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)

Overproduction of uPA by prostate cancer cells in vivo results in tumor invasiveness and osteoblastic skeletal metastasis due to its mitogenic actions in osteoblasts. In the present study we have examined the effect of several growth factors and steroid hormones on regulating uPA gene expression in the human prostate cancer cell line (PC-3). Treatment of these cells with dexamethasone (Dex) caused a decrease, whereas epidermal growth factor (EGF) and fetal bovine serum (FBS) increased uPA expression in a dose-dependent manner. Trans retinoic acid (RA) also induced uPA mRNA and protein production in a dose-dependent manner (10(-6) to 10(-9) M). This increase was seen as early as 2 hr of treatment until 48 hr. Dex treatment resulted in decreased tumor cells invasiveness, whereas exposure to EGF and RA caused an increase in the invasive capacity of PC-3 cells. These studies should help to better understand the control mechanism of uPA expression in prostate cancer, where uPA has been implicated as a major pathogenetic factor.
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PMID:Induction of urinary plasminogen activator by retinoic acid results in increased invasiveness of human prostate cancer cells PC-3. 747 94

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

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 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

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

Despite our recent advances in characterizing the molecular basis of breast and prostate cancer and their early detection with the aid of new imaging and diagnostic techniques, these cancers continue to be the leading causes of cancer-related deaths. This limited success in achieving our ultimate goal of cancer control is due to our inability to block the production of various factors produced in the later stages of these cancers that cause this high rate of mortality. A key requirement in the complex process of tumor invasion is the ability of tumor cells to produce and recruit growth factors and proteolytic enzymes within the tumor cell environment to promote neovascularization, tumor growth and promote extracellular matrix (ECM) degradation to facilitate tumor metastasis. One such protease, urokinase (uPA), has been strongly implicated in the progression of several malignancies including breast and prostate cancer. Along with uPA, its cell surface receptor (uPAR) is also believed to be involved due to its ability to recruit uPA within the tumor cell environment. In recent years, novel in vivo models of breast and prostate cancer have been developed which have clearly demonstrated the significance of uPA and uPAR in the invasion and metastases of these hormone-dependent cancers. The availability of these in vivo models has now permitted us to evaluate the molecular, chemical and immunotherapeutic strategies targeted against the uPA/uPAR system. This review describes the mechanism of uPA actions in tumor progression and analyses the usefulness of these in vivo models to authenticate uPA/uPAR as a therapeutic target and evaluates the benefits of blocking uPA/uPAR interactions alone or in combination with currently available treatment modalities against this cancer. Based on these results, there is an urgent need to develop and optimize strategies which will ultimately allow us to control the progression of these malignancies and enhance our ability to effectively manage these patients.
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PMID:Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. 949 55

The malignant phenotype of prostatic tumor cells correlates with the expression of both uPA and its cell-membrane receptor (uPAR); however, there is little information concerning the role of cell-bound uPA in matrix degradation and invasion. Our results suggest that cell-associated uPA plays a key role in regulating the amount of plasmin present at the surface of prostatic carcinoma (PRCA) cells and show that differential production of uPA corresponds with the capacity to bind and activate plasminogen. In addition, we provide direct evidence that both uPA secretion and the presence of uPA-uPAR complexes characterize the invasive phenotype of PRCA cells and suggest the existence of several pathways by which tumor cells acquire plasmin activity. LNCaP cells (which do not produce uPA but express uPAR) may activate plasmin through exogenous uPA. In vivo, the source of uPA may be infiltrating macrophages and/or fibroblasts as observed in several other systems. PAI-1 accumulation in the conditioned medium (CM) limits plasmin action to the pericellular microenvironment. Our results indicate that MMP-9 and MMP-2 are also activated by plasmin generated by cell-bound but not by soluble, extracellular uPA. Plasmin activation and triggering of the proteolytic cascade involved in Matrigel invasion is blocked by antibodies against uPA (especially by anti- A-chain of uPA which interacts with uPAR) and by PA inhibitors such as p-aminobenzamidine which may regulate levels of cell-bound uPA. uPA may also regulate growth in PRCA cells. Indeed, antibodies against uPA A-chain (and also p-aminobenzamidine treatment) interfere with the ATF domain and inhibit cell growth in uPA-producing PC3 and DU145 prostate cancer cell lines, whereas exogenous uPA (HMW-uPA with ATF) induces growth of LNCaP prostate tumor cell line. These data support the hypothesis that in prostatic cancer patients at risk of progression, uPA/plasmin blockade may be of therapeutic value by blocking both growth of the primary tumor and dissemination of metastatic cells.
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PMID:Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells. 987 99

We examined whether two newly defined parameters, the density of urokinase-type plasminogen activator (uPAD) and the density of its receptor (uPARD), which were determined by dividing the serum levels of uPA and uPAR by the prostate volume, respectively, could be used as predictors of the progression and prognosis of prostate cancer (PC). Serum levels of uPA and uPAR in 40 healthy controls, 70 patients with benign prostatic hypertrophy (BPH) and 80 patients with PC were measured by a sandwich enzyme immunoassay, and prostate volume was measured by ultrasonography. The mean levels of uPAD and uPARD in patients with PC were significantly higher than those in healthy controls and patients with BPH. Furthermore, the uPAD and uPARD levels in PC patients with metastasis were significantly elevated compared with those in patients without metastasis. Among patients who underwent radical prostatectomy, the levels of uPAD and uPARD in patients with pathologically organ-confined disease were significantly lower than in those with advanced disease. The overall survival rate of PC cancer patients with elevated levels of either uPAD or uPARD, or of both, was significantly lower than that of patients with normal levels of uPAD and uPARD. In addition, Cox's multivariate analysis revealed that the elevation of uPAD or uPARD level, or of both, was strongly associated with overall survival in PC patients. These findings suggest that the elevation of uPAD or uPARD, or of both, could be used as new predictors of progression and prognosis in patients with PC.
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PMID:Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer. 1002 88

During the complex multistep process of tumor progression, prostate cancer is initiated as an androgen-sensitive, nonmetastatic cancer, followed by a gradual transition into a highly metastatic and androgen-insensitive variety that lacks the expression of functional androgen receptors (AR). Urokinase (uPA), a member of the serine protease family, has been implicated in the progression of various human malignancies, including prostate cancer. Although uPA production is regulated by various growth factors and cytokines, the role of sex steroids (androgens) in regulating uPA gene expression in prostate cancer is poorly understood. In the current study, we have examined the role of androgens in regulating uPA production and the invasive capacity of the androgen insensitive PC-3 cells transfected with the full-length human AR complementary DNA (PC-3T). Restoration of androgen responsiveness in PC-3T cells caused a marked decrease in cell doubling time. Treatment of PC-3T cells with dihydroxytestosterone (DHT) caused a dose-dependent decrease in uPA messenger RNA and protein production, resulting in their decreased ability to invade through the Matrigel. Nuclear runoff assays revealed that these effects were attributable to the ability of DHT to inhibit uPA gene transcription. AR antagonist flutamide (Flu) reversed the effect of DHT on proliferation and invasion of PC-3T cells. Both control (PC-3) and experimental (PC-3T) cells were injected into the right flank of male BALB/c nu/nu mice. Control animals developed palpable tumors and microscopic tumor metastases at lymph nodes, lungs, and liver at 6-week posttumor cell inoculation. In contrast to this, because of androgen sensitivity of PC-3T cells, palpable tumors were observed only at week 12, with occasional tumor metastases in lungs. Furthermore, inoculation of PC-3T cells into surgically castrated host animals resulted in the development of tumors at a much earlier time (week 10) and a high incidence of metastases, compared with regular animals receiving PC-3T cells. Collectively, these results demonstrate the ability of androgen to regulate uPA production, which may directly effect prostate cancer growth, invasion, and metastasis in vitro and in vivo.
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PMID:Regulation of urokinase production by androgens in human prostate cancer cells: effect on tumor growth and metastases in vivo. 1046 76


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