Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pro-protein convertases (PCs) are proteases that recognize and cleave precursor proteins. Furin, a well-studied PC, is ubiquitously expressed, and it has been implicated in many physiological and pathological processes. Some substrates for furin, such as membrane type 1 (MT1) matrix metalloproteinase (MMP), an MMP that activates gelatinase, a collagen-degrading enzyme, are associated with the advanced malignant phenotype. This report examines the expression of furin in carcinoma cell lines of different invasive ability. The levels of furin mRNA and protein correlated with the aggressiveness of tumor cell lines derived from head and neck and lung cancers. Furin expression also was investigated in primary head and neck squamous cell carcinomas (HNSCCs). Furin mRNA was not detected in nonmetastasizing carcinomas. In contrast, furin mRNA was expressed in metastasizing HNSCCs. Immunohistochemistry and Western blot analysis confirmed these results at the protein level. Furin activity was investigated indirectly by evaluating the expression of the pro-form and the processed form of MT1-MMP. Metastasizing HNSCCs showed increased expression of MT1-MMP. Furthermore, pro-MT1-MMP expression was noted in most of the nonmetastasizing HNSCCs analyzed by Western blot, and it was absent in the metastasizing HNSCCs. This finding suggests a lower level of furin-mediated MT1-MMP activation in the less aggressive cancers. These observations indicate that furin plays a role in tumor progression. Its overexpression in more aggressive or metastasizing cancers resulted in increased MMP processing.
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PMID:Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. 1153 72

Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling. We previously found that a membrane-anchored glycoprotein, RECK, negatively regulates MMP-9 and inhibits tumor invasion and metastasis. Here we show that RECK regulates two other MMPs, MMP-2 and MT1-MMP, known to be involved in cancer progression, that mice lacking a functional RECK gene die around E10.5 with defects in collagen fibrils, the basal lamina, and vascular development, and that this phenotype is partially suppressed by MMP-2 null mutation. Also, vascular sprouting is dramatically suppressed in tumors derived from RECK-expressing fibrosarcoma cells grown in nude mice. These results support a role for RECK in the regulation of MMP-2 in vivo and implicate RECK downregulation in tumor angiogenesis.
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PMID:The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. 1174 14

Membrane-type (MT) 1 matrix metalloproteinase (MMP) is up-regulated in many tumor types and has been implicated in tumor progression and metastasis. MT1-MMP is critical for pericellular degradation of the extracellular matrix, thereby promoting tumor cell invasion and dissemination. To grow efficiently in vivo, tumor cells induce angiogenesis in both primary solid tumors and metastatic foci. The present study describes a functional link between the expression of MT1-MMP and vascular endothelial growth factor (VEGF) production in human glioma U251 xenografts in athymic mice. To investigate the effects of MT1-MMP on VEGF expression, U251 cells were stably transfected with MT1-MMP to generate the U-MT cell line overexpressing the enzyme. In vitro, the U-MT cells had an increased rate of proliferation and migration as well as the ability to activate the MMP-2 proenzyme and directionally remodel a three-dimensional collagen matrix. These findings suggested higher tumorigenicity of U-MT cells relative to the vector-control U-neo cells. In agreement with the in vitro data, U-MT xenografts in BALB/c nu/nu mice displayed markedly increased growth rates and elevated levels of angiogenesis. In contrast, U-neo cells formed small, minimally vascularized tumors. The elevated angiogenesis in U-MT xenografts was associated with an up-regulation of VEGF expression in tumor cells. In addition, U-MT cells in vitro secreted twice as much VEGF as the control cells. GM6001, a hydroxamate inhibitor of MMP activity, down-regulated the production of VEGF in U-MT cells to the levels observed in the U-neo control. Our results demonstrate that the enhanced tumorigenicity of glioma cells overexpressing MT1-MMP involves stimulation of angiogenesis through the up-regulation of VEGF production.
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PMID:Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. 1180 13

Membrane-type metalloproteinase-1 (MT1-MMP) is a transmembrane metalloproteinase overexpressed in tumors, which plays a major role in the first step of pro-MMP-2 activation, leading to the generation of an intermediate 62 kDa species. The second step of MMP-2 activation that yields to the mature form is less understood and could involve an autocatalytic process and/or the activity of the plasminogen/plasmin system. Human melanoma A2058 cells, which express MMP-2 only in its pro-form, were used to determine the role of MT1-MMP during pericellular proteolysis and tumor progression. The induction of MT1-MMP overexpression by MT1-MMP cDNA transfection initiated the first step of MMP-2 activation. We provide evidence that a cooperation between the plasminogen/plasmin system and MT1-MMP endowed the cells with the ability to fully activate MMP-2 and with enhanced invasive properties in vitro. When injected subcutaneously in nude mice, MT1-MMP expressing clones induced rapid tumor growth and high tumor vascularization, while the control clones were poorly or not tumorigenic. Our data provide the first demonstration, in an experimental model, that MT1-MMP expression by tumor cells promotes tumor vascularization.
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PMID:Expression of membrane type 1 matrix metalloproteinase (MT1-MMP) in A2058 melanoma cells is associated with MMP-2 activation and increased tumor growth and vascularization. 1185 80

Matrix metalloproteinases (MMPs) are a family of proteases that degrade extracellular matrix components and are involved in tumor progression and metastasis. We studied the pattern of expression of MMP-2 by human hepatoma cell lines and human hepatic myofibroblasts and its regulation in co-culture between these cell types. MMP-2 expression was studied by zymography and semi-quantitative RT-PCR. The expression of MT1-MMP (involved in MMP-2 activation) was studied by Western blot analysis and RT-PCR and the secretion of TIMP-2 by ELISA and RT-PCR. Myofibroblasts expressed high levels of MMP-2, MT1-MMP and TIMP-2. The hepatoma cell lines HepG2, HuH7 and Hep3B did not express MMP-2 and weakly expressed TIMP-2 and MT1-MMP. In co-culture, no modulation of MT1-MMP or TIMP-2 expression was observed. A strong decrease in myofibroblast MMP-2 expression was seen in the presence of hepatoma cell lines. This was partly reproduced by their conditioned media. We conclude that hepatoma cell lines down-regulate the expression of MMP-2 by myofibroblasts.
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PMID:Hepatocarcinoma cell lines down-regulate matrix metalloproteinase-2 expression in human hepatic myofibroblasts. 1201 89

The microenvironment of cancer cells, composed of extracellular matrix (ECM) macromolecules, plays a pivotal function in tumor progression. ECM preexisting modules or cryptic sites revealed by partial enzymatic hydrolysis positively or negatively regulate matrix metalloproteinase (MMP) expression and activation, further influencing matrix invasion by cancer cells. Pericellular activation of gelatinase A (MMP-2) proceeds via the formation of a complex involving its inhibitor, TIMP-2, its activator(s), MT-MMPs and alphavbeta3 integrin forming a docking system. This proteinase has been invariably linked to cancer cell invasive potential and is often predictive of a poor survival. MMP-2 degrades most ECM macromolecules and appears to act as a main 'decryptase'. ECM modulation of MMP-2 activation pathway thus influences angiogenesis and tumor growth. For instance the noncollagenous domain of alpha3 chain of type IV collagen, through alphavbeta3 integrin binding, inhibits both MT1-MMP and alphavbeta3 integrin expression from melanoma cells and empedes cell migration and proliferation. At the opposite, a particular module in elastin (VGVAPG) with type VIII beta turn conformation stimulates MT1-MMP and proMMP-2 activation through binding to S-gal elastin receptor, and increases the matrix invasive capacity of several cancer cell lines and endothelial cells. Endocytosis emerges as a main mechanism controlling MMP-2, and also other MMPs; it proceeds via the formation of a MMP-thrombospondin(s) complex further recognized by the LRP scavenger receptor. ECM undergoes conspicuous variations with aging linked to alterations of tissue organization and post-translational modifications of matrix constituents that modify cell-matrix interactions and MMP-2 activation pathway.
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PMID:Matrix-directed regulation of pericellular proteolysis and tumor progression. 1208 53

Matrix metalloproteinases (MMPs) play crucial roles in tumor progression. To investigate the roles of MMPs in the progression of nasopharyngeal carcinoma (NPC), the expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-12, MMP-13, MMP-14, and MMP-19 was explored by microarray assay. Among them, MMP-1 was significantly up-regulated in NPC biopsies. These results were confirmed further by real-time quantitative PCR in additional NPC biopsies and comparison with normal tissues and other head and neck cancers. Moreover, the use of RNA from different cellular constituents of NPC biopsies revealed that MMP-1 was detected predominantly in epithelial cells. Immunohistochemical staining of paraffin-fixed NPC sections confirmed that MMP-1 protein was expressed in the epithelial tumor cells. Because EBV is strongly associated with NPC formation, we sought a correlation between viral gene expression and MMP-1 up-regulation. The results showed clearly that the amounts of transcripts, proteins, and enzyme activities of MMP-1 were increased in cells expressing EBV proteins, LMP1 (latent membrane protein 1) and Zta (Z transactivator; also named as BZLF1 or ZEBRA) but not EBNA-1 (EBV nuclear antigen-1). Additionally, the mobility of LMP1 and Zta transfectants was increased in scrape-wound migration assays. The invasiveness and ability to survive in a three-dimensional collagen gel also were enhanced in LMP1- and Zta-expressing cells. Furthermore, anti-MMP-1 antibody and peptide inhibitors could block the invasiveness and survival properties of LMP1 and Zta transfectants, suggesting a real contribution of MMP-1 to cell mobility and survival. Taken together, our data show that the viral LMP1 and Zta proteins regulate the expression and activity of MMP-1, and thereby confer the invasive properties of the cells. This study presents the first evidence that viral proteins are capable of regulating MMP-1 and also provides clues for the role of EBV in NPC progression.
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PMID:Regulation of matrix metalloproteinase-1 by Epstein-Barr virus proteins. 1251 6

The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.
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PMID:Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis. 1271 42

The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III-IV ovarian carcinomas were analyzed for the expression of alpha v and beta1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. Alpha v integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of beta1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of beta1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between alpha v integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of alpha v integrin subunit and labeling for IL-8 in carcinoma cells. The presence of beta1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of beta1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.
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PMID:Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway? 1271 42

Pericellular proteolysis plays a pivotal function in cell invasion, a hallmark of tumor growth and metastasis. The minidegradome constituted of two matrix metalloproteinases (MMP), i.e. MMP-2 and MT1-MMP, associated with tissue inhibitor of metalloprotease-2 (TIMP-2) and integrin (alpha(v)beta(3)) or CD(44), is mainly involved in such invasive program. It catalyzes matrix degradation but, alternatively, proteolytic exposure of matricryptic sites or matrikines liberation by those enzymes regulates either positively or negatively tumor cell migration. That applies to types I and IV collagens, elastin, laminin 5, as described here, but such phenomenon might be extended to other matrix macromolecules. The development of tumors from epithelium origin is related to aging. Senescent fibroblasts are characterized by increased expression of MMPs, (particularly collagenase-1 (MMP-1) and stromelysin-1 (MMP-3)) and deposited matrix by those aged cells was shown to favor cancer cell growth. Thus, compositional variation of matrix-surrounding tumor cells, with formation of matricryptic sites and matrikines, can be considered as one main epigenetic factor contributing to tumor progression. A matrix-directed pharmacological approach in cancer is now emerging.
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PMID:Proteolyzed matrix as a template for the regulation of tumor progression. 1288 58


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