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)

Interactions between specific cell-surface molecules, which include the urokinase receptor (uPAR) and integrins, are crucial to processes of tumor invasion and metastasis. Here we demonstrate that uPAR and beta1-integrins may cluster at distinct sites at the cell surface of metastatic MDA-MB-231 breast cancer cells and form functional complexes. Attachment assays performed in the presence of a synthetic peptide (p25), which interferes with the formation of uPAR-integrin complexes, reveal that uPAR is able to regulate the adhesive function of integrins in breast cancer cells. On dissociation of the uPAR-integrin complexes by p25, tumor cell attachment to the extracellular matrix was either decreased (vitronectin) or increased (fibronectin). Moreover, the tumor cells display remarkable morphological changes when cultured on fibronectin in the continuous presence of p25, leading to increased cell spreading and attachment. In marked contrast to control conditions, increased cellular adhesion to fibronectin after p25 treatment was entirely beta1-integrin-mediated. The role of uPAR-integrin complexes in tumor progression was studied in an in vivo bone xenograft model. Stably transfected MDA-MB-231 cells that overexpress p25 showed a significant reduction in tumor progression in bone (P < or = 0.0001 versus mock-control). In line with these observations, continuous administration of p25 (25 microg/mouse/day, osmotic minipumps) for 28 days resulted in significantly reduced tumor progression of MDA-MB-231 cells in bone (P < or = 0.005) when compared to scrambled control peptide. In conclusion, our data demonstrate that uPAR can act as an adhesion receptor in breast cancer and is capable of regulating integrin function. Our findings strongly suggest that adhesive and proteolytic events are tightly associated in metastatic breast cancer cells and that functional integrin-uPAR complexes are involved in tumor progression in vivo.
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PMID:Urokinase-receptor/integrin complexes are functionally involved in adhesion and progression of human breast cancer in vivo. 1154 90

Melanoma antigen (MAGE)-A-derived peptides elicit a strong in vitro T-cell response against tumor cells. For determination of MAGE-A1, -2, -3, -4, -6, and -12 expression profile in invasive breast cancer, we developed a multiplex seminested reverse transcription-PCR-method. In total, 18 of 67 (27%) tumors were positive for at least one of these MAGE transcripts, and the expression pattern was heterogeneous: MAGE-A1 was positive in 4 of 67 (6%), MAGE-A2 in 13 of 67 (19%), MAGE-A3 in 7 of 67 (10%), MAGE-A4 in 9 of 67 (13%), MAGE-A6 in 10 of 67 (15%), and MAGE-A12 in 6 of 67 (9%) patients. The MAGE-A transcripts were more frequently expressed in ductal breast carcinomas compared with other histomorphological types. We observed a preferential expression of MAGE-A in patients at a higher risk of recurrence: those harboring tumors with high levels of the protease urokinase-type plasminogen activator and its inhibitor plasminogen activator inhibitor 1, high score of the Ki-67 proliferation antigen, and lesser degree of differentiation. Our findings suggests a potential involvement of MAGE-A in tumor progression, with potential implications for active immunotherapy.
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PMID:MAGE-A gene expression pattern in primary breast cancer. 1155 35

Urokinase-type plasminogen activator (u-PA) contributes to tumor progression in prostate cancer (CaP). We have previously shown that u-PA expression is upregulated through the AP-1 and PEA3 sites and repressed by androgen. However, signaling pathways mediating u-PA gene expression in CaP are not delineated. We hypothesized that MAPK pathways mediate u-PA in CaP, and thereby studied specific ERK, JNK, and P38-MAPK pathway mutant constructs and inhibitors in vitro. Human, androgen insensitive CaP PC3 cells stably transfected with the androgen receptor expression vector and vector alone were used. A u-PA promoter CAT vector transiently expressed with dominant negative mutant signaling constructs was studied. All mutants drastically reduced u-PA promoter activity. Furthermore, inhibition of PI3K, an upstream regulator in the JNK/SAPK pathway, decreased u-PA promoter transcription. Collectively, these results show that MAPK pathways ERK, JNK/SAPK, and P38-MAPK represent a significant component in the regulation of u-PA expression in human CaP.
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PMID:Signal transduction-mediated regulation of urokinase gene expression in human prostate cancer. 1167 74

Human tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase-type plasminogen activator, tissue plasminogen activator, or thrombin. Preliminary findings in our laboratory suggested that the expression of TFPI-2 is downregulated or lost during tumor progression in human gliomas. To investigate the role of TFPI-2 in the invasiveness of brain tumors, we stably transfected the human high-grade glioma cell line SNB19 and the human low-grade glioma cell line Hs683 with a vector capable of expressing a transcript complementary to the full-length TFPI-2 mRNA in either sense (0.7 kb) or antisense (1 kb) orientations. Parental cells and stably transfected cell lines were analysed for TFPI-2 protein by Western blotting and for TFPI-2 mRNA by Northern blotting. The levels of TFPI-2 protein and mRNA were higher in the sense clones (SNB19) and decreased in the antisense (Hs683) clones than in the corresponding parental and vector controls. In spheroid and matrigel invasion assays, the SNB19 parental cells were highly invasive, but the sense-transfected SNB-19 clones were much less invasive; the antisense-transfected Hs683 clones were more invasive than their parental and vector controls. After intracerebral injection in mice, the sense-transfected SNB19 clones were less able to form tumors than were their parental and vector controls, and the antisense-Hs683 clones but not the parental or vector controls formed small tumors. This is the first study to demonstrate that down- or upregulation of TFPI-2 plays a significant role in the invasive behavior of human gliomas.
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PMID:A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion. 1168 73

The plasminogen/plasmin system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumour cell migration. High levels of components of the plasminogen activation system, and paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been correlated with a poor prognosis for patients with cancers of different types. Recent findings clearly suggest that PAI-1 is essential for capillary sprouting during tumour angiogenesis. Moreover, there is accumulating evidence that both the urokinase receptor and PAI-1 are multifunctional proteins involved not only in extracellular matrix proteolysis but also in cellular adhesion and migration through their binding site for vitronectin. The understanding of whether PAI-1 plays a regulatory role in angiogenesis by tightly controlling proteolytic activity or by influencing cell migration could allow a new anti-angiogenic approach for tumour therapy.
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PMID:[Role of plasminogen activator inhibitor type 1 in tumor angiogenesis]. 1180 82

Invasion and dissemination of well-differentiated carcinomas are often associated with loss of epithelial differentiation and gain of mesenchymal-like capabilities of dedifferentiated tumor cells at the invasive front. However when analysing central areas of metastases of colorectal carcinomas one finds a regain of the differentiated epithelial growth patterns like in the primary tumor. More than 80% of these tumor have loss of function mutations in the APC tumor suppressor gene, leading to an overexpression of beta-catenine. In its nuclear pool beta-catenine acts as a transcription factor and is now considered as one of the main oncogenic proteins in colorectal carcinogenesis. We could define several molecules important for the processes of invasion and dissemination, like MMP-7, uPA, laminin-5, as target genes activated by nuclear beta-catenine. Moreover the characteristic phenotypic changes during tumor progression were associated with distinct expression patterns of beta-catenine and E-cadherin. Nuclear beta-catenine was found in dedifferentiated mesenchyme-like tumor cells at the invasive front, but strikingly, like in central areas of the primary tumors, was localized to the membrane and cytoplasm in polarized epithelial tumor cells in the metastases. This was accompanied by changes in the proliferative activity. Based on these data, we postulate that an important driving force for progression of well-differentiated colorectal carcinomas is the specific environment, initiating two transient phenotypic transition processes by modulating intracellular beta-catenine distribution in the tumor cells.
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PMID:[The Rudolf Virchow Prize 2001. The role of the oncoprotein beta-catenin ni the progression of colorectal cancers]. 1189 5

The serine protease urinary plasminogen activator or urokinase (uPA), produced in abundance by many malignancies, plays a key role in tumor cell invasion and metastasis. uPA is localized within the malignant cell milieu via its cell surface receptor [uPA receptor (uPAR)], which is expressed by tumor and tumor-associated cells. In the present study, we have used a syngeneic model of rat breast cancer to directly evaluate the role of uPAR as a diagnostic and therapeutic target in metastatic breast cancer. A polyclonal antibody against the ligand-binding NH(2)-terminal domain of rat uPAR (ruPAR) was developed. This antibody recognizes ruPAR by both immunofluorescence and Western blot analysis. Recombinant ruPAR and ruPAR IgG displaced the binding of (125)I-labeled ruPAR IgG to rat prostate cancer cells (Dunning R3227 Mat Ly Lu) and breast cancer cells (Mat B-III) overexpressing ruPAR (Mat B-III-uPAR). ruPAR IgG also blocked the invasive capacity of these tumor cells in a dose-dependent manner. Mat B-III-uPAR cells were inoculated s.c. into the mammary fat pad of syngeneic female Fischer rats. On day 10 after tumor cell inoculation, animals were injected with (125)I-labeled preimmune or ruPAR IgG and then sacrificed at timed intervals. Maximum (125)I uptake was observed in primary tumors and in tissues commonly affected by tumor metastases (liver, spleen, lungs, and lymph nodes) at 12 h. Injection of (125)I-labeled preimmune or ruPAR IgG into normal non-tumor-bearing animals resulted in minimal basal levels of uPAR expression and established the specificity of the ruPAR IgG. Similar results were obtained by Northern blot and PCR analysis of mRNA isolated from tissues of normal and tumor-bearing animals. To evaluate the effectiveness of this antibody in tumor progression, ruPAR IgG (50-100 microg/day) was injected s.c. for 7 days (day 1-7) at the site of tumor cell inoculation (mammary fat pad), and animals were sacrificed at various time points for evaluation of tumor growth and metastases. Animals receiving ruPAR IgG showed a marked decrease in tumor growth and metastases as compared with control tumor-bearing animals receiving the same dose of preimmune rabbit IgG. Histological analysis of experimental primary tumors showed marked tumor necrosis that was due to increased tumor cell apoptosis as determined by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Together, these studies demonstrate the ability of anti-uPAR antibody to decrease tumor volume and detect the presence of microscopic occult tumor metastases in malignancies where uPA/uPAR play a key role in tumor progression.
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PMID:Urokinase receptor antibody can reduce tumor volume and detect the presence of occult tumor metastases in vivo. 1195 2

Urokinase-type plasminogen activator (uPA) is a serine protease that is causally involved in cancer progression, especially invasion and metastasis. Multiple studies have shown that breast cancer patients whose primary cancer contains high levels of uPA have a significantly worse outcome than patients with low levels. As a prognostic marker for breast cancer the information supplied by uPA is both independent of traditionally used factors and significant in the important subgroup of axillary-node patients. Paradoxically, high levels of plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of uPA, also predict for aggressive disease. Recently, the prognostic impact of both uPA and PAI-1 in axillary node-negative breast cancer was confirmed using two different Level 1 Evidence studies, i.e. in both a randomized prospective trial and a pooled analysis. Therefore, uPA and PAI-1 appear to have fulfilled all the criteria for the routine assessment of prognosis in newly diagnosed breast cancer patients.
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PMID:Urokinase-type plasminogen activator: a potent marker of metastatic potential in human cancers. 1202 52

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is a highly specific enzyme whose only known substrate is the GPI anchor of cell surface proteins. GPI-PLD measurements, however, are technically difficult since the enzyme is expressed at low levels in cells and tissues, and serum contains large amounts of inactive, latent GPI-PLD interfering with protein-based assays. We have therefore developed a semi-quantitative RT-PCR method to measure mRNA expression of all known GPI-PLD isoforms in cells and tissues. In human ovarian cancer cell lines, GPI-PLD mRNA expression correlated with GPI-PLD enzyme activity and with the shedding of the GPI-anchored tumor and prognostic markers, urokinase receptor and CA125, from the cell surface. This supports a potential role for this enzyme in the generation of circulating prognostic markers in malignant tumors. Similarly, in human epithelial cells of the skin, GPI-PLD mRNA expression increased with tumor progression. Whereas normal keratinocytes did not express significant amounts of GPI-PLD mRNA, expression was dramatically induced by serum in immortalized HaCaT keratinocytes and constitutively high and independent of serum in tumorigenic A431 epidermoid carcinoma cells. In addition, GPI-PLD expression was significantly increased in highly malignant. H-ras-transfected murine bladder carcinoma cells as compared to the low malignant, non-transfected parental cells. The competitive RT-PCR described here represents the first quantitative assay specific for cellular GPI-PLD isoforms, and our in vitro analyses suggest that GPI-PLD expression might be associated with tumor malignancy.
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PMID:GPI-specific phospholipase D mRNA expression in tumor cells of different malignancy. 1209 Apr 69

By primarily measuring changes in transcript and protein abundance, conventional genomics and proteomics methods may fail to detect significant posttranslational events that regulate protein activity and, ultimately, cell behavior. To address these limitations, activity-based proteomic technologies that measure dynamics in protein function on a global scale would be of particular value. Here, we describe the application of a chemical proteomics strategy to quantitatively compare enzyme activities across a panel of human breast and melanoma cancer cell lines. A global analysis of the activity, subcellular distribution, and glycosylation state for the serine hydrolase superfamily resulted in the identification of a cluster of proteases, lipases, and esterases that distinguished cancer lines based on tissue of origin. Strikingly, nearly all of these enzyme activities were down-regulated in the most invasive cancer lines examined, which instead up-regulated a distinct set of secreted and membrane-associated enzyme activities. These invasiveness-associated enzymes included urokinase, a secreted serine protease with a recognized role in tumor progression, and a membrane-associated hydrolase KIAA1363, for which no previous link to cancer had been made. Collectively, these results suggest that invasive cancer cells share discrete proteomic signatures that are more reflective of their biological phenotype than cellular heritage, highlighting that a common set of enzymes may support the progression of tumors from a variety of origins and thus represent attractive targets for the diagnosis and treatment of cancer.
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PMID:Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness. 1214 57


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