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)

A large body of evidence suggests a role for the proteolytic plasminogen activation system in invasion and metastatic spread of tumor cells including melanoma cells. Plasminogen activation by human melanoma cell lines and B16 mouse melanoma cell lines has been extensively studied. Apart from expression of urokinase-type plasminogen activator, melanoma cells differ from cells derived from other tumors in the abundant expression of tissue-type plasminogen activator. The possible role of both types of plasminogen activator in metastatic spread of melanoma cells is discussed. In recent years the localization of mRNAs and proteins of the plasminogen activation system and of related proteins in cutaneous melanocytic tumor progression has been well documented. A possible mechanism for migration of melanoma cells in vivo is suggested.
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PMID:The plasminogen activation system in melanoma cell lines and in melanocytic lesions. 879 Dec 64

To investigate the role of plasmin(ogen) in mammary tumor development and progression, plasminogen-deficient mice were crossed with transgenic mice expressing Polyoma middle T antigen under the control of the mouse mammary tumor virus long terminal repeat. Virgin females carrying the Polyoma middle T antigen uniformly developed multiple, bilateral mammary tumors, regardless of the presence or absence of circulating plasminogen. Both the age at which these tumors became palpable and subsequent tumor growth were indistinguishable between plasminogen-deficient mice and plasminogen-expressing littermates. However, plasminogen was found to greatly modify the metastatic potential in this model system; lung metastasis in plasminogen-deficient mice was significantly reduced as compared to littermate controls with respect to frequency of occurrence, total number of metastases, and total metastatic tumor burden. Plasminogen activators, as well as other key factors that govern the conversion of plasminogen to plasmin, were expressed within the mammary tumors, suggesting that the plasminogen/plasmin system may promote metastasis by contributing to tumor-associated extracellular proteolysis. The data provide direct evidence that plasmin(ogen) is a tumor progression factor in PymT-induced mammary cancer, and support the hypothesis that hemostatic factors play an important role in tumor biology.
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PMID:Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice. 967 88

Effects of all-trans retinoic acid (RA) on the net enzymatic activity of secreted, extracellular urokinase-type plasminogen activator (u-PA) in DU-145 human prostatic carcinoma cells were examined to assess the potential use of retinoids in human prostate cancer prevention and treatment. u-PA is associated with tumor progression involving invasion and metastasis. Based on a chromogenic substrate assay, results show that DU-145 cells secrete five times more u-PA than normal human prostatic epithelium. DU-145 cells were treated with 0.1 to 10 micrometer RA for 48 h. This short treatment of cells with RA did not inhibit growth. After a 48-h treatment of cultures with RA, serum-free conditioned medium was analyzed for u-PA activity by SDS-PAGE zymography. Two major bands of u-PA with Mr of approximately 54,000 (high molecular weight u-PA) and approximately 33,000 (low molecular weight u-PA) were detected. Plasminogen-dependent catalytic activity of these bands could be specifically inhibited with antibody to u-PA, confirming that these bands represent u-PA. A 48-h treatment with 1.0 micrometer RA reduced u-PA activity in conditioned medium to 51.6% of control. A 50% reduction in free u-PA antigen level, as compared to control, was further demonstrated at 1.0 micrometer RA by Western blot analysis and densitometry. These results show that RA can decrease the net extracellular urokinase activity produced by prostatic carcinoma cells. It is proposed that these effects of RA may have important implications not only in the chemoprevention of prostate cancer, by inhibition of promotion of prostatic intraepithelial neoplasia to invasive carcinoma, but also in tumor progression during invasion and metastasis, by decreasing extracellular matrix degradation, as shown in our accompanying article (M. M. Webber and A. Waghray, Clin. Cancer Res., 1: 755-761, 1995).
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PMID:Retinoic acid modulates extracellular urokinase-type plasminogen activator activity in DU-145 human prostatic carcinoma cells. 981 41

Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, inactivates urokinase-type plasminogen activator (uPA) and regulates degradation of the extracellular matrix; whether it functions for or against tumor progression, however, has been the subject of controversy. To assess the role of PAI-1 in invasion and proliferation of hepatocellular carcinoma (HCC) cells, HLE cells were transfected with a vector capable of expressing an antisense PAI-1 transcript. Analysis of seven stably transfected clones (PAI-1-) showed reductions of 81% in PAI-1 mRNA by northern blot analysis and 63% in the cellular PAI-1 antigen level by enzyme-linked immunosorbent assay (ELISA). There was no change in the levels of secreted PAI-1 or PAI-2. The activity of cellular uPA increased by 54%, without change in the protein level or the secreted uPA activity evaluated by ELISA. Morphologically, PAI-1 antisense induced a spindle shape with narrower cytoplasmic processes in HLE cells. The forced inhibition of PAI-1 increased the invasion and the growth of PAI-1- cells by 75% and 82%, respectively. These results suggest that PAI-1 plays a role in inhibiting invasion and proliferation, and the balance between uPA and PAI-1 expression is important to assess the invasiveness of HCC cells.
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PMID:Inhibitory role of plasminogen activator inhibitor-1 in invasion and proliferation of HLE hepatocellular carcinoma cells. 1047 Feb 87

Plasminogen activator inhibitor type 1 (PAI-1) plays a key role in tumor progression and is believed to control proteolytic activity and cell migration during angiogenesis. We report here that host PAI-1, at physiological concentration, promotes in vivo tumor invasion and angiogenesis. In sharp contrast, inhibition of tumor vascularization was observed when PAI-1 was produced at supraphysiologic levels, either by host cells (transgenic mice overexpressing PAI-1) or by tumor cells (after transfection with murine PAI-1 cDNA). This study provides for the first time in vivo evidence for a dose-dependent effect of PAI-1 on tumor angiogenesis. Of great interest is the finding that PAI-1 produced by tumor cells, even at high concentration, did not overcome the absence of PAI-1 in the host, emphasizing the importance of the cellular source of PAI-1.
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PMID:Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. 1528 8

Plasminogen activator inhibitor-1 (PAI1) can promote cancer progression, and its protein expression in tumors is an independent indicator of poor prognosis in many forms of cancer. Here, we show that high PAI1 mRNA levels also predict for shorter overall survival in two independent breast cancer data sets, highlighting the importance of its transcriptional regulation. The -675insG (4G/5G) single-nucleotide polymorphism in the PAI1 gene promoter has been shown to influence PAI1 transcription, with the 4G allele eliciting higher reporter gene expression in vitro and higher levels of circulating PAI1 in vivo. Nevertheless, its genotypic distribution in 2,539 British women with invasive breast cancer was virtually identical to that seen in 1,832 matched controls (P = 0.72), and annual mortality rates for 4G4G, 4G5G, and 5G5G cases were 2.6%, 2.8%, and 3.1% per year, respectively (P = 0.10). Thus, there was no association with breast cancer incidence or outcome, and in a separate set of breast cancers, the 4G/5G single-nucleotide polymorphism showed no association with PAI1 mRNA expression (P = 0.85). By contrast, connective tissue growth factor (CTGF), which can regulate PAI1 expression in culture, was associated with PAI1 expression in three independent cohorts (P << 0.0001). In addition, PAI1 gene copy number differences in the tumors were correlated with PAI1 mRNA expression (P = 0.0005) and seemed to affect expression independently of CTGF. Thus, local factors, such as CTGF and genomic amplification, seem to be more important than germ line genetic variation in influencing PAI1 expression and its untoward effects in breast cancer.
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PMID:Prognostic value of PAI1 in invasive breast cancer: evidence that tumor-specific factors are more important than genetic variation in regulating PAI1 expression. 1711 35

The remodelling of extracellular matrix and angiogenesis represent two essential processes for tumor growth and metastatic dissemination. These phenomena imply many interactions between tumor cells and host cells via action of various proteases including metalloproteinases (MMPs) whose activity is controlled by TIMPs and serine proteases (tissue type Plasminogen Activator (tPA), urokinase type Plasminogen Activator (uPA) and plasmin) inhibited in particular by PAI-1 (Plasminogen Activator Inhibitor- 1). Evolution of tumors depends on the joint action of these enzymes, as well as precise balance between these proteases and their physiological inhibitors. Proteases regulate the fate and activity of many proteins by controlling appropriate intra- or extracellular localization; shedding from cell surfaces ; activation or inactivation of proteases and other enzymes, cytokines, hormones or growth factors and exposure of cryptic neoproteins. Hence, proteases initiate, modulate and terminate a wide range of important cellular functions by processing bioactive molecules an thereby control essential biological processes, such as DNA replication, cell-cycle progression, cell proliferation, differentiation and migration, morphogenesis and tissue remodelling, neuronal outgrowth, haemostasis, wound healing, immunity, angiogenesis and apoptosis. Work completed has for objective to elucidate the specific part played by serine proteases and MMPS produced by the host cells in the processes of tumor growth and angiogenesis. By using an original model of transplantation of malignant murine keratinocytes (PDVA cell line) into deficient mice (-/-) and wild type mice (+/+), we showed the essential proteolytic role of PAI-1 produced by host cells in the tumor progression and angiogenesis. This mechanism of PAI-1 action was confirmed by using the model in vitro aorta rings. By using deficient mice for one or two MMPs combined (MMP-2, MMP-3, MMP-9, MMP-11, MMP-2&9, MMP3&9), we demonstrated that only the combined deficiency of MMP-2 and -9 showed an absence of tumor invasion and angiogenesis. These data suggest the existence of compensatory mechanisms of a MMP by another MMP or another proteolytic way. These phenomena of redundancy are to be known and detailed to elaborate in a near future, the development of specific inhibitors of MMPS.
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PMID:[Roles of serine proteases and matrix metalloproteinases in tumor invasion and angiogenesis]. 1728 5

Plasminogen activator inhibitor-1 (PAI-1) is an important endogenous inhibitor of urokinase-type plasminogen activator. Its action in tumor angiogenesis is complicated, varying with experimental setting and its cellular origin. To further understand the mechanism of the effect of PAI-1 on tumor angiogenesis, especially newly established tumor vasculature in early tumor progression, stable transfectants (TO-PAI-1) of the human prostate adenocarcinoma, PC3, were generated in which PAI-1 expression is under the control of the tetracycline-responsive promoter (Tet-On system). The TO-PAI-1 transfectants exhibit tight inducibility of expression of biologically active PAI-1 in vitro. Induction of PAI-1 expression in nude mice resulted in significant inhibition of tumor growth. This inhibition appears to be due to the effect of PAI-1 on angiogenesis, because it is manifested by an initial wave of tumor endothelial apoptosis accompanied by induction of tumor cell apoptosis and inhibition of tumor cell proliferation. Similar endothelial apoptosis is observed in vitro when human microvascular endothelial cells are physically cocultivated with TO-PAI-1 cells on vitronectin-coated plate. Taken together, these data show for the first time that PAI-1 induces endothelial apoptosis in the newly established tumor vasculature.
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PMID:Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. 1848 10

Plasminogen activator inhibitor-1 (PAI-1) paradoxically enhances tumor progression and angiogenesis; however, the mechanism supporting this role is not known. Here we provide evidence that PAI-1 is essential to protect endothelial cells (ECs) from FasL-mediated apoptosis. In the absence of host-derived PAI-1, human neuroblastoma cells implanted in PAI-1-deficient mice form smaller and poorly vascularized tumors containing an increased number of apoptotic ECs. We observed that knockdown of PAI-1 in ECs enhances cell-associated plasmin activity and increases spontaneous apoptosis in vitro. We further demonstrate that plasmin cleaves FasL at Arg144-Lys145, releasing a soluble proapoptotic FasL fragment from the surface of ECs. The data provide a mechanism explaining the proangiogenic activity of PAI-1.
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PMID:Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. 1883 34

Plasminogen activator inhibitor (PAI)-1 is associated with cancer progression, fibrosis and thrombosis. It is expressed in the stomach but the mechanisms controlling its expression there, and its biological role, are uncertain. We sought to define the role of gastrin in regulating PAI-1 expression and to determine the relevance for gastrin-stimulated cell migration and invasion. In gastric biopsies from subjects with elevated plasma gastrin, the abundances of PAI-1, urokinase plasminogen activator (uPA), and uPA receptor (uPAR) mRNAs measured by quantitative PCR were increased compared with subjects with plasma concentrations in the reference range. In patients with hypergastrinemia due to autoimmune chronic atrophic gastritis, there was increased abundance of PAI-1, uPA, and uPAR mRNAs that was reduced by octreotide or antrectomy. Immunohistochemistry revealed localization of PAI-1 to parietal cells and enterochromaffin-like cells in micronodular neuroendocrine tumors in hypergastrinemic subjects. Transcriptional mechanisms were studied by using a PAI-1-luciferase promoter-reporter construct transfected into AGS-G(R) cells. There was time- and concentration-dependent increase of PAI-1-luciferase expression in response to gastrin that was reversed by inhibitors of the PKC and MAPK pathways. In Boyden chamber assays, recombinant PAI-1 inhibited gastrin-stimulated AGS-G(R) cell migration and invasion, and small interfering RNA treatment increased responses to gastrin. We conclude that elevated plasma gastrin concentrations are associated with increased expression of gastric PAI-1, which may act to restrain gastrin-stimulated cell migration and invasion.
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PMID:Gastrin stimulates expression of plasminogen activator inhibitor-1 in gastric epithelial cells. 2119 25


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