UMLS:C0007097 - FACTA Search

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Query: UMLS:C0007097 (carcinoma)
152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plasminogen activator (PA)/plasmin system is thought to be involved in processes such as tumor invasion and wound healing, during which epithelial and mesenchymal cells come close together. However, information on regulation of the PA/plasmin system during epithelial-mesenchymal interactions is scarce. Therefore, we examined the in vitro modulation of the production and activity of the components of the PA/plasmin system in squamous carcinoma cells (SCC-4) and normal human keratinocytes in relation to cell density and the presence or absence of fibroblasts (3T3 cells). There was an inverse relation between cell density and mRNA expression for urokinase-type plasminogen activator (u-PA) and u-PA receptor in both SCC-4 cells and keratinocytes. In addition, such a relation was found for plasminogen activator inhibitor types 1 (PAI-1) and 2 (PAI-2) in SCC-4 monocultures, but not in keratinocyte monocultures. In contrast to monocultures, variation of cell density did not affect the mRNA expression of the components of the PA/plasmin system in cocultures of SCC-4 cells or keratinocytes with 3T3 cells. However, the relative expression of mRNAs in co-cultures was clearly different from that in monocultures, especially at low cell density. For most of the components of the PA/plasmin system, a decrease in mRNA expression and u-PA receptor protein was observed at most cell densities, whereas for PAI-1 only in keratinocytes a marked increase was documented. Zymography of supernatants revealed that the levels of both free u-PA and PA-PAI were increased in SCC-4/3T3 co-cultures, whereas in keratinocytes/3T3 co-cultures, only levels of the PA-PAI complex were increased, while the amount of free u-PA activity decreased. This occurred despite the increase u-PA immunoreactivity and was probably caused by the markedly elevated levels of immunoreactive PAI-1. The results of the present study reveal that the production and synthesis of various components of the PA/plasmin system in keratinocytes and SCC-4 cells depend on the density of epithelial cells and are modulated by fibroblasts, probably through a direct cell-cell or cell-matrix contact. Fibroblast-induced modulations are similar in keratinocytes and SCC-4 cells except for the regulation of PAI-1, which is markedly enhanced only in keratinocytes. This suggests that the modulation of PA activity in the direct microenvironment may be different under physiologic and pathologic conditions.
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PMID:Differential regulation of plasminogen activation in normal keratinocytes and SCC-4 cells by fibroblasts. 786 Oct 5

The plasminogen (Plg) system on rat yolk sac carcinoma (L2) cells was characterized by zymography, Western and immunoprecipitation analysis, reverse-transcriptase polymerase chain reaction, binding, and activity assays. The L2 cells produced tissue Plg activator but not urokinase Plg activator and contained RNA for Plg activator inhibitor 1, but Plg activator inhibitor 1 was not detectable by zymography or Western analysis and contained the receptor for urokinase Plg activator. Plg bound to the cells in a saturable manner when plasmin inhibitors were present with a dissociation constant of 1.34 +/- 0.18 x 10(-6) M and 1.54 +/- 0.25 x 10(7) sites/cell. Immunoprecipitation analysis showed that Plg was binding to gp330, a known Plg receptor. Once bound to the L2 cells, Plg was activated by tissue Plg activator to plasmin in a time- and concentration-dependent manner. Under saturating Plg conditions, most of the plasmin produced was released into the medium. Inhibition of plasmin activation occurred when Plg activator inhibitor 1, anticatalytic tissue Plg activator antibody, or Heymann nephritis autoantibody was present.
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PMID:Characterization of plasminogen system on rat yolk sac carcinoma (L2) cells. 786 83

Current evidence regarding the regulation of urokinase-dependent extracellular proteolysis indicates that plasminogen activation is a surface-associated process. We have compared the histological localization of urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) in breast cancer sections using a panel of monoclonal antibodies. First, the ability of six different anti-uPA monoclonal antibodies to recognize pro-uPA, uPA, and in vitro-formed complexes of uPA with either soluble uPAR or with plasminogen activator inhibitor type 1 was compared. Then the reactivity of the anti-uPAR antibodies was tested, and the occurrence of an uPA receptor of about M(r) 55,000 in samples from breast carcinoma was assessed by immunoprecipitating the uPA receptor from an in vitro 125I-labeled tumor extract. Immunocytochemical data from adjacent sections of 10 tumor specimens showed that antibodies recognizing free and bound uPA mostly stain the cytoplasm and the membrane of epithelial tumor cells in confined areas of the tumor and some fibroblast-like stromal cells. Acid pretreatment of tumor sections, which removes receptor-bound uPA, causes a strong reduction of the immunocytochemical reactivity of epithelial tumor cells, whereas staining of fibroblast-like cells is not considerably affected. Consistent with these results, epithelial tumor cells were mostly unreactive to anti-uPAR antibodies unless pretreated with acidic buffer, whereas fibroblast-like stromal cells showed a faint but acid-resistant staining with all anti-uPARs. In conclusion, these results show that occupied uPA receptors are definitely present on the membrane of epithelial tumor cells and suggest the occurrence of uPA-uPAR-dependent proteolytic activity on the surface of breast cancer cells.
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PMID:Tissue distribution of soluble and receptor-bound urokinase in human breast cancer using a panel of monoclonal antibodies. 792 78

The aim of the present paper is to elucidate the pathogenesis of gastric scirrhous carcinoma with special reference to fibrogenesis in cancer stroma and to the mode of cancer invasions. First, there are two hypotheses concerning the origin of the marked increase of collagen fibers in this type of carcinoma. One is thought to be production by fibroblasts stimulated by cancer cells; the other is synthesis by neoplastic cells. Our studies revealed that gastric cancer cells enhanced collagen production by fibroblasts in vitro, suggesting the contribution to the formation of stromal collagen in human gastric scirrhous cancer. However, one of four gastric scirrhous cancer cell lines, NKPS, was found to slightly from collagen fibers in the brain of the nude mouse. We also calculated the number of fibroblastic cells in gastric scirrhous and normal stroma by microscopical image analysis. The results showed that fibroblastic cells in scirrhous stroma were increased four-fold over those in normal stroma. This finding suggests that the mechanism by which fibrous stroma is produced in scirrhous carcinoma may be affected by the increased fibroblastic cells which were stimulated by many kinds of growth factors produced by cancer cells. It is also well known that the infiltrative growth and dispersion of scirrhous cancer cells within the gastric wall is very fast. To assess the mode of cancerous invasion of this carcinoma, we examined the urokinase-type plasminogen activator (uPA) activity of both types of cells (cancer cells and fibroblasts) with a coculture method. Scirrhous cancer cells enhanced production of uPA by fibroblasts. However, non-scirrhous gastric cancer cells produced much uPA by themselves. This finding suggests that scirrhous cancer cells can invade the gastric wall by use of uPA produced by enhanced fibroblasts, but that non-scirrhous cancer cells synthesize much uPA by themselves and can infiltrate the gastric wall.
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PMID:[Pathogenesis and progression of scirrhous carcinoma]. 794 78

The effect of two growth factors ellicited in response to surgical woundings (transforming growth factor alpha [TGF alpha] and beta 1) on the regulation of cellular plasminogen activator activity (PAA) in human transitional carcinoma cell lines, with differing baseline PAA (253J--high; 647V--low), was studied. mRNA transcript levels of PA regulatory proteins in both cell lines were responsive to TGF alpha and TGF beta 1. However, both the magnitude and nature of the response differed markedly between the two lines. TGF alpha increased uPA transcript levels in both cell lines in a dose-dependent fashion. In the case of uPA receptor, exogenous TGF alpha concentrations which increased receptor levels over fivefold in the 253J line had no effect on this transcript in the 647V line. This differential responsiveness was even more pronounced for TGF beta 1. TGF beta 1 appeared to increase uPA transcript in the 253J line in a dose dependent manner while decreasing transcript levels in the 647V line. uPAr mRNA in 253J cells increased over a 19-fold range in response to TGF beta 1 while this same transcript was decreased 14-fold in 647V cells. The most pronounced effect of TGF beta 1 was seen on PAI1 transcript levels in the 253J line. This transcript increased in a concentration dependent fashion from non-detectable levels. These findings demonstrate that growth factors ellicited by surgical wounding may alter the biology of neoplastic cells. Both the growth factor milieu, and intrinsic cellular regulatory mechanism, appear important in determing net PAA in transitional carcinoma cell lines.
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PMID:Regulation of plasminogen activator activity in transitional carcinoma cell lines by wound site growth factors. 795 2

Human colorectal carcinogenesis has been shown previously to be associated with impressive changes in the tissue levels of plasminogen activators and their inhibitors, exemplified by an increase in the urokinase-type plasminogen activator (u-PA) and the inhibitors PAI-1 and PAI-2, and a decrease in tissue-type plasminogen activator (t-PA). In the present study we evaluated the prognostic significance of these parameters to the overall survival of patients with colorectal cancer, in conjunction with several major clinicopathological parameters like age, gender, differentiation grade, and Dukes' stage. Univariate analyses revealed that a low t-PA antigen level, low t-PA activity, and high u-PA/t-PA antigen ratio in normal mucosa and a high u-PA and PAI-2 antigen level in carcinomas are prognostic for a poor overall survival of patients with colorectal cancer. The prognostic value of t-PA antigen and activity in normal mucosa, the antigen ratio of u-PA in carcinoma (C) and t-PA in corresponding normal (N) mucosa [u-PA(C)/t-PA(N) antigen ratio], and PAI-2 antigen in carcinomas was found to be independent from clinicopathological parameters by multivariate analyses. These observations illustrate the clinical importance of the plasminogen activation cascade at the tissue level in colorectal cancer invasion, metastasis, and survival.
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PMID:Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. 803 38

We have studied the prognostic value of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and type 1 plasminogen activator inhibitor (PAI-1) in tumor extracts from 84 patients with squamous cell lung carcinoma and 38 patients with large cell lung carcinoma, measuring each molecule with sandwich enzyme-linked immunosorbent assays. High uPAR levels were significantly associated with short overall survival in patients with squamous cell lung carcinomas when the median value was used as a cutoff point (P = 0.038), while no statistically significant prognostic impact of uPA and PAI-1 levels was found in this group of patients. The combination of high uPAR and high PAI-1 levels did, however, have a particular significant association with short overall survival (P = 0.008). None of the 3 components was found to have a statistically significant prognostic impact in the group of 38 large cell lung cancer patients. There was a positive correlation between uPAR and PAI-1 levels in both groups and between uPA and uPAR levels in the large cell carcinoma patients. In a multivariate analysis, high uPAR was found to be an independent prognostic variable in squamous cell carcinoma patients, with a relative risk of 2.1 (95% confidence interval, 1.1-4.0) and tumor size the only other significant prognostic parameter. These data suggest that uPAR is an important prognostic factor in squamous cell lung carcinoma. In addition to the potential direct clinical usefulness, this information could be helpful in understanding the biology of this disease and developing new therapeutic approaches.
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PMID:Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. 806 62

We previously reported that urokinase (uPA) is produced by the human prostate cancer cell line, PC-3, and could function as a growth factor for cells of the osteoblast phenotype. To examine the role of uPA in metastasis to the skeleton and to extraskeletal sites, we have developed a homologous model of uPA overexpression in a rat prostate cancer cell line. Full length cDNA encoding rat (r) uPA was isolated and subcloned as a 1.4-kilobase XbaI-BspHI fragment in the sense and antisense orientation into the Moloney murine leukemia retroviral vector pYN. The control (pYN) and experimental (pYN-ruPA, pYN-ruPA-AS) plasmids were transfected into Dunning R 3227, Mat LyLu rat prostate carcinoma cells. Experimental clones expressing at least 5-fold higher (pYN-ruPA) or 3-fold lower (pYN-ruPA-AS) than controls were selected, and control and experimental cells were inoculated into the left ventricles of inbred male Copenhagen rats. Animals were sacrificed at timed intervals to examine the evolution of metastatic lesions. Control animals developed metastases to the lumbar vertebrae resulting in spinal cord compression and hind limb paralysis at 20-21 days postinoculation. Animals inoculated with cells overexpressing uPA developed hind limb paralysis significantly earlier (by day 14-15 postinoculation). Additionally, more widespread skeletal (ribs, scapula, and femora) metastases were seen. Serum from experimental animals showed a progressive elevation in alkaline phosphatase levels, and histological examination of lumbar metastases revealed markedly increased osteoblastic activity over that observed in control animals. In contrast to this, animals inoculated with cells underexpressing uPA developed hind limb paralysis significantly later (days 25-29 postinoculation) and displayed decreased tumor metastasis. These studies support a role for the catalytic domain of uPA in enhancing both skeletal and nonskeletal prostate cancer invasiveness and are consistent with a role for the growth factor domain of uPA in mediating an osteoblastic skeletal response.
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PMID:Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. 816 83

Recent studies have shown that molecules involved in generation and regulation of extracellular proteolytic activity are often expressed by non-malignant stromal cells during human cancer invasion. We have studied the expression of the urokinase-type plasminogen activator and the urokinase-type plasminogen activator cell-surface receptor in xenografts of human MDA-MB-231 mammary carcinoma cells growing invasively in nude mice. Northern analysis showed the presence of both human and mouse urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor mRNA in tumor extracts. By in situ hybridization, mRNA for human urokinase-type plasminogen activator and its receptor was detected in virtually all the cancer cells, while mouse urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor mRNA was expressed by tumor-infiltrating fibroblast-like and macrophage-like cells. In invasive areas the cells expressing the 2 murine mRNAs were either the same or located immediately adjacent to each other. This model system has several advantages for studies of the mechanism by which cancer cells induce or recruit stromal cells to produce molecules involved in proteolysis.
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PMID:Expression of uPA and its receptor by both neoplastic and stromal cells during xenograft invasion. 818 59

Baseline cellular plasminogen activator (PA) activity, the cellular proteins responsible for variations in PA activity and the effect of cellular PA activity on cellular adherence to and lysis of fibrin substrate were evaluated in three human transitional carcinoma cell lines. Net PA activity in the cell lines 253J, 639V and 647V was measured using a chromogenic substrate assay. These lines were then analyzed to determine the specific protein(s) responsible for differences in PA activity. mRNA and protein levels of cellular uPA, tPA, PAI1 and PAI2 were measured using Northern blot analysis and ELISA assays. Intact cells were used in an in vitro fibrinolysis assay so as to correlate cell biology with protein and mRNA level observations. Net cellular PA activity in the three cell lines varied over a 20-fold range (253J > 639V > 647V). Net PA activity demonstrated a direct correlation with mRNA transcript and protein levels of uPA/low levels of tPA mRNA were detected in the 253J line. However, tPA protein was not detectable in any of the lines. Both PAI1 and PAI2 were detected in varying amounts in each of the three cell lines. In vitro assays demonstrated a direct correlation between net PA activity and plasminogen dependent fibrin substrate lysis. Cellular adherence to fibrin varied as an inverse function of net PA activity. These findings suggest that variations in cellular uPA levels are principally responsible for variations in PA activity between cell lines. Variations in net PA activity are in turn reflected at the cellular level by differences in ECMP substrate lysis and cellular adherence to fibrin.
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PMID:Diversity and modulation of plasminogen activator activity in human transitional carcinoma cell lines. 818 98

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