with components of the immune system.  相似文献   

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Matrix metalloproteinases (MMPs) are enzymes with metal ion-dependent activity that degrade extracellular matrix (ECM) glycoproteins. MMPs play a vital role in various biological processes, such as embryogenesis, tissue remodeling, angiogenesis, and wound healing, and in certain disease processes, for example, metastasis of cancer cells. Following their activation, MMPs are believed to modulate both cell-cell and cell-matrix interactions, which in turn regulate cellular differentiation, migration, proliferation, and cell survival. Being involved in pericellular proteolysis, they maintain a gradient of ECM proteins by balancing ECM synthesis and degradation. Such a balance is critical for various mammalian developmental processes during embryonic life and also for the homeostasis of various organs and reparative processes in later life. During the past two decades the role of MMPs in the morphogenesis of various organs, including that of the metanephros, has been investigated extensively. Mammalian nephrogenesis comprises a series of intricate events characterized by a sustained remodeling and turnover of ECM, suggesting a potential role of MMPs in renal development. Conceivably, reciprocal inductive epithelial-mesenchymal interactions that take place at the very commencement of nephrogenesis are modulated by a number of ECM proteins. Their expression, especially at the epithelial-mesenchymal interface, are critical for metanephric development, and such a strategic expression is likely to be modified by a number of different macromolecules that exhibit spatiotemporal and stage-specific expression. Among them the most suitable candidate that could exert such a control would be MMPs. This review addresses the current status of our understanding of the functions and the role of MMPs in renal development.  相似文献   

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基质金属蛋白酶与肿瘤侵袭和转移   总被引:39,自引:0,他引:39  
Gao Q  Wu B 《中华病理学杂志》1998,27(2):155-156
基质金属蛋白酶与肿瘤侵袭和转移高庆吴秉铨从原位的增殖性肿瘤到侵袭转移癌的演进过程中,肿瘤细胞必须具备降解细胞外基质的能力。细胞外基质的降解主要依靠蛋白水解酶。基质金属蛋白酶(matrixmetaloproteinase,MMP)是四类蛋白水解酶:丝氨...  相似文献   

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Metalloproteinases and their inhibitors are known to play an important role in the extracellular matrix remodeling associated with preinvasive lesions and invasive carcinomas; however, little is known about their role in early lung carcinoma. Immunohistochemical studies were made of the reactivity of bronchial squamous preneoplastic lesions from cigarette smokers, including basal cell hyperplasia, squamous metaplasia, dysplasia, carcinoma in situ, and invasive squamous cell carcinoma for matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), and type IV collagen in 13 patients. Staining for type IV collagen disclosed discontinuities in basement membranes from basal cell hyperplasia to dysplasia, progressing to destruction in carcinoma in situ and invasive carcinoma. Reactivity for MMP-9 was mild in basal cell hyperplasia and squamous metaplasia, increasing in carcinoma in situ and invasive carcinoma. In contrast, reactivity for MMP-1 was strong in basal cell hyperplasia and squamous metaplasia, decreasing in carcinoma in situ and invasive carcinoma. Some neoplastic cells in carcinoma in situ and invasive carcinoma were MMP-3 positive. Staining for MMP-2 and TIMP-1 was moderate to strong in all squamous preinvasive lesions. Confocal microscopy showed MMP-9-positive cells passing through fragmented basement membranes in which type IV collagen and MMP-9 were colocalized. Type IV collagen colocalized with MMP-2 in all lesions and with TIMP-1 in basal cell hyperplasia and squamous metaplasia. The inverse relationships between the reactivity for MMP-1 and MMP-9 with progression of bronchial squamous preinvasive lesions suggest important roles for these MMPs in basement membrane remodeling in these lesions.  相似文献   

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T. TOMITA 《Histopathology》1996,31(2):150-156
Aims : Hyperplastic C-cells of the thyroid and medullary thyroid carcinomas (MTCs) were studied immunocytochemically for calcitonin, carcinoembryonic antigen (CEA), chromogranin A, matrix metalloproteinase (MMP)-2 and -9, and tissue inhibitor of metalloproteinase (TIMP)-1 and -2. Methods and results : Non-neoplastic C-cells were positive for all these substances whereas MTC tumour cells were relatively weaker stained, and thyroid follicular cells were negative for all the substances studied. We have recently reported that pancreatic islet cells and islet cell tumours were positive for MMPs and TIMPs, and, in addition, anterior pituitary cells and pituitary adenomas and parathyroid gland and its adenomas were also positively stained. The MMP- and TIMP-positive endocrine cells correspond to Pearse's APUD cells, derived from neural crest and endodermal cells. Conclusions : MMPs and TIMPs may well be added as newly recognized markers for neuroendocrine cells. The possible function of MMP-TIMP homeostasis in C-cells and MTCs is discussed.  相似文献   

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T. TOMITA 《Histopathology》1997,31(2):150-156
Aims: Hyperplastic C-cells of the thyroid and medullary thyroid carcinomas (MTCs) were studied immunocytochemically for calcitonin, carcinoembryonic antigen (CEA), chromogranin A, matrix metalloproteinase (MMP)-2 and -9, and tissue inhibitor of metalloproteinase (TIMP)-1 and -2. Methods and results: Non-neoplastic C-cells were positive for all these substances whereas MTC tumour cells were relatively weaker stained, and thyroid follicular cells were negative for all the substances studied. We have recently reported that pancreatic islet cells and islet cell tumours were positive for MMPs and TIMPs, and, in addition, anterior pituitary cells and pituitary adenomas and parathyroid gland and its adenomas were also positively stained. The MMP- and TIMP-positive endocrine cells correspond to Pearse's APUD cells, derived from neural crest and endodermal cells. Conclusions: MMPs and TIMPs may well be added as newly recognized markers for neuroendocrine cells. The possible function of MMP-TIMP homeostasis in C-cells and MTCs is discussed.  相似文献   

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Matrix metalloproteinases (MMPs) are single-chain zinc-containing metalloenzymes. The MMP gene family currently includes more than 19 endopeptidases. Both MMP-2 and 9 are widely expressed by many stromal and endothelial cells. Tissue inhibitors of metalloproteinases (TIMPs) form complexes with MMPs, which in turn inhibit active MMPs. MMP and TIMP homeostasis has been implicated in many aspects of both physiological and pathological processes. The latter include tumor invasion and metastasis. Although ductal adenocarcinomas of pancreas were immunocytochemically faintly stained for MMPs and TIMPs, normal pancreatic islets in the normal adjacent pancreas were found to be strongly stained for MMPs and TIMPs. Five kinds of islet cell tumors, including insulinomas, gastrinomas, glucagonomas, pancreatic polypeptide- (PP) omas, and nonfunctioning islet cell tumor, were stained for MMPs and TIMPs. The tumor cells were relatively weakly stained for MMPs and TIMPs compared to normal islets. Similarly, weaker staining for MMPs and TIME’s was noted for medullary thyroid carcinomas (MTCs) and pituitary adenomas. There was no correlation between immunostaining intensity of protein hormones and MMPs and TIMPs. However parathyroid hyperplasia, adenoma, and carcinoma that stained for MMPs and TIMPs were weaker, which paralleled the weaker immunostaining for parathyroid hormone and chromogranin. This weaker staining for MMPs and TIMPs in endocrine tumors may imply a less significant role of tumor invasion and metastasis by MMP and TIMP homeostasis. At present, immunocytochemical staining for MMPs and TIMPs may well be used as new markers for neuroendocrine cells and their tumors.  相似文献   

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The pseudojoint cavity formed in patients undergoing total hip arthroplasty (THA) is later remodeled to synovial membrane-like tissue, which produces pseudosynovial fluid. This pseudosynovium also is an important source of matrix metalloproteinases (MMPs). As it is widely speculated that synovial fluid MMPs may contribute to local tissue degradation in rheumatoid arthritis (RA) and osteoarthritis (OA), we hypothesize that locally produced MMPs are found in the pseudosynovial fluid, via which they have access to the implant-host interface, and that if they retain their proteolytic potential, they might contribute to aseptic loosening. Enzyme-linked immunosorbent assay (ELISA), immunoblotting, and zymography were used to analyze MMPs and tissue inhibitors of metalloproteinases (TIMPs) in synovial fluid in aseptic loosening, which was compared to RA and OA. Pseudosynovial THA fluid was characterized using low levels of MMP-1 but moderate levels of MMP-13 and MT1-MMP (MMP-14). Due to the lack of an appropriate assay, MMP-13 and MT1-MMP were not similarly assessed, but the immunoblotting indicated that they were in the 56 kD intermediate proteolytically processed forms. The MMP-9 level was intermediate between RA and OA. MMP-2 was on a significant level, but there were no differences among study groups. The THA group also was characterized using relatively high levels of TIMP-1 and TIMP-2. Accordingly, MMP-9 and MMP-2 were found to occur in the 92 kD and 72 kD proenzyme form, respectively, with full activity retained in all study groups. The data suggest that proMMP-2-TIMP-2 and proMMP-9-TIMP-1 complexes are formed in the pseudosynovial fluid due to the excess of TIMPs over MMPs in aseptic loosening of THA. TIMP-complexed MMPs are resistant to MMP-mediated proteolytic activation, which may explain their latency and proenzyme zymogen form. Thus, formation of stabilizing proMMP-TIMP complexes enable transportation of proMMPs far from their original site of production. Due to motion-associated cyclic changes of the intra-articular pressure, fluid-phase MMPs stabilized by TIMPs might be absorbed to implant surfaces and interface tissues and help to dissect the implant/cement-to-bone interface in situ. Consequently, they may contribute to local proteolytic/tissue destructive events and aseptic loosening.  相似文献   

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Matrix metalloproteinases as mediators of reproductive function   总被引:39,自引:1,他引:39  
The organs of the adult reproductive system can undergo extensive remodelling, experiencing rapid changes in tissue mass and function. Much of this matrix remodelling is attributed to the action of matrix metalloproteinases. Matrix metalloproteinase family members are expressed in a highly-regulated manner in many reproductive processes, including menstruation, ovulation, implantation, and uterine, breast, and prostate involution. Metalloproteinase concentrations and activity can be regulated by reproductive hormones, as well as by growth factors and cytokines that participate in reproductive events. In addition to playing a role in the loss of connective tissue mass, the metalloproteinases can influence the phenotype of the cellular components of the tissues, altering basic cellular functions such as proliferation, differentiation, and apoptosis. This review focuses on the expression of matrix metalloproteinases in reproductive tissues, and discusses the evidence supporting a role for these enzymes in modulating the structure and function of reproductive organs.   相似文献   

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Atherosclerosis is a complex chronic inflammatory and metabolic disease that involves the collaboration of several cellular components of the immune system and results in thickening of the arterial wall. Atherosclerosis is also the primary cause of coronary artery and cerebrovascular diseases. A multitude of immune cell subsets, soluble molecules such as chemokines and cytokines, and circulating lipids play pivotal roles in atherosclerosis development. In this review, we highlight the role of the immune system in the course of atherosclerotic disease development and discuss the mechanisms involved.  相似文献   

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Vu TH  Werb Z 《Genes & development》2000,14(17):2123-2133
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