Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effect of urokinase on the tumor growth and metastasis formation of rabbit V2 carcinoma, having low thromboplastic and high fibrinolytic activities, was examined. Weight of the tumor and lymphogenous metastases tended to increase, but the number of metastatic foci in the lungs was unchanged by the administration of urokinase. Diminution of fibrin deposits and connective tissue reaction in association with increase in the pattern of invasive growth was recognized at the advancing border of the tumors in the urokinase-treated group. In the intravenously induced pulmonary metastases, the number of metastatic foci decreased significantly in the urokinase-treated group. Fibrin was demonstrated at the site of tumor cell embolism by the conjugated anti-rabbit fibrinogen antibody. The growth of metastatic foci in the lungs was not affected by the treatment with urokinase. Enhancing effect of urokinase on fibrin resolution might promote the local tumor growth and release of tumor cells into the vessels, but interfere with the lodgement of tumor cells in remote organs.
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PMID:Effect of urokinase on growth and metastases of rabbit V2 carcinoma. 64 Mar 28

The invasiveness of human gastric carcinoma cell lines (MKN45 and MKN28) in the subcutaneous tissue of nude mice and the degrading capacities of extracellular matrix (ECM) were studied. MKN45 cells were more invasive than were the MKN28 cells. Immunostaining revealed dense lamellar accumulation of fibronectin (FN) around the tumors. Along the front of the invasive MKN45 growth, however, the FN fibers were discontinuous and/or had completely vanished; the MKN28 tumor showed no FN fiber disconnection. ECM components other than FN never displayed such peritumoral massive accumulation. Cocultivation of human fibroblasts with MKN45 cells, more evidently than with MKN28 cells, revealed degradation of FN produced by fibroblasts in contact with each tumor. Both cell lines produced several FN-degrading enzymes in serum-free cultures. Proteases from the MKN45 medium were more active than were those of MKN28 in urokinase-type plasminogen activator (uPA) and metal-dependent serine proteinase-like proteases of 75 and 68 kDa in molecular weight (MW). Type I collagen-degrading 48-kDa protease was also detected from MKN45 medium but not from the MKN28 medium. MKN28 cells secreted other kinds of FN-degrading enzymes, estimated at approximate MWs of 29 and 100-150 kDa. We found no distinct differences in capacity to produce ECM components or ability to adhere to purified ECM components between these two cell lines. From these results we conclude that the stromal invasion of these cells into the subcutaneous tissue of nude mice is profoundly related to their FN-degrading capability. This capability may be catalyzed by uPA and/or metal-dependent serine proteinase-like proteases of 75 and 68 kDa.
Invasion Metastasis 1992
PMID:Fibronectin degradation by human gastric carcinoma cell lines and its associated proteases in relation to stromal invasion in nude mice. 129 40

The human epidermoid carcinoma cell line HEp-3 gives rise to spontaneous metastases in nude mice and in the chick chorioallantoic membrane (CAM) assay system. Cells passaged continuously on the CAM retain their ability to form metastases, while cells carried in vitro lose metastatic potential with time. A HEp-3 cell line derived from a highly metastatic CAM tumor was grown continuously in vitro for 16 weeks. At 2-week intervals the cells were tested on the CAM for metastatic ability and assayed for expression of urokinase-type plasminogen activator (uPA) and the M(r) 92,000 and M(r) 72,000 gelatinase/type IV collagenases, enzymes the expression of which has previously been shown to correlate with tumor cell dissemination. Expression of proteins which modulate the degradative potential of these enzymes, plasminogen activator inhibitors 1 and 2 (PAI-1, PAI-2), uPA receptor, and tissue inhibitors of metalloproteases 1 and 2 (TIMP-1 and TIMP-2), were also assayed. As previously reported the metastatic ability of these cells decreased with time in culture and was almost completely lost by 8 weeks in vitro. Secreted uPA activity remained essentially unchanged, even though uPA mRNA levels decreased with time. There was also a decrease in PAI-1 and PAI-2 mRNA. However, PAI-1 protein concentration in conditioned medium remained relatively constant, and only trace amounts of PAI-2 protein could be detected in cell lysates. Steady-state levels of uPA receptor were lowest at 2 weeks then increased sharply at 4 weeks and remained relatively constant thereafter. A decrease in secreted M(r) 92,000 and M(r) 72,000 gelatinase activities and their corresponding mRNAs was observed well after the loss of the metastatic phenotype. During the 16 weeks in culture TIMP-1 mRNA levels changed slightly, while TIMP-2 mRNA increased more than 2-fold. These data suggest that a metalloproteinase other than the gelatinase/type IV collagenases may be involved in HEp-3 metastasis.
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PMID:Loss of the metastatic phenotype by a human epidermoid carcinoma cell line, HEp-3, is accompanied by increased expression of tissue inhibitor of metalloproteinase 2. 132 11

We studied the role of the fibrinolytic function in the invasiveness of murine melanoma B16F1 and F10 cells using a reconstituted matrix on a filter in a modified Boyden chamber. The main species of plasminogen activators (PAs) synthesized in cell lysates and released into conditioned media by these cells was found to be tissue-type PA (t-PA). The invasiveness of these cell lines was enhanced by adding plasminogen to the gel matrix. This enhancing effect of plasminogen was markedly suppressed by adding anti-t-PA IgG and plasmin inhibitors into the gel matrix, but less affected by anti-urokinase-type PA (u-PA) IgG, offering more evidence to the hypothesis that the activation of the fibrinolytic system by PAs plays an important role in the invasiveness of murine melanoma B16 cell lines, and indicating that t-PA contributed more than u-PA to the invasive potential of these cells into the pericellular matrix.
Invasion Metastasis 1992
PMID:Fibrinolysis activity promotes tumor invasiveness of B16 melanoma cell lines through a reconstituted gel matrix. 138 Sep 52

The study of the plasminogen-plasmin system has, in the past, contributed much to the understanding of fibrinolysis and thrombolysis. Attention is now focused on the role of the components of this system in many biologic functions. Findings of uPA, its receptor and its inhibitor in many tumor tissues and tumor cell lines, strongly implicate their involvement in tumor invasion, tumor cell proliferation and metastasis. The characteristics of the plasminogen activators, the uPA receptor and the plasminogen activator inhibitors as well as their expression and regulation in tumors and tumor cell lines are reviewed.
Cancer Metastasis Rev 1992 Nov
PMID:The plasminogen-plasmin system in malignancy. 142 20

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. Receptor-bound urokinase-type plasminogen activator (uPA) appears to play a key role in these events. uPA converts plasminogen into plasmin and thus mediates pericellular proteolysis during cell migration and tissue remodeling under physiological and pathophysiological conditions. uPA is secreted as an enzymatically inactive proenzyme (pro-uPA) by tumor cells and stroma cells. uPA exerts its proteolytic function on normal cells and tumor cells as an ectoenzyme after having bound to a high-affinity cell surface receptor. After binding, pro-uPA is activated by serine proteases (e.g. plasmin, trypsin or plasma kallikrein) and by the cysteine proteases cathepsin B or L, resp. Receptor-bound enzymatically active uPA converts plasminogen to plasmin which is bound to a different low-affinity receptor on tumor cells. Plasmin then degrades components of the tumor stroma (e.g. fibrin, fibronectin, proteoglycans, laminin) and may activate procollagenase type IV which degrades collagen type IV, a major part of the basement membrane. Hence receptor-bound uPA will promote plasminogen activation and thus the dissolution of the tumor matrix and the basement membrane which is a prerequisite for invasion and metastasis. Tissues of primary cancer and/or metastases of the breast, ovary, prostate, cervix uteri, bladder, lung and of the gastrointestinal tract contain elevated levels of uPA compared to benign tissues. In breast cancer uPA and PAI-1 antigen in tumor tissue extracts are independent prognostic factors for relapse-free and overall survival.
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PMID:Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. 151 91

The production of metastasis appears to involve a number of different proteases including the urokinase form of plasminogen activator, cathepsin B, cathepsin D and various metalloproteases. Early data implicating these proteases in metastasis were mostly indirect and based on correlation studies in animal models. More recent work, using specific protease inhibitors and antibodies against proteases to block experimental metastasis, have provided more direct evidence that proteases play a role in cancer spread. In addition, transfection of genes encoding certain proteases increases the metastatic phenotype of the recipient cells. In human tumours, a number of different proteases also correlate with metastatic potential. It is concluded that certain proteases may be new prognostic markers in cancer as well as new targets for anti-metastatic therapy.
Clin Exp Metastasis 1992 May
PMID:The role of proteolytic enzymes in cancer invasion and metastasis. 158 84

Murine melanoma B16-F1 cells of low metastatic potential were transfected with the human gene for the prepro form of urokinase in an SV40 expression vector (plasmid pSV2-uPA), and cells expressing high amounts of the human urokinase gene product were selected for by an enzyme-linked immunosorbent assay specific for human high molecular weight urokinase. Southern analysis showed one of the cell lines (clone 7) had incorporated 150 copies of the pSV2-uPA plasmid into its genomic DNA. The human urokinase synthesized by the pSV2-uPA-transfected murine B16 cells was found to be glycosylated and did not bind to the murine cell surface urokinase receptor sites. In an in vivo assay that measures metastasis from a primary tumor (spontaneous metastatic assay), clone 7 cells showed an increased ability to metastasize (12 of 12 mice showed metastatic tumors), while control cells showed a lower ability to metastasize (only 2 of 11 mice showed metastatic tumors). In a second in vivo assay, which measures only the steps of the metastatic migration process during which tumor cells extravasate from the blood and then grow into pulmonary tumors (lung colonization assay), a significant multifold increase in the ability to form lung tumors was shown by the high human urokinase-secreting B16-F1 cells. In B16-F10 cells incorporating an antisense sequence to preprourokinase (plasmid pSV1-ASuPA-265) and secreting significantly decreased amounts of murine urokinase, a corresponding significant decrease in lung colonization was observed. These results provide direct experimental support for a role of secreted (non-surface-bound) urokinase in the colonization steps of the metastatic process. Furthermore, the data indicate that the higher lung colonization ability of the B16-F10 line than of the B16-F1 line is primarily based on the quantitative differences in their abilities to produce urokinase.
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PMID:Relationship between secreted urokinase plasminogen activator activity and metastatic potential in murine B16 cells transfected with human urokinase sense and antisense genes. 170 50

Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a solid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM produced in vitro and in basement membranes of the cornea and blood vessels in vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.
Cancer Metastasis Rev 1990 Nov
PMID:Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. 170 86

The correlation between the production of plasminogen activators (PA), especially urokinase-type PA (u-PA), by cancer cells and their metastatic potential was studied. For this purpose, cells from the human rectal adenocarcinoma tumor line (RCM-l/nu) originally maintained by serial passage in nude mice as the solid subcutaneous tumor, were injected into the spleen. Cancer cells from liver metastatic foci were suspended and then injected into the spleen. After 10 cycles of this selection, a highly metastatic liver tumor line termed L-10 was obtained. The amount of u-PA in the supernatant of the tumor homogenate of L-10 was larger than that of RCM-l/nu. Using an in vitro culture system, the media conditioned by L-10 cells had a higher PA activity and a higher u-PA antigen level than by RCM-l/nu cells. The apparent difference in u-PA activity and antigen levels of these two lines was not due to the difference in the production of plasminogen activator inhibitor (PAI), because PAI antigen level and PAI activity in the culture media were almost equal between them. No tissue-type PA production was detectable in these tumor lines. From these results we deduce that u-PA may play an important role in tumor metastasis.
Invasion Metastasis 1991
PMID:Correlation between urokinase-type plasminogen activator production and the metastatic ability of human rectal cancer cells. 176 31


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