基质金属蛋白酶及其抑制物与肿瘤侵袭转移的关系

基质金属蛋白酶(MMP)家族是降解细胞外基质的重要酶类.组织金属蛋白酶抑制物(TIMP)是MMP的天然抑制物.在细胞外基质中MMP和TIMP的失衡已证实与多种病理状态,尤其是与肿瘤的侵袭与转移密切相关.抑制MMP活性是抗肿瘤转移的一个新的靶点.     

Matrix metalloproteinases in tumor invasion and metastasis

Extensive work on the mechanisms of tumor invasion and metastasis has identified matrix metalloproteinases (MMPs) as key players in the events that underlie tumor dissemination. Studies using natural and synthetic MMP inhibitors, as well as tumor cells transfected with cDNAs encoding the MMPs characterized thus far have provided compelling evidence that MMP activity can induce or enhance tumor survival, invasion and metastasis. Because of the ability of MMPs to degrade extracellular matrix (ECM) proteins, the principal mechanism whereby MMPs promote tumor development has been thought to be the proteolytic breakdown of tissue barriers to invasion and the associated facilitation of circulating tumor cell extravasation. However, recent evidence stemming from the use of novel experimental approaches indicates that MMPs do not play a major role in the process of extravasation itself. Rather, they appear to promote intravasation (the process of penetrating the circulation following invasion of blood vessels) and regulate the relationship between tumor cells and host tissue stroma subsequent to extravasation. In addition, the discoveries that a growing number of proteolytically active MMPs may localize to the cell surface in association with adhesion receptors, and that MMP substrates include latent cytokines and growth factors, provide a new conceptual framework for the mechanisms whereby MMPs influence tumor behavior.     

Chemokines in tumor angiogenesis and metastasis

Chemokines are a large group of low molecular weight cytokines that are known to selectively attract and activate different cell types. Although the primary function of chemokines is well recognized as leukocyte attractants, recent evidences indicate that they also play a role in number of tumor-related processes, such as growth, angiogenesis and metastasis. Chemokines activate cells through cell surface seven trans-membranes, G-protein-coupled receptors (GPCR). The role played by chemokines and their receptors in tumor pathophysiology is complex as some chemokines favor tumor growth and metastasis, while others may enhance anti-tumor immunity. These diverse functions of chemokines establish them as key mediators between the tumor cells and their microenvironment and play critical role in tumor progression and metastasis. In this review, we present some of the recent advances in chemokine research with special emphasis on its role in tumor angiogenesis and metastasis.     

Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets

Degradation of extracellular matrix is crucial for malignant tumour growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumour tissue or serum of patients with advanced cancer and their role as prognostic indicators in cancer is studied. In addition, therapeutic intervention of tumour growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors are in clinical trials in cancer. In this review, we discuss the current view on the feasibility of MMPs as prognostic markers and as targets for therapeutic intervention in cancer.     

Matrix metalloproteinases and metastasis

Metastatic disease is responsible for the majority of cancer-related deaths, either directly due to tumor involvement of critical organs or indirectly due to complications of therapy to control tumor growth and spread. An understanding of the mechanisms of tumor cell invasion and metastasis may be important for devising therapies aimed at preventing tumor cell spread. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases whose enzymatic activity is directed against components of the extracellular matrix (ECM). In humans, 16 members of this family have been identified by cloning and sequencing. These proteinases are linked by a core of common domain structures and by their relationship to a family of proteinase inhibitors called the tissue inhibitors of metalloproteinases (TIMPs). Four members of the TIMP family have been cloned and sequenced in humans and they inhibit MMPs by forming tight-binding, noncovalent associations with the active site of the MMPs. MMPs facilitate tumor cell invasion and metastasis by at least three distinct mechanisms. First, proteinase action removes physical barriers to invasion through degradation of ECM macromolecules such as collagens, laminins, and proteoglycans. This has been demonstrated in vitro through the use of chemoinvasion assays and in vivo by the presence of active MMPs at the invasive front of tumors. Second, MMPs have the ability to modulate cell adhesion. For cells to move through the ECM, they must be able to form new cell-matrix and cell-cell attachments and break existing ones. Using a cell transfection system that altered the ratio of MMP-2 to TIMP-2 we have demonstrated significant variation in the adhesive phenotype of tumor cells. Finally, MMPs may act on ECM components or other proteins to uncover hidden biologic activities. For example, the angiogenesis inhibitor angiostatin may be produced from plasminogen by MMP action and laminin-5 is specifically degraded by MMP-2 to produce a soluble chemotactic fragment. Thus MMPs play multiple key roles in facilitating the metastasis of tumor cells. Therapies designed to interfere with specific MMP actions may be useful in the control of metastatic disease.     

Matrix degrading metalloproteinases

Summary Matrix degrading metalloproteinases are enzymes that degrade proteins in tissue extracellular matrices. These proteinases exhibit specific, well defined properties that allow them to be classified into a family of enzymes. They are secreted by various cell types as the cells effect their surrounding extracellular matrix. Such effects occur during normal physiologic tissue remodeling but also during pathologic processes such as tumor cell invasion and metastases. Currently there are seven proteases classified as members of the matrix metalloproteinase family and there are two putative members. Direct correlations can be made between the matrix metalloproteinases and normal tissue functions such as bone remodeling, uterine and mammary gland function and ovulation. The matrix metalloproteinases are also strongly associated with cancer progression in that they function to degrade epithelial basement membrane and stromal matrices in many different malignancies including brain tumors.     

转移相关基因-2调控肿瘤侵袭转移的研究

转移相关基因-2（MTA2）是转移相关基因家族成员之一,其蛋白质序列及功能结构域编码序列与MTA1具有高度同源性。MTA2参与构成核小体重构及组蛋白去乙酰化酶（NuRD）复合物,并可与多种转录因子相互作用,参与基因转录调控。MTA2在多种恶性肿瘤中异常表达,并与肿瘤恶性生物学行为密切相关,提示MTA2在肿瘤发生、发展过程中发挥重要作用。本文将对MTA2在肿瘤中的表达情况、生物学功能以及在肿瘤侵袭、转移中的相关分子机制等进行综述。     

Matrix metalloproteinase and their inhibitors: Molecular aspects of their roles in the tumor metastasis

Tumor cell invasion and metastasis are now regarded as multi-step phenomena, involving proteolytic degradation of extracellular matrix (ECM), altered cell adhesion, physical movement of tumor cells and angiogenesis. Extracellular proteinases are essential for tumor cells to be able to penetrate the basement memberane. Proteolytic degradation of ECM is also necessary when invasive tumor cells penetrate tissue, gain access to blood vessels and colonize distant sites (metastasis). In addition, …     

Pro-angiogenic cytokines and their role in tumor angiogenesis

The development of solid tumors depends upon an adequate supply of blood. This can be achieved by way of co-option of preexisting blood vessels and by the induction of angiogenesis. During the past 30 years, tumor angiogenesis had been found to play a crucial role in the progression of solid tumors. Tumor angiogenesis was found to be induced by a variety of pro-angiogenic cytokines of which the best characterized is vascular endothelial growth factor (VEGF). Indeed, the first FDA approved anti-angiogenic drug for the treatment of cancer is Avastin^TM, a neutralizing antibdy directed against VEGF. This review focuses on cytokines which have been reported to induce tumor angiogenesis.     

The neuropilins and their role in tumorigenesis and tumor progression

The neuropilins were originally described as receptors for the six axon guidance factors belonging to the class-3 semaphorins. They were subsequently found to function in addition as receptors for specific splice forms of angiogenic factors belonging to the VEGF family. The neuropilins are expressed in many types of cancer cells, in endothelial cells and in additional many types of normal diploid cell types. Recent findings indicate that the neuropilins and their associated plexin and tyrosine-kinase VEGF receptors play a regulatory role in developmental angiogenesis as well as in tumor angiogenesis. The neuropilin ligands belonging to the semaphorin family as well as the various VEGF's function as modulators of angiogenesis and tumor angiogenesis. Furthermore, since many types of cancer cells express neuropilins and neuropilin associated receptors, it is not surprising that various neuropilin ligands can modulate the behavior of cancer cells directly leading to the potentiation or inhibition of tumor progression.     

基质金属蛋白酶及其抑制剂与肺癌的侵袭和转移

基质金属蛋白酶(MMPs)家族是细胞外基质降解过程中的重要酶类,与多种病理过程尤其是肿瘤侵袭和转移有密切关系,因此成为肿瘤治疗的新靶点,本文就MMPs、TIMPs的生物学作用,与肺癌侵袭转移的关系及MMP合成抑制剂的开发研究情况等方面做一综述.     

Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model

Purpose In an effort to study the importance of stromal involvement in angiogenesis, we developed a novel, multicellular model that utilizes three of the primary cell types involved in tumor angiogenesis.Methods Fluorescently labeled human microvascular endothelial cells (HMVECs), 10T1/2 cells and myofibroblasts were incubated in the presence of a three-dimensional tumor cell cluster resuspended in collagen and embedded in Matrigel.Results HMVECs cultured in the presence of a human SKOV-3 ovarian carcinoma tumor cell cluster, surrounded the tumor cell cluster, while myofibroblasts invaded the cluster, localizing within the tumor cell mass. In contrast, 10T1/2 cells, a pluripotent mouse mesenchymal cell line with pericyte-like properties, did not demonstrate the same invasive phenotype. HMVECs cultured in the presence of myofibroblasts invaded the tumor cell cluster and colocalized with the myofibroblasts as demonstrated by fluorescent microscopy and immunohistochemistry. The angiogenesis inhibitors SU6668 and paclitaxel inhibited stromal invasion, while a broad-spectrum matrix metalloproteinase inhibitor did not.Conclusions This model emphasizes the critical interaction between endothelial cells and myofibroblasts and provides a more complete in vitro model for studying angiogenesis and tumor progression.     

Contributions of tumor and stromal matrix metalloproteinases to tumor progression,invasion and metastasis

Summary The malignant progression of tumors is driven by the expression of oncogenes and loss of expression of tumor suppressor genes; factors that are intrinsic to cancer cells. The phenotypic changes brought about by the gain or loss of expression of oncogenes and tumor suppressor genes lead to the acquisition of malignant traits, namely, the ability to invade into and grow in ectopic tissue environments. Recently, however, focus in cancer research has widened from the cancer cell to include the surrounding tumor stroma as an integral player in the process of tumor progression. One of the areas in cancer research contributing to this enhanced appreciation of stromal involvement in tumor progression and metastasis is that of matrix metalloproteinases (MMPs).This review provides an overview of the characteristics of MMPs and discusses their role in the progression and metastasis of tumors. Initially, attention will focus on the regulation of MMPs in tumor cells but will switch to discourse on stromal expression of MMPs in tumors and speculation on the functional consequences of stromal expression of MMPs.     

乙酰肝素酶与肿瘤转移研究进展

乙酰肝素酶是目前发现的哺乳动物细胞中唯一能切割细胞外基质中硫酸肝素蛋白多糖侧链的内源性糖苷酶。本文对乙酰肝素酶的结构、功能、分子特性、基因定位、核苷酸序列及其对血管生成的影响,在正常组织、肿瘤组织及转移癌组织中的表达和该酶参与肿瘤转移的机制等方面进行了综述。对用筛选乙酰肝素酶抑制剂的方法、寻找抗肿瘤新药的最新进展做了概述,旨在为肿瘤转移机制研究、寻找治疗方法提供一些线索。     

CTGF increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating miR-519d

Osteosarcoma, the most common primary malignant bone tumor, shows potent capacity for local invasion and distant metastasis. Connective tissue growth factor (CTGF/CCN2), a secreted protein, binds to integrins, modulates invasive behavior of certain human cancer cells. Effect of CTGF in metastasis of human osteosarcoma is unknown. We found overexpression of CTGF increasing matrix metalloproteinases (MMPs)-2 and MMP-3 expression as well as promoting cell migration. MicroRNA (miRNA) analysis of CTGF-overexpressed osteosarcoma versus control cells probed mechanisms of CTGF-mediated promotion of migration. Among miRNAs regulated by CTGF, miR-519d was most downregulated after CTGF treatment. Co-transfection with miR-519d mimic reversed CTGF-mediated MMPs expression and cell migration. Also, MEK and ERK inhibitors or mutants reduced CTGF-increased cell migration and miR-519d suppression. By contrast, knockdown of CTGF diminished lung metastasis in vivo. Clinical samples indicate CTGF expression as linked with clinical stage and tumor metastasis. Taken together, data show CTGF elevating MMPs expression and subsequently promoting tumor metastasis in human osteosarcoma, down-regulating miR-519d via MEK and ERK pathways, making CTGF a new molecular therapeutic target in osteosarcoma metastasis.     

中介素与肿瘤

中介素可通过多种信号通路促进肿瘤血管生成,并受肿瘤细胞缺氧影响表达增加.近年来,国内外出现多项中介素与肿瘤发生、发展、侵袭之间相互关系及作用机制的研究,有望为肿瘤治疗提供新靶点.     

中介素与肿瘤

中介素可通过多种信号通路促进肿瘤血管生成,并受肿瘤细胞缺氧影响表达增加。近年来,国内外出现多项中介素与肿瘤发生、发展、侵袭之间相互关系及作用机制的研究,有望为肿瘤治疗提供新靶点。     

血管生成抑制剂TNP—470抑制Lewis肺癌生长和转移的实验研究

目的采用Ｌｅｗｉｓ肺癌来验证血管生成抑制剂ＴＮＰ－４７０对肿瘤生长和转移的抑制作用。方法将Ｌｅｗｉｓ肺癌细胞接种于Ｃ５７ＢＬ小鼠皮下（２．４×１０６／鼠）。将２０只小鼠随机分成对照组和治疗组,自第２天起分别给予溶剂（３％酒精）０．２ｍｌ和ＴＮＰ－４７０（４０ｍｇ／ｋｇ）,隔天给药１次,共８次。第２２天时,测定对照组和治疗组的皮下瘤重及肺转移率,分别进行ｔ检验和χ２检验。结果两组皮下瘤重分别为３．７７±１．０５ｇ和１．９８±０．９６ｇ（Ｐ＝０．０００９）;两组肺转移率分别为８０％和３０％（Ｐ＝０．０３）。结论血管生成抑制剂ＴＮＰ－４７０能明显抑制Ｌｅｗｉｓ肺癌的生长和转移。     

Angiogenesis and anti-angiogenesis in hepatocellular carcinoma

Experimental and clinical data indicate that in human hepatocellular carcinoma (HCC) tumor progression is associated with angiogenesis and that an increase in microvascular density is associated with a poor prognosis. This review summarizes the literature concerning the relationship between angiogenesis and progression in HCC. It is becoming increasingly evident that agents which interfere with blood vessel formation also block tumor progression. Accordingly, anti-angiogenic tumor therapy has gained much interest in preclinical and clinical assessments. The recent applications of anti-angiogenic agents which interfere or block HCC progression are reviewed.