Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the ability of important regulators of osteoblast function, such as insulin-like growth factor I (IGF-I), transforming growth factor beta 1 (TGF beta 1), and urokinase-type plasminogen activator (uPA) to act as mediators in cell-cell interactions between osteoblast-like cells and metastatic prostate cancer cells, in vitro. In addition, we assessed whether these growth substances can (a) mediate glucocorticoid receptor (GR) function and (b) be implicated in dexamethasone-induced regression of osteoblastic tumors. Exogenous IGF-I, rat/human uPA, and PA-III (rat)/PC-3 (human) prostate cancer cells conditioned media (CM) stimulated the proliferation of rat (UMR 106 cells) and human (MG-63 cells) osteosarcoma cells. This mitogenic activity was completely neutralized by anti-IGF-I specific antibody. In addition, dexamethasone decreased cell growth, up regulated TGF beta 1 mRNA, and down regulated uPA mRNA expression in prostate cancer cells. Furthermore, it inhibited cell growth by activating latent-TGF beta 1 in osteoblast-like cells. In addition, dexamethasone down regulated the expression of IGF-I mRNA in osteoblast-like cells. Therefore, it is conceivable that uPA, TGF beta 1 and IGF-I mediate at least in part cell-cell interactions and GR function in osteoblastic metastases. Conceivably, regression of the osteoblastic tumors produced by high-dose dexamethasone treatment in hormone-refractory prostate cancer patients is been mediated by differential regulation of growth factors, locally.
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PMID:Growth factors mediate glucocorticoid receptor function and dexamethasone-induced regression of osteoblastic lesions in hormone refractory prostate cancer. 917 84

Prostate cancer (PRCA) cells metastasize to bone with high frequency, inducing typical osteosclerotic lesions. To establish if local stimuli on the bone tissue may derive from metastatic colonies of prostatic origin, we evaluated the biologic activities secreted by human prostatic epithelium and effective on osteoblast-like cells in vitro. Supernatant from short-term tissue cultures of human prostatic tissue samples obtained from PRCA (35 cases) and benign prostatic hyperplasia (BPH, 12 cases) patients were applied to three models of cells with osteoblastic phenotype: two normal [rabbit osteoblasts (OB) and rat periosteal cells (PO)] and one transformed (human osteosarcoma cell line, MG63). Proliferative activity was monitored through enzymatic reduction of tetrazolium salts and expressed as relative mitogenic activities (RMA). Analysis of proliferation and alkaline phosphatase (ALP) activity, a marker of osteoblast function, demonstrates that conditioned media (CM) from PRCA cultures stimulate both growth and activity of osteoblast-like cells to a greater extent compared to CM from BPH. Furthermore, cell growth and activity of osteoblast-like cells are progressively increased by CM derived from patients with stage B (tumor confined within the prostate capsule), stage C (locally invasive tumor), and stage D (invasive tumor with distant metastasis) disease. One of the mechanisms potentially underlying the CM-stimulated effects on bone cells is associated with the urokinase (uPA) enzyme route, whose release progressively increases with the stage of disease. However, antibodies against uPA and p-aminobenzamidine (a low molecular weight urokinase inhibitor) treatment, which both inhibit the proliferative and differentiative effects induced by exogenous urokinase, partially slow down the effects of CM from PRCA tissue cultures, suggesting that additional factors are secreted by prostatic tumor cells in vitro. In conclusion, we show that the mitogenic and differentiative activities for osteoblasts produced by prostatic tumor cells in short-term tissue cultures are related to PRCA stage and may predict the behavior of skeletal metastases in single cases of tumor. In addition, the culture methods used may represent a valid model to study prostatic and bone cellular interactions, which may indicate new therapeutic approaches in metastatic prostate tumors.
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PMID:Human prostatic tumor cells in culture produce growth and differentiation factors active on osteoblasts: a new biological and clinical parameter for prostatic carcinoma. 943 95

Expression of urokinase-type plasminogen activator (u-PA) strongly correlates with a malignant tumor cell phenotype. In the multistep process of metastasis, different cellular functions are influenced by urokinase. The enzyme is known to be effective via both proteolytical and signal transduction mechanisms. In the present study, the osteosarcoma cell line MNNG/HOS was transfected with a vector capable of expressing an antisense transcript, complementary to 1,021 bases of the 3' end of u-PA cDNA. This construct was most effective in reducing u-PA expression in previous experiments. Stably transfected antisense (as) cell lines were characterized and compared with the parental MNNG/HOS. Antisense transfection of MNNG/HOS gave the following results: (1) stable incorporation of the construct into the genome of as-clones, as detected by Southern blot analysis; (2) decreased mRNA level of u-PA, as detected by Northern blot analysis; (3) approximately 50% reduced enzyme expression in cell culture medium and cell homogenate; and (4) unchanged cellular proliferation activity and u-PAR expression. In further functional analysis, as-clones showed (1) significantly reduced invasion and motility in modified Transwell chambers (random migration and chemotaxis with collagen I as a chemoattractant); (2) significantly reduced adhesion on matrices of collagen I and vitronectin; (3) unchanged adhesion properties on Matrigel matrix; and (4) reduced metastatic potential to lungs and especially liver in chick embryos after i.v. infection into chorioallantoic membrane veins. Our data show that in MNNG/HOS urokinase influences cellular malignancy by promoting migration and selective adhesion. These specific functions were notable in addition to the effects on invasion and basement membrane degradation.
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PMID:Antisense inhibition of urokinase: effect on malignancy in a human osteosarcoma cell line. 963 7

In the multistep process of tumor metastasis, different cellular functions are known to be influenced by the urokinase plasminogen activator (u-PA). In different types of malignancies, u-PA has been shown to correlate strongly with a malignant tumor cell phenotype. Besides its proteolytic activity, the enzyme is effective by signal transduction mechanisms. To elucidate u-PA functions in osteosarcoma, in the present study, the osteosarcoma cell line MNNG/HOS was transfected with an antisense (as) expression vector encoding the 3' end of u-PA-cDNA. Several stably transfected cell clones were characterized and compared with the parental cell line. The antisense transfection resulted in: (1) stable incorporation of the vector construct into cellular genome, as demonstrated in Southern blot; (2) decreased u-PA expression in Northern blot; (3) 50% reduced u-PA protein expression in both cell homogenate and cell culture medium; (4) unchanged cellular proliferation and u-PAR (urokinase plasminogen activator receptor) expression. In comparing functional analysis, as-clones showed (I) significant reduced in vitro invasion and motility (chemotaxis with collagen I); (II) significantly reduced adhesion activity to both vitronectin and collagen I matrices but unchanged adhesion on matrigel; (III) reduced in vivo metastasis in chick embryos after i.v.-application. All together, this data show that malignancy of the osteosarcoma cell line MNNG/HOS is positively influenced by urokinase in terms of migration and selective adhesion. Both effects were observed besides the previously described enzyme functions in tumor cell invasion and basement membrane degradation.
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PMID:[Antisense inhibition of urokinase in a human osteosarcoma cell line]. 1009 29

Increased activity, membrane association, and secretion of cathepsin B have been shown to correlate positively with invasiveness and the metastatic properties of many tumor entities. Cathepsin B is able to directly facilitate invasion by degrading extracellular matrix components or to indirectly facilitate invasion by activating other matrix-degrading proteases like the urokinase-type plasminogen activator. To investigate the role of cathepsin B in bone tumor invasion, the osteosarcoma cell line MNNG/HOS was stably transfected with an expression vector capable of expressing the antisense cDNA transcript of cathepsin B. Five stably transfected antisense cell clones, the control (vector) cell clones, and the parental cells were characterized. At first, the stable incorporation of the constructs was demonstrated by Southern blot analysis. In ELISA assays, all antisense clones showed a significant reduction at the cathepsin B antigen level (about 70%) as compared with the control cell clones and MNNG/HOS. Similar results were obtained for cathepsin B activity in the antisense-transfected cells. In the antisense cell clones, Northern blot analysis and reverse transcription-PCR revealed a considerable decrease of approximately 50% in the levels of cathepsin B mRNA. Expression of cathepsins L and K (sequence homologies) was not affected. The invasive potential and migration of untransfected and transfected tumor cell clones in vitro were analyzed in Transwell chambers. Antisense-transfected cells showed a markedly lower invasion and motility than did MNNG/HOS and the controls. Adhesion to collagen I and matrigel matrices was not affected. These results demonstrate that cathepsin B is involved in the complex proteolytic processes in invasive osteosarcomas.
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PMID:Inhibitory effects of antisense cathepsin B cDNA transfection on invasion and motility in a human osteosarcoma cell line. 1060 50

The effects of heat treatment on the viability and fibrinolytic potential of four cultured human carcinoma cell lines, fibrosarcoma cells (HT-1080), lung adenocarcinoma cells with highly metastatic potential (HAL-8), melanoma cells (Bowes) and osteosarcoma cells (NY), determined by measuring their levels of urokinase-type plasminogen activator (u-PA) and its specific receptor (u-PAR), were investigated by comparing them with those of human umbilical vein endothelial cells (HUVECs). HUVECs incubated at 43 degrees C for 120 min exhibited no decrease in viability but exhibited an increase in both u-PA and u-PAR. HT-1080 and HAL-8 showed a moderately high heat-resistance (viability, 60-90%) that correlated with the reduction of u-PAR but not u-PA. On the other hand, Bowes and NY cells, with poor heat-resistance (viability, 20-50%), exhibited stronger cell-associated u-PA activity when they survived at 43 degrees C for 120 min. Since the u-PA/u-PAR system is directly involved in the invasiveness and metastatic potential of carcinoma cells, hyperthermia would alter the biological activity of these carcinoma cells.
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PMID:Effect of hyperthermia on the viability and the fibrinolytic potential of human cancer cell lines. 1080 68

FSAP (Factor VII-activating protease) is a new plasma-derived serine protease with putative dual functions in haemostasis, including activation of coagulation Factor VII and generation of urinary-type plasminogen activator (urokinase). The (auto-)activation of FSAP is facilitated by polyanionic glycosaminoglycans, such as heparin or dextran sulphate, whereas calcium ions stabilize the active form of FSAP. In the present study, extracellular RNA was identified and characterized as a novel FSAP cofactor. The conditioned medium derived from various cell types such as smooth muscle cells, endothelial cells, osteosarcoma cells or CHO (Chinese-hamster ovary) cells contained an acidic factor that initiated (auto-)activation of FSAP. RNase A, but not other hydrolytic enzymes (proteases, glycanases and DNase), abolished the FSAP cofactor activity, which was subsequently isolated by anion-exchange chromatography and unequivocally identified as RNA. In purified systems, as well as in plasma, different forms of natural RNA (rRNA, tRNA, viral RNA and artificial RNA) were able to (auto-)activate FSAP into the two-chain enzyme form. The specific binding of FSAP to RNA (but not to DNA) was shown by mobility-shift assays and UV crosslinking, thereby identifying FSAP as a new extracellular RNA-binding protein, the K(D) estimated to be 170-350 nM. Activation of FSAP occurred through an RNA-dependent template mechanism involving a nucleic acid size of at least 100 nt. In a purified system, natural RNA augmented the FSAP-dependent Factor VII activation several-fold (as shown by subsequent Factor Xa generation), as well as the FSAP-mediated generation of urokinase. Our results provide evidence for the first time that extracellular RNA, present at sites of cell damage or vascular injury, can serve an important as yet unrecognized cofactor function in haemostasis by inducing (auto-)activation of FSAP through a novel surface-dependent mechanism.
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PMID:Extracellular RNA is a natural cofactor for the (auto-)activation of Factor VII-activating protease (FSAP). 1565 66

The urokinase-type plasminogen activator (uPA) receptor (uPAR) has been implicated in signal transduction and biological processes including cancer metastasis, angiogenesis, cell migration, and wound healing. It is a specific cell surface receptor for its ligand uPA, which catalyzes the formation of plasmin from plasminogen, thereby activating the proteolytic cascade that contributes to the breakdown of extracellular matrix, a key step in cancer metastasis. We have synthesized three different DNA enzymes (Dz372, Dz483 and Dz720) targeting uPAR mRNA at three separate purine (A or G)-pyrimidine (U or C) junctions. Two of these DNAzymes, Dz483 and Dz720, cleaved uPAR transcript in vitro with high efficacy and specificity at a molar ratio (uPAR to Dz) as low as 1 : 0.2. When analyzed over 2 h with a 200-fold molar excess of DNAzymes to uPAR transcript, Dz720 and Dz483 were able to decrease uPAR transcript in vitro by approximately 93% and approximately 84%, respectively. They also showed an ability to cleave uPAR mRNA in the human osteosarcoma cell line Saos-2 after transfection. The DNAzyme Dz720 decreased uPAR mRNA within 4 h of transfection, and inhibited uPAR protein concentrations by 55% in Saos-2 cells. The decrease in uPAR mRNA and protein concentrations caused by Dz720 significantly suppressed Saos-2 cell invasion as assessed by an in vitro Matrigel assay. The use of DNAzyme methodology adds a new potential clinical agent for decreasing uPAR mRNA expression and inhibiting cancer invasion and metastasis.
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PMID:Inhibition of urokinase receptor gene expression and cell invasion by anti-uPAR DNAzymes in osteosarcoma cells. 1600 57

Interleukin-1 (IL-1) plays key roles in altering bone matrix turnover. This turnover is regulated by matrix metalloproteinases (MMPs), tissue inhibitor of matrix metalloproteinases (TIMPs), and the plasminogen activation system, including tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) , and plasminogen activator inhibitor type-1 (PAI-1). In this study, we examined the effect of IL-1alpha on the expression of the MMPs, TIMPs, tPA, uPA, and PAI-1 genes in osteoblasts derived from the rat osteosarcoma cell line ROS 17/2.8. The cells were cultured in alpha-minimum essential medium containing 10% fetal bovine serum with 0 or 100 U/ml of IL-1alpha for up to 14 days. The levels of MMPs, TIMPs, uPA, tPA, and PAI-1 expression were estimated by determining the mRNA levels using real-time RT-PCR and by determining protein levels using ELISA. In IL-1alpha cultures, the expression levels of MMP-1, -2, -3, -13, and -14 exceeded that of the control through day 14 of culture, and the expression of MMPs increased markedly from the proliferative to the later stages of culture. The TIMP-1, -2, and -3 expression levels increased from the initial to the proliferative stages of culture. The expression of tPA increased greatly during the proliferative stage of culture, and uPA expression increased throughout the culture period, increasing markedly from the proliferative to the later stages of culture. In contrast, PAI-1 expression decreased in the presence of IL-1alpha through day 14. These results suggest that IL-1alpha stimulate bone matrix turnover by increasing MMPs, tPA, and uPA production and decreasing PAI-1 production by osteoblasts, and incline the turnover to the resolution.
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PMID:The effect of IL-1alpha on the expression of matrix metalloproteinases, plasminogen activators, and their inhibitors in osteoblastic ROS 17/2.8 cells. 1631 28

Silibinin is a natural flavonoid antioxidant with anti-hepatotoxic properties and pleiotropic anticancer capabilities. We tested the hypothesis that silibinin inhibits cellular invasiveness by down-regulating the focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK)-dependent c-Jun/activator protein-1 (AP-1) induction, which leads to inhibition of urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) expressions in human osteosarcoma MG-63 cells. We found that silibinin decreased cell adhesion and invasiveness, as well as inhibited u-PA and MMP-2 expressions. Silibinin reduced ERK 1/2 phosphorylation, but had no effects on the phosphorylation of c-Jun N-terminal kinases (JNKs) 1/2, p38 and Akt. Silibinin suppressed AP-1-binding activity and c-Jun levels and its phosphorylation without changes of c-Fos and Ets-1 levels. Silibinin also inhibited interleukin-6-induced ERK 1/2 and c-Jun phosphorylation, and cell invasiveness. Thus, silibinin may possess an anti-metastatic activity in MG-63 cells.
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PMID:Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2. 1711 26


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