Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The usefulness of routine clinical application of the urokinase plasminogen activator in prostate cancer was evaluated. The urokinase values of prostate cancer confined to the organ, with extraprostatic spread and with metastatic disease did not differ and showed no significant difference in comparison with benign prostatic hyperplasia. Urokinase is not a useful parameter in clinical routine.
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PMID:Prognostic value of urokinase plasminogen activator for prostatic carcinoma. 751 34

Prostate cancer has a slow growing noninvasive phase, but, in general, is invasive on diagnosis. An initial step in the invasion of surrounding normal tissue is the activity of proteolytic enzymes such as components of the plasminogen activator system (PA). In cell culture, the primary human prostate cancer cell line 1013L expressed no urokinase type-PA (uPA), while DU 145, a cell line derived from a metastatic lesion, expressed high levels of uPA. The DU 145 cells grew easily as xenografts but the establishment of 1013L in the SCID mice was possible only with the aid of a gelatin sponge (Spongostan). The latency period was 42-64 days, followed by a slow growth phase before a fast growth phase occurred. This fast growth phase was characterized by rapid degeneration of tumor tissue, while high proliferation occurred around the blood vessels. On serial transplantation of tumor material, the growth pattern was similar. Furthermore, the 1013L tumor was encapsulated by connective tissue and no invasiveness could be detected. We found that 1013L tumor homogenates had hardly detectable levels of uPA, i.e., 300-fold lower than we found in the invasive prostate xenograft DU 145. In addition, no expression of uPA was found in the plasma of 1013L tumor-bearing mice whilst uPA antigen was detected in the plasma of DU 145 tumor-bearing mice. In conclusion, the 1013L cell line, which exhibits a nonaggressive pattern, could be a good model for studying progression of prostate cancer to a more aggressive phenotype in vivo and in vitro.
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PMID:Differential expression of uPA in an aggressive (DU 145) and a nonaggressive (1013L) human prostate cancer xenograft. 753 48

Components of malignant invasion, namely cellular adhesion, motility, and proteolytic capability provide potential sites of pharmacological intervention for malignancy. In this study, a series of experiments were performed to examine the effects of N-(4-hydroxyphenyl) retinamide (4-HPR, Fenretinide) on cellular adhesion, motility and proteolytic activity of established prostate cancer cell lines, TSU-PR 1 and PC-3. Radioadhesion study showed that the treatment of TSU-PR 1 and PC-3 cells with 10(-6) M of 4-HPR resulted in a 32% and 37% reduction (p < 0.05), respectively, in the cellular adhesion to the matrigel extract. Radiomigration assay also demonstrated that 4-HPR concentration of 10(-6) M reduced the cellular motility by 29% in TSU-PR1 and 28% in PC-3 cells (p < 0.05). Spectrolyse PL indirect chromogenic assay revealed an increase in total activatable uPA activity (TSU-PR 1: 25%, PC-3: 32%, P < 0.05), while Spectrolyse UK direct assay demonstrated a mild, but a statistically significant reduction (PC-3: 5%, TSU-PR1: 9%, P < 0.05) in active uPA activity. Northern analysis and ELISA assays showed that 4-HPR at 10(-6) M enhances the expression of type 1 plasminogen activator inhibitor (PAI-1). Type IV collagenase western blot analysis and densitometry did not demonstrate suppression of the enzyme secretion, but in fact suggested increased translation of the enzyme when treated with 10(-6) M concentration of fenretinide. The results of this study demonstrate that 4-HPR inhibits in vitro cellular adhesion and motility of human prostate adenocarcinoma cell lines, TSU-PR1 and PC-3. Additionally, uPA and PAI-1 assay results suggest that 4-HPR may impair active uPA's proteolytic activity while upregulating the expression of total activatable uPA and PAI-1. The results of this study therefore support 4-HPR's role as a potential anti-invasive agent.
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PMID:In vitro anti-invasive effects of N-(4-hydroxyphenyl)-retinamide on human prostatic adenocarcinoma. 765 32

The transplantation of PA-III rat prostate cancer cells onto rat skeleton produces osteoblastic metastases. Therefore w e studied the paracrine interactions between the PA-III cells and osteoblast-derived osteosarcoma cells (UMR 106 cells). A serine protease secreted by PA-III cells hydrolyzed IGF-binding protein-1 and IGF-binding protein-2 (IGFBP-1 and IGFBP-2) detected in the cell culture media (CM) of OMR 106 cells by western ligand blotting. The serine protease of PA-III cell CM was purified using a benzamidine affinity column. This protease was a protein of 45-50 kDa on polyacrylamide gel electrophoresis under non-reducing conditions but generated two protein bands under reducing conditions; a) one of 33-35 kDa possessing protease activity and b) another of 20-25 kDa which was proteinolytically inactive. Sequence analysis identified the amino acid sequence of the a-chain (20-25 kDa band) and of the b-chain (33-35 kDa band) of rat urokinase-type plasminogen activator molecule. Urokinase purified from PA-III cell CM hydrolyzed IGFBPs of UMR 106 cells and stimulated the proliferation of UMR 106 cells in serum-free cultures. Its protease activity was abolished by benzamidine and aprotinin. Its mitogenic activity for osteoblasts was inhibited by anti-IGF-I monoclonal antibody. Northern blot analysis documented the expression of the urokinase-type plasminogen activator gene in the mRNA extracted from PA-III cells. Urokinase expression was inhibited by dexamethasone. Therefore, we conclude that urokinase-type plasminogen activator stimulates osteoblasts via an IGF-I dependent mechanism. Hydrolysis of the IGFBOPs at the sites of PA-III cell-induced bone tumors account for an increased bioavailability of IGFs. This may facilitate the development and the growth of PA-III cell-induced bone tumor and can also mediate the subsequent local osteoblastic reaction.
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PMID:Urokinase-type plasminogen activator: a paracrine factor regulating the bioavailability of IGFs in PA-III cell-induced osteoblastic metastases. 768 89

We developed a three-dimensional type I collagen gel cell culture system that allows coculturing of human MG-63 osteoblast-like cells and various human cancer cells. Inoculation of human PC-3 metastatic prostate cancer cells into this type I collagen gel containing human MG-63 osteoblast-like cells produced an osteoblastic-like reaction that presented as an increased number of MG-63 cells and increased density of type I collagen around MG-63 cells adjacent to inoculated PC-3 cells by microscope analysis. Under identical experimental conditions, inoculation of cell-free medium, human KLE endometrial adenocarcinoma cells, and Calu-1 lung cancer cells did not produce this blastic-like reaction. In situ hybridization documented the uniform expression of insulin-like growth factor I (IGF-I) and of urokinase-type plasminogen activator (uPA) mRNA in MG-63 and PC-3 cells separately cultured in this substrata. The uniform expression of uPA was also documented by immunocytochemistry using a monoclonal and a polyclonal antihuman uPA antibody. The relative expression of uPA was higher in PC-3 cells than in MG-63, KLE, and Calu-1 cancer cells. We conclude that this novel cell culture system may become a useful model to study the pathophysiology of the osteoblastic reaction in vitro.
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PMID:Three-dimensional type I collagen gel system for the study of osteoblastic metastases produced by metastatic prostate cancer. 786 32

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

The presence of procoagulants and fibrin deposition have been demonstrated in malignant tumors. Although thrombin, a key enzyme in coagulation, has other various biological functions, the significance of its presence in tumors is not known. We studied the effects of thrombin on the expression of urokinase-type plasminogen activator (uPA) which is known to play a role in tumor invasion, using a human prostate cancer cell line PC-3. Human alpha-thrombin added to cultures of PC-3 produced a dose-dependent and time-dependent increased secretion of uPA that was greatest at 3-6 h after exposure to thrombin. Increase in uPA antigen paralleled the increase in mRNA level, which reached a maximum at 4 h. Thrombin showed the maximum effect on uPA expression at a concentration 1-2 units/ml. Zymography showed that transient exposure to thrombin induced an increase in fibrinolytic activity which could be quenched by anti-uPA antibody. The thrombin receptor-activating peptide also caused an increase in uPA protein and mRNA level, indicating the presence of the same thrombin specific receptor on PC-3 cells as on platelets and endothelial cells. Thrombin did not affect the expression of other components of the plasminogen activation system, tissue-type plasminogen activator and type-1 plasminogen activator inhibitor, and uPA receptor. These results indicate that thrombin increases uPA expression selectively by the stimulation of a functional thrombin receptor on PC-3 cells. Since uPA is known to play a role in pericellular proteolysis of extracellular matrix, thrombin may be involved in the regulation of tumor invasion and metastasis.
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PMID:Enhancement of the expression of urokinase-type plasminogen activator from PC-3 human prostate cancer cells by thrombin. 820 53

The plasminogen activator urokinase (u-PA) mediates proteolysis by a variety of human tumor cells. Competitive displacement of u-PA from cellular binding sites results in decreased proteolysis in vitro, suggesting that the cell surface is the preferred site for u-PA-mediated protein degradation. We studied the effect of u-PA receptor blockade on the metastatic capacity of human PC3 prostate carcinoma cells, using transfectants which expressed chloramphenicol acetyl-transferase (CAT). Eight weeks after subcutaneous inoculation of these cells into nude mice, CAT activity was detected in regional lymph nodes, femurs, lungs, and brain, thereby mimicking the organ tropism observed for naturally occurring metastases of prostate cancer. In a second transfection, CAT-expressing PC3 cells received cDNA encoding a mutant u-PA (Ser356-->Ala) which lacks enzymatic activity but which retains full receptor binding affinity. Three mutant u-PA expressors, each with < 5% of wild-type cell-associated u-PA activity, were compared in vivo with independently derived controls. Primary tumor growth was similar in each group of animals and all tumors expressed comparable CAT activity. In contrast, metastasis (as assessed by CAT activity) was markedly inhibited when cell surface u-PA activity was blocked. Levels of CAT activity were reduced by a factor of > 300 in regional lymph nodes, 40-100 in brain tissue, and 10-20 in lung tissue. Metastatic capacity was inhibited similarly when animals were given intermittent intraperitoneal injections of a u-PA/IgG fusion protein capable of displacing u-PA activity from the tumor cell surface. Our results indicate that cell surface u-PA activity is essential to the metastatic process. In addition, the assay system employed in these experiments may be generally useful in testing other therapeutic modalities to limit the spread of primary tumors.
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PMID:Prevention of metastasis by inhibition of the urokinase receptor. 838 64

Metastatic prostate cancer is unique in its ability to induce the osteoblastic reaction in skeleton. This phenomenon is probably the result of complex paracrine/autocrine cell interaction between prostate cancer cells and bone cells at the metastatic sites. Recently the use of various in vivo and in vitro systems made possible the confirmation of certain cellular interactions that may participate in this process. The role of IGFs/GFBPs, urokinase-type plasminogen activator (uPA), as well as of TGF beta 1 and glucocorticoids is discussed in this review.
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PMID:Osteoblastic metastasis in advanced prostate cancer. 851 61

The prostate gland is the most common site of cancer in men in the United States. The biologic behavior of an individual tumor, however, varies widely, with some cancers taking a relatively indolent course and other progressing rapidly to disseminated disease. Prognostic factors that might help predict a tumor's aggressiveness and invasiveness are limited. The expression of urokinase plasminogen activator was evaluated in 36 human prostate cancer specimens. Using an immunohistochemical method with monoclonal antibody #394, 70.6% (12 of 17) of cancer specimens with extracapsular extension showed increased expression of urokinase plasminogen activator, compared with 26.6% (4 of 15) of specimens without capsular invasion. Increased expression was localized to the glandular cytoplasm, with tumor stroma yielding predominantly negative results. These findings provide additional evidence of the role of urokinase in determining the biologic behavior and metastatic potential of prostate cancer.
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PMID:Urokinase-type plasminogen activator expression in human prostate carcinomas. 868 32


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