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

Cell-cell and cell-matrix interactions are key events in morphogenetic processes during development and tissue remodelling. In the vascular system, overexpression of adhesion receptors such as integrins, protease (receptors) or dysregulation of adhesive interactions are directly related to the pathophysiology of cardiovascular diseases (atherosclerosis, restenosis, thrombosis) or angiogenesis-driven tumor progression. Protease cascades such as the plasminogen activation system exhibit a dual role in cell invasion by promoting pericellular proteolysis as well as by regulating cell adhesion and migration in a non-proteolytic fashion. In both these mechanisms, the urokinase receptor (uPAR) plays a central role and may become engaged in complexes with beta1-, beta2-, and beta3-integrins. This article will focus on the molecular and functional interactions between the uPAR system and vascular integrins and discuss implications for cardiovascular function.
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PMID:The dual role of the urokinase receptor system in pericellular proteolysis and cell adhesion: implications for cardiovascular function. 1054 6

Tumor progression and metastasis may result in part from the selection of cell clones competent for survival, invasion and growth at secondary sites and characterized by loss of growth inhibitory responses, acquisition of increased adhesiveness and enhanced motility and protease expression. Transforming growth factor-beta1 (TGF-beta1) is produced by osteoblasts (OB) in a latent form and is activated by proteases in a cell-dependent manner. We show here that OB conditioned medium (OB CM) modulates Matrigel invasion of a bone metastatic prostate cancer cell line (PC3) and that this effect is blocked by antibody against TGF-beta1 and by uPA/plasmin inhibitors, suggesting that TGF-beta1 can modulate OB-mediated cell recruitment and that PC3 cells can activate TGF-beta1. TGF-beta1 induces uPA and PAI-1 secretion and promotes binding of uPA at the external plasma membrane with increased membrane-associated plasmin activity. Matrix metalloprotease-9 (MMP-9) is induced both in the medium and in the membrane associated form. Moreover, the balance between proteolytic activity and inhibition is crucial in the metastatic event. Indeed, the increment of PAI-1 could have an important regulatory role on the extracellular proteolysis and might explain the decrease of net PA and gelatinolytic activities measured in the medium. In addition, PAI-1 plays a regulative role localizing matrix degradation in some specific sites, such as areas of cell-to-cell or cell-to-ECM contacts. In conclusion, TGF-beta1 enhances PC3 Matrigel invasion by a uPA/plasmin-dependent mechanism, also involving the MMP-9, and thus may play a central role in malignant prostate tumor progression as a result of stimulating bone matrix invasion.
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PMID:Osteoblast-derived TGF-beta1 modulates matrix degrading protease expression and activity in prostate cancer cells. 1065 34

Adhesion and signaling by integrins require their dynamic association with nonintegrin membrane proteins. One such protein, the glycolipid-anchored urokinase receptor (uPAR), associates with and modifies the function of the beta(2)-integrin Mac-1 (CD11b/CD18). In this study, a critical non-I-domain binding site for uPAR on CD11b (M25; residues 424-440) is identified by homology with a phage display peptide known to bind uPAR. Recombinant soluble uPAR and cells expressing uPAR bound to immobilized M25, binding being promoted by urokinase and blocked by soluble M25, but not a scrambled control or homologous peptides from other beta(2)-associated alpha-chains. Mac-1, but not a mutated Mac-1 in which M25 was replaced with the homologous sequence of CD11c, co-precipitated with uPAR. In the beta-propeller model of alpha-chain folding, M25 spans an exposed loop on the ligand-binding, upper surface of alphaM, identifying uPAR as an atypical alphaM ligand. Although not blocking ligand binding to Mac-1, M25 (25-100 microM) inhibited leukocyte adhesion to fibrinogen, vitronectin, and cytokine-stimulated endothelial cells. M25 also blocked the association of uPAR with beta(1)-integrins and impaired beta(1)-integrin-dependent spreading and migration of human vascular smooth muscle cells on fibronectin and collagen. These observations indicate that uPAR associates with integrins directly and that disruption of this association broadly impairs integrin function, suggesting a novel strategy for regulation of integrins in the settings of inflammation and tumor progression.
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PMID:Identification of a urokinase receptor-integrin interaction site. Promiscuous regulator of integrin function. 1074 8

Progression of tumor cells toward a high malignancy phenotype and metastasis is a multi-event cascade involving inter alia alterations in the expression of various genes. The focus of our laboratory is on genes whose altered expression may lead, directly or indirectly, to an increased malignancy phenotype. The identification of such genes and the evaluation of the consequences of their altered expression is essential for attempts to halt tumor progression and prevent metastasis formation. Published work originating in our laboratory showed that members of the murine Ly-6 supergene family are involved in the progression of certain mouse tumors. The expression level of several members of this family was higher on highly malignant cells than on tumor cells expressing a lower malignancy phenotype. Sorting by flow cytometry of tumor cells to subpopulations expressing either high or low levels of Ly-6E.1 yielded correspondingly cells expressing a high or a low malignancy phenotype. The high malignancy, high Ly-6E.1-expressing cells also expressed high levels of the receptor for urokinase plasminogen activator (uPAR), whereas low malignancy, low Ly-6E.1-expressing cells also expressed low levels of uPAR. Transfection studies indicated that uPAR was causally involved in conferring a high malignancy phenotype upon tumor cells expressing high levels of Ly-6E.1. E48 is a human homologue of the murine ThB protein, a member of the Ly-6 supergene family (but distinct from the Ly-6E.1 protein mentioned above) and expressed on head and neck squamous carcinoma cells. Experiments currently in progress are aimed to find out whether E48 is involved in the progression of such cancer cells. Using the differential display technology, it was shown that ligation of E48 on tumor cells by the corresponding antibodies (serving as a surrogate for an as yet unidentified E48 ligand) upregulates an enzyme (FX) involved in the biosynthesis of GDP-L-fucose. Fucose is an essential component of certain selectin ligands.
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PMID:Differential expression of genes by tumor cells of a low or a high malignancy phenotype: the case of murine and human Ly-6 proteins. 1076 16

Transforming growth factor-beta 1 (TGF-beta 1) stimulates migration/invasion of mouse transformed keratinocytes and increases urokinase (u-PA) expression/secretion. In this report, we analyzed the biological behavior of two naturally occurring inhibitors of protein tyrosine kinases, genistein and curcumin, that could abrogate the enhancement of u-PA levels induced by TGF-beta 1 in transformed keratinocytes. Our results showed that genistein and curcumin blocked this response in a dose-dependent manner and also inhibited the TGF-beta 1-induced synthesis of fibronectin, an early responsive gene to the growth factor. Both compounds also reduced TGF-beta 1-stimulated cell migration and invasiveness. These results suggest that a tyrosine kinase-signaling pathway should be involved in TGF-beta 1-mediated increased malignancy of transformed keratinocytes and that genistein and curcumin could play an important role in inhibiting tumor progression.
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PMID:Genistein and curcumin block TGF-beta 1-induced u-PA expression and migratory and invasive phenotype in mouse epidermal keratinocytes. 1096 19

In a variety of cell types, the glycolipid-anchored urokinase receptor (uPAR) is colocalized pericellularly with components of the plasminogen activation system and endocytosis receptors. uPAR is also coexpressed with caveolin and members of the integrin adhesion receptor superfamily. The formation of functional units with these various proteins allows the uPAR to mediate the focused proteolysis required for cell migration and invasion and to contribute both directly and indirectly to cell adhesive processes in a non-proteolytic fashion. This dual activity, together with the initiation of signal transduction pathways by uPAR, is believed to influence cellular behaviour in angiogenesis, inflammation, wound repair and tumor progression/metastasis and open up the way for uPAR-based therapeutic approaches.
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PMID:Urokinase receptor: a molecular organizer in cellular communication. 1097 99

In vivo tumor progression in mice with targeted deficiencies in urokinase-type plasminogen activator (UPA-/-) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1-/-), was studied using a fibrosarcoma tumor model. Murine T241 fibrosarcoma cells were s.c. implanted into three groups of mice with the following genotypes, wild-type (WT), UPA-/-, and PAI-1-/-. A significantly diminished primary tumor growth in UPA-/- and PAI-1-/- mice occurred, relative to WT mice. Tumors in UPA-/- and PAI-1-/- mice displayed lower proliferative and higher apoptotic indices and displayed a different neovascular morphology, as compared with WT mice. These results are consistent with the decreased growth rates of this tumor in these gene-deleted mice. Immunohistochemical analyses of the tumors revealed a decrease in vascularity and vascular endothelial growth factor expression only in tumors in PAI-1-/- mice. Analyses of the relative extents of corneal angiogenesis in these same animals, induced by basic fibroblast growth factor, corroborated the resistance of PAI-1-/- mice to neovascularization. The results obtained suggest that the host fibrinolytic system plays an important role in tumor growth in this model. Alterations in host expression of components of this system may alter tumor growth and dissemination by affecting the balance between tumor cell death and proliferation, as well as extracellular matrix changes needed for invasiveness and angiogenesis.
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PMID:Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. 1105 81

The plasminogen activation system plays an important role in enhancing pericellular proteolysis of tumor invasion/metastasis and in autocrine/paracrine tumor growth stimulation. To investigate the prognostic significance of the plasminogen activation system in human chondrosarcoma, the immunohistochemical expression of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor, 1 (PAI-1) and 2 (PAI-2) were analyzed in 28 patients with chondrosarcoma. In multivariate survival analysis, histological grade (p = 0.0008) and location (p = 0.02) were independent risk factors for local relapse. For metastasis-free survival, uPA index (p = 0.006) and PAI-2 index (p = 0.04) were independent prognostic factors. PAI-2 index (p = 0.02), uPAR index (p = 0.02) and histological grade (p = 0.03) predicted total survival. These results demonstrated the usefulness of uPA, uPAR and PAI-2 expression as biological prognostic indicator and the importance of the plasminogen activation system in tumor progression and metastasis in chondrosarcoma.
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PMID:Prognostic relevance of urokinase type plasminogen activator, its receptor and inhibitors in chondrosarcoma. 1106 19

Human tissue factor pathway inhibitor-2 (TFPI-2) is a 32-kDa serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase and tissue-type plasminogen activators or thrombin. After discovering that TFPI-2 expression is down-regulated or lost during tumor progression, we investigated the role of TFPI-2 in the invasiveness of the prostate cancer cell line (LNCaP). We stably transfected LNCaP cells with a 0.7-kb vector expressing TFPI-2 in the sense orientation and measured the expression of TFPI-2 protein and mRNA by these cells by western and northern blotting. Neither TFPI-2 protein nor mRNA was expressed by parental LNCaP cells or vector-transfected controls, but levels of both protein and mRNA were significantly increased in the sense-TFPI-2 clones. The sense clones were less invasive than the control cells in Matrigel invasion and spheroid migration assays. This is the first demonstration that upregulation of TFPI-2 plays a significant role in the invasive behavior of human prostate cancer cells.
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PMID:Overexpression of tissue factor pathway inhibitor-2 (TFPI-2), decreases the invasiveness of prostate cancer cells in vitro. 1111 49

Deregulation of several signaling pathways have been found to be critical for the development of different types of tumors, both in transgenic and spontaneous models. The role of proteases and adhesion molecules during the early stages of tumor progression induced by oncogenes in epithelial and mesenchymal tumors has remained relatively unexplored. This review summarizes recent work showing that different but overlapping signaling effector modules (PKC, v-Ras-RalA-PLD1 or v-Src-RalA-PLD1) induce changes in the production of proteases (uPA and MMPs) and adhesion molecules (fibronectin, CD44, beta 1-integrin) in normal epithelial or mesenchymal cell lines, associated with tumor development in vivo. Overexpression of PKC gamma in normal mammary epithelial cells or of v-Src and v-Ras in NIH3T3 fibroblasts induced in all cases overproduction of uPA and MMPs and a tumorigenic phenotype. Proteases production and tumorigenicity in transformed NIH3T3 cells were dependent on the GTPase RalA. In contrast to the common outcome in protease production by the different tumor promoting stimuli, fibronectin production was high in PKC-overexpressing mammary epithelial cells and it was organized into a rich fibrillar matrix, while oncogene transformed fibroblasts displayed reduced fibronectin production and a total loss of FN fibrillogenesis, an effect also dependent on RalA. These results show that protease overexpression is a common denominator in the acquisition of a malignant phenotype both in mesenchymal and epithelial cells. In contrast there is a dramatic difference in the expression and function of adhesion molecules like fibronectin between these two cell types, suggesting different regulatory roles for this glycoprotein during tumor progression, in cells of different tissular origin.
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PMID:[Signaling pathways regulating the expression of proteases during tumor progression]. 1118 28


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