UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer is the most common cancer in North American men. Currently available prognostic factors inadequately predict which cancers will be aggressive and which will lead an indolent course. This study was aimed at investigating the role of matrix metalloproteinase (MMP)-2 in prostate cancer disease-free survival. We correlated MMP-2 expression by malignant prostatic epithelium and stromal cells with prostate cancer disease-free survival in 187 stage pT3NxM0 prostate carcinomas using immunohistochemistry. MMP-2 was expressed by cancer cells in 131 cases (70.0%) and by stromal cells in 142 cases (75.9%). MMP-2 expression by stromal cells was not associated with progression (P = 0.7270). However, in multivariate analyses, adjusting for the Gleason score, tumor-node-metastasis stage, and initial serum prostate-specific antigen, MMP-2 expression by >50% of malignant epithelial cells was associated with decreased disease-free survival (hazard ratio, 4.267; P = 0.0012). Increased MMP-2 expression by malignant prostatic epithelia is an independent predictor of decreased prostate cancer disease-free survival.
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PMID:Significance of MMP-2 expression in prostate cancer: an immunohistochemical study. 1467 18

The type I insulin-like growth factor receptor (IGF-IR) is involved in tumour cell proliferation, invasion, and cancer cell survival. Several studies indicate that the IGF axis contributes to prostate cancer pathogenesis, but there is no consensus regarding the relative expression of the IGF-IR in benign and malignant prostate epithelium. In this study, endogenous IGF-IR gene expression was reduced in stably transfected PC-3 cells by employing an antisense RNA strategy which resulted in significant suppression of both PC-3 cell invasion and proliferation in vitro. Furthermore, it was demonstrated that a direct correlation exists between the inhibition of IGF-IR gene expression and either up-regulation of IGF binding protein (BP)-3 or down-regulation of matrix metalloproteinase (MMP)-2 expression in androgen-independent PC-3 cells. Moreover, inhibition of IGF-IR gene expression in transfected PC-3 cells leads to an enhanced rate of spontaneous apoptosis. In addition, expression analyses by quantitative RT-PCR on RNA from laser microdissected matched normal prostate and prostate tumour samples revealed that IGF-IR gene expression was up-regulated in nine of 12 prostate cancers, whereas IGFBP-3 gene expression was down-regulated in all 12 prostate carcinomas analysed. These results indicate an important role for IGF-IR and IGFBP-3 in the homeostasis of prostate carcinoma cells and provide a further basis for targeting IGF-IR or IGFBP-3 gene expression in order to improve understanding of the IGF-IR-activated signalling pathways and as a potential treatment for prostate cancer.
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PMID:Blockade of the type I IGF receptor expression in human prostate cancer cells inhibits proliferation and invasion, up-regulates IGF binding protein-3, and suppresses MMP-2 expression. 1469 21

Prostate cancer (PCA) is the second most frequently diagnosed and leading cause of cancer-related deaths in men in the USA. The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis of PCA has led to the development of MMP inhibitors as cancer therapeutic agents. As part of our efforts to develop newer and effective chemopreventive agents for PCA, we evaluated the effect of proanthocyanidins from grape seeds (GSP) on metastasis-specific MMP-2 and -9 in human prostate carcinoma DU145 cells by employing western blot and gelatinolytic zymography. Treatment of GSP dose-dependently inhibited cell proliferation (15-100% by 5-80 microg/ml of GSP), viability (30-80% by 20-80 microg/ml of GSP) and fibroblast conditioned medium (FCM)-induced expression of MMP-2 and -9 in DU145 cells. Since the signaling cascade of mitogen-activated protein kinases (MAPK) have been shown to regulate the expression of MMPs in tumor cells, we found that the treatment of DU145 cells with GSP (20-80 microg/ml) resulted in marked inhibition of FCM-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 and p38 but had little effect on c-Jun N-terminal kinase under similar experimental conditions. GSP treatment (20-80 microg/ml) to DU145 cells also dose-dependently inhibited FCM-induced activation of NF kappa B concomitantly with inhibition of MMP-2 and -9 expression in the same system. Additionally, the treatment of inhibitors of MEK (PD98059) and p38 (SB203580) to DU145 cells resulted in the reduction of FCM-induced phosphorylation of ERK1/2 and p38 concomitantly marked reduction in MMP-2 and -9 expressions. In further studies, treatment of androgen-sensitive LNCaP cells with a synthetic androgen R1881, resulted in an increase of MMP-2 and -9, which were completely abrogated in the presence of GSP (20-60 microg/ml). These data suggest that inhibition of metastasis-specific MMPs in tumor cells by GSP is associated with the inhibition of activation of MAPK and NF kappa B pathways, and thus provides the molecular basis for the development of GSP as a novel chemopreventive agent for both androgen-sensitive and -insensitive prostate cancer therapies.
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PMID:Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. 2253 77

The expression and activation of matrix metalloproteinases (MMPs) by tumor cells is correlated with progression to invasive and metastatic status. The purpose of this study was to examine the role of increased MMP-2 (gelatinase A) expression in prostate cancer progression utilizing human prostate PC-3 cancer cells that overexpress MMP-2 using gene transfection. PC-3 cells were transfected with pCR-3 vector only and pCR-3 MMP-2 plasmids employing the LipofectAMINE method, and stable transfectants were selected with G418. The expression of MMP-2, tissue inhibitor of metalloproteinase-2 (TIMP-2), and membrane-type MMP 1 (MT1-MMP) in PC-3 parental and transfected cells under serum-free conditions was determined by zymography, immunoblotting, immunofluorescent microscopy, Northern blotting, and/or reverse transcriptase-polymerase chain reaction (RT-PCR). MMP-2 transfected cells produced primarily the proenzyme form of MMP-2; the parental and vector control transfected PC-3 cells did not express any MMP-2 that was detectable by the methods we employed. Treatment of PC-3 MMP-2 transfected cells with Concanavalin A (Con A), in contrast to HT-1080 cells, processed only a small amount of the secreted 72-kd proenzyme to a 62-kd intermediate and a cell-associated 59-kd active form. The low level of secreted pro-MMP-2 processing induced by Con A was inhibited by serine protease inhibitors and was unaffected by cyclic adenosine monophosphate (cAMP). Immunoblotting showed that these cells produced abundant TIMP-2 and lower amounts of MT1-MMP in comparison with Con A-responding HT-1080 cells. HT-1080 cells respond to Con A by translocating MT1-MMP from intracellular localization sites to the plasma membrane, an effect not observed in PC-3 cells. The molecular basis for the low level of processing of pro-MMP-2 by PC-3 cells may be due to an overabundance of TIMP-2 and/or a low level of cell surface active MT1-MMP.
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PMID:Limited processing of pro-matrix metalloprotease-2 (gelatinase A) overexpressed by transfection in PC-3 human prostate tumor cells: association with restricted cell surface localization of membrane-type matrix metalloproteinase-1. 1476 14

Despite the specificity inferred by its name, glycogen synthase kinase (GSK)-3beta is an important kinase with a plethora of significant cellular targets, including cytoskeletal proteins and transcription factors, and its activity is regulated by phosphorylation on tyrosine/serine residues. As part of our efforts to dissect the molecular basis responsible for androgen-independent progression of prostate cancer, we investigated the role of GSK-3beta in androgen-stimulated gene expression in human prostate cancer cells. Pretreatment of prostate cancer cells harboring wild-type or mutant androgen receptor with the GSK-3beta inhibitors, lithium chloride (LiCl), RO318220, or GF109203X, inhibited R1881-stimulated androgen-responsive reporter activity in a dose- and time-dependent manner. In addition, the expression of two endogenous androgen-stimulated gene products, prostate-specific antigen and matrix metalloproteinase-2, was suppressed by the GSK-3beta inhibitors in those cells. Most importantly, knocking down GSK-3beta expression via a small interference RNA-mediated gene silencing approach also reduced R1881-stimulated gene expression, demonstrating the specificity of GSK-3beta involvement. Moreover, R1881 treatment of the cells increased phosphorylation status of GSK-3beta on tyrosine residue Y(216) but not on serine residue S(9). Pretreatment of the cells with phosphatidylinositol 3-kinase inhibitor LY294002 or wortmannin, which blocks androgen action in cells, abolished R1881-induced GSK-3beta Y(216) phosphorylation. However, the phosphatidylinositol 3kinase or GSK-3beta inhibitors did not block R1881-induced nuclear translocation of androgen receptor. Finally, knocking down the expression of Akt or beta-catenin, the two GSK-3beta-related signaling molecules, via siRNA-mediated gene silencing did not significant affect R1881-stimulated gene expression. These findings suggest that GSK-3beta activity is required for androgen-stimulated gene expression in prostate cancer cells.
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PMID:Glycogen synthase kinase-3beta activity is required for androgen-stimulated gene expression in prostate cancer. 1498 90

Bone remains one of the major sites, and most lethal host organs, for prostate cancer metastasis. Prostate cell spread and establishment in bone depends on multiple reciprocal modifications of bone stromal and epithelial cancer cell behaviors. This review focuses on recent advances in the characterization of cell-cell and cell-matrix interplay, effects on cell growth, adhesion and invasion, and several therapeutic possibilities for co-targeting prostate cancer cells and bone stroma. We address the topic from three main perspectives: (1) the normal and aging bone stromal environment, (2) the "reactive" bone stromal environment, and (3) the cancerous prostate epithelial cells themselves. First, normal, and especially aging, bones provide uniquely rich and "fertile soil" for roaming cancer cells. The interactions between prostate cancer cells and insoluble extracellular matrices, soluble growth factors, and/or sex steroid hormones trigger bone remodeling, through increased osteoclastogenesis and furthur matrix metalloproteinase activity. Second, after cancer cell arrival and establishment in the bone, host stromal cells respond, becoming "reactive" in a process again involving extracellular matrix remodeling, together with growth factor and steroid receptor signaling this process ultimately enhances cancer cell migration, stromal transdifferentiation, and invasion of the cancer tissues by stromal, inflammatory, and immune-responsive cells. Third, prostate cancer cells also respond to supportive bone microenvironments, where soluble and matrix-associated molecules affect cancer cell growth and gene expression, especially altering cancer cell surface receptor and integrin-mediated cell signaling. We discuss both integrin cell-matrix and gap junctional cell-cell communication between cancer cells and their microenvironments during prostate cancer progression.
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PMID:Modulation of prostate cancer growth in bone microenvironments. 1499 61

To study the expression of matrix metalloproteinase-2 and -9 in human prostate cancer, matrix metalloproteinase-2 and -9 were immunohistochemically detected in tissues of prostate cancer and benign prostatic hyperplasia (BPH). Our results showed that matrix metalloproteinase-2 and -9 levels in prostate cancer were much higher than those in tissues of BPH, with the cancer invasion being positively correlated with the expression of the metalloproteinases. It is concluded that matrix metalloproteinase-2 and -9 are better molecular markers, which are of help in the diagnosis and prediction of prognosis of prostate cancer.
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PMID:Immunohistochemical studies of the expression of matrix metalloproteinase-2 and metalloproteinase-9 in human prostate cancer. 1501 39

Adenocarcinoma of the prostate is the most common cancer diagnosed in men in the United States, with approximately 189,000 new cases estimated to be diagnosed in 2002. It is believed that men with this disease pass through a series of clinical states. In the intramural program of the National Cancer Institute, we have designed clinical trials that have addressed each disease state. In addition to clinical endpoints, each trial also encompasses molecular or immunologic endpoints in an attempt to determine if our therapy is acting on its presumed target. In patients with localized disease, we are evaluating cancer vaccines in combination with radiation therapy as well as comparing this vaccine against second-line hormonal therapy in patients with rising serum prostate-specific antigen (PSA) but no radiographically measurable disease. We are also evaluating the ability of the antiangiogenesis agent thalidomide to prolong the rest period in patients with a biochemical recurrence (stage D0) that are receiving intermittent hormonal therapy. In patients with metastatic prostate cancer, we are evaluating the addition of the bisphosphonate alendronate when added to ketoconazole for impact on matrix metalloproteinase (MMP)-2 and MMP-9 as well as traditional clinical endpoints. In addition, we have 3 ongoing trials involving the chemotherapeutic agent docetaxel. One trial is examining the combination of thalidomide with docetaxel. The other 2 trials are exploring the PSA vaccine with docetaxel and the combination of docetaxel with ketoconazole. As we obtain information from these ongoing studies, we will be able to take this information and integrate it in the development of newer and more successful treatment regimens as well as look for novel agents that may help in the fight against this disease.
Clin Prostate Cancer 2002 Dec
PMID:National Cancer Institute intramural approach to advanced prostate cancer. 1504 90

We have previously reported that high extracellular Ca2+ stimulates parathyroid hormone-related protein (PTHrP) release from human prostate and breast cancer cell lines as well as from H-500 rat Leydig cancer cells, an action mediated by the calcium-sensing receptor (CaR). Activating the CaR leads to phosphorylation of mitogen-activated protein kinases (MAPKs) that participate in PTHrP synthesis and secretion. Because the CaR is a G protein-coupled receptor (GPCR), it is likely to transactivate the epidermal growth factor receptor (EGFR) or the platelet-derived growth factor receptor (PDGFR). In this study, we hypothesized that activation of the CaR transactivates the EGFR or PDGFR, and examined whether transactivation affects PTHrP secretion in PC-3 human prostate cancer cells. Using Western analysis, we observed that an increase in extracellular Ca2+ resulted in delayed activation of extracellular signal-regulated kinase (ERK) in PC-3 cells. Pre-incubation with AG1478 (an EGFR kinase inhibitor) or an EGFR neutralizing antibody inhibited the high Ca2+ -induced phosphorylation of ERK1/2. GM6001, a pan matrix metalloproteinase (MMP) inhibitor, also partially suppressed the ERK activation, but AG1296 (a PDGFR kinase inhibitor) did not. High extracellular Ca2+ stimulates PTHrP release during a 6-h incubation (1.5- to 2.5- and 3- to 4-fold increases in 3.0 and 7.5 mM Ca2+, respectively). When cells were preincubated with AG1478, GM6001, or an antihuman heparin-binding EGF (HB-EGF) antibody, PTHrP secretion was significantly inhibited under basal as well as high Ca2+ conditions, while AG1296 had no effect on PTHrP secretion. Taken together, these findings indicate that activation of the CaR transactivates the EGFR, but not the PDGFR, leading to phosphorylation of ERK1/2 and resultant PTHrP secretion, although CaR-EGFR-ERK might not be the only signaling pathway for PTHrP secretion. This transactivation is most likely mediated by activation of MMP and cleavage of proheparin-binding EGF (proHB-EGF) to HB-EGF.
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PMID:Calcium-sensing receptor activation stimulates parathyroid hormone-related protein secretion in prostate cancer cells: role of epidermal growth factor receptor transactivation. 1533 2

Carcinoma-associated fibroblasts (CAF) promote tumor progression of pre-neoplastic epithelial cells. To investigate the basis of this phenomenon, we compared the properties of fibroblasts cultured from normal human prostate (NHPF) to prostate CAF. NHPF and CAF were assayed for growth potential, cell death and proliferative capacity by measuring population doubling time, cell cycle distribution and capability to form colonies in soft agar. Resistance to genotoxic (UV radiation: 0-50 J/cm2) and chemotoxic (0-200 nM Taxol) agents were compared between CAF and NHPF by measuring cell viability and cell cycle analysis. Transforming growth factor beta1 (TGF-beta1) immunoreactivity was assessed in non-malignant and malignant prostatic tissue. No detectable differences were found when comparing CAF and NHPF with respect to population doubling time, cell cycle distribution and response to genotoxic and chemotoxic agents. The mean number of colonies in soft agar was 120.5 for CAF vs. 18.2 for NHPF (p < 0.05). Because TGF-beta1 and matrix metalloproteinase (MMP)-9 have been associated with growth of fibroblasts in soft agar and tumor promotion, we measured the expression of these factors in NHPF and CAF by ELISA. There was no difference in expression of MMP-9; however, TGF-beta1 was expressed in higher concentrations in CAF than in NHPF (p < 0.0014). Furthermore, TGF-beta1 expression was higher in the carcinoma-associated stroma of prostate cancer tissue than stroma of non-malignant prostatic tissue. Increased capability of CAF as compared to NHPF to form colonies in soft agar may be due to a higher expression of TGF-beta1 and correlates with the ability of CAF to promote malignant progression of prostate epithelial cells.
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PMID:Expression of transforming growth factor-beta 1 and growth in soft agar differentiate prostate carcinoma-associated fibroblasts from normal prostate fibroblasts. 1582 77

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