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

A human prostate cancer model was established by inoculating a prostate specific antigen (PSA)-producing LNCaP cell line with either prostate or bone fibroblasts. Alternatively, this human prostate cancer model can also be established by inoculating LNCaP cells with growth factor(s) (GFs) and extracellular matrix (ECM) immobilized on Gelfoam. The resulting LNCaP tumors were used to evaluate PSA production and excretion in athymic hosts. This model was also employed to examine the biochemical nature of mesenchymal cell-derived growth-promoting protein(s) and to assess the efficacy of potential chemotherapeutic agents. Because of the propensity of human prostate cancer to metastasize to the bone, this study defined a 1.0 M NaCl-eluted fraction, MS1, from the conditioned medium of a bone stromal cell line (MS) by heparin-affinity column chromatography. The growth-promoting activity was assayed both in vivo (e.g., tumor formation) and in vitro (e.g., soft agar colony formation). We found that the growth-promoting activity was trypsin- and heat-sensitive, and partially degraded by acid and dithiothreitol. Immunochemical studies indicated that the polyclonal antibody raised against MS1 blocked the growth-promoting effect elicited by the bone-conditioned media. This growth-promoting factor was found to be immunochemically dissimilar to KGF, HGF, and bFGF. However, addition of bFGF, HGF and NGF, but not aFGF, TGF beta, IGF1, IGF2, PDGF, EGF, TGF alpha and KGF, stimulated anchorage-independent growth of prostate cells, a condition closely parallel to tumor formation in vivo. We found that the MS1 fraction also contained fibronectin and tenascin but not laminin or collagen IV.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human prostate cancer model: roles of growth factors and extracellular matrices. 128 80

Prostate-specific antigen (PSA), a M(r) 34,000 serine protease, is recognized as a useful marker for the detection and prognosis of patients with prostate cancer. Although serum PSA is an excellent prognostic indicator, an increasing number of factors were found to regulate the PSA expression of prostatic cancer cells, which include androgenic steroids, the growth factors (GFs) and the extracellular matrix. The purpose of this study is to define a novel protein factor that may be responsible for regulating PSA expression by androgen-independent (AI) human prostate cancer cells. We have established a LNCaP subline (C4) from a parental LNCaP tumor grown in a castrated host. The C4 subline overexpressed PSA mRNA and protein. Serum-free conditioned medium (CM) isolated from the C4 subline is able to stimulate PSA gene expression in parental LNCaP cells in a concentration-dependent manner. This autocrine PSA-inducing activity was found to be organ specific because CMs from other fibroblast cell lines (such as bone, prostate, kidney, and lung fibroblasts) and the CMs from several prostatic carcinoma cell lines (such as parental LNCaP, PC-3, DU-145) and a bladder transitional carcinoma cell line (WH) fail to exhibit similar activity. The activity of the CM from the C4 subline cannot be substituted by GFs such as TGF-alpha, TGF-beta, bFGF, HGF, KGF, or NGF; neuropeptide (bombesin/GRP); secondary messenger analogue (dibutyryl cAMP); beta 2-adrenergic agonist (isoproterenol); or alpha 1-adrenergic agonist (phenylephrine), indicating that the factor(s) may be a novel prostate-specific autocrine factor (PSAF). Both androgen and PSAF exhibit an additive effect on up-regulating PSA gene expression, suggesting that the signal transduction pathway elicited by PSAF may differ from that mediated by the androgen receptor. Further characterization of PSAF by heat, acid, and trypsin digestion revealed that the PSAF may be a protein factor with a unique amino acid composition. These observations suggest that a novel autocrine pathway mediated by PSAF may be responsible for the overexpression of PSA mRNA and protein in a human prostatic cancer cell line. The potential clinical significance of this factor will be discussed.
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PMID:Autocrine regulation of prostate-specific antigen gene expression in a human prostatic cancer (LNCaP) subline. 768 49

The effect of an EGF-R selective tyrosine kinase inhibitor ZM252868 was evaluated on the proliferation of PC-3 and DU-145 prostate cancer cell lines, which are purported to utilize an EGF-R-mediated autocrine pathway for regulation of cell growth. Basal growth of DU-145 cells was inhibited in a dose-dependent manner by the inhibitor, showing a 70% reduction at 1 microM, whilst the growth of PC-3 cells was not affected at this concentration. In the presence of 0.1 microM inhibitor, EGF and TGF alpha-stimulated DU-145 cell growth was decreased to below basal levels, while only TGF alpha-stimulated PC-3 cell growth was inhibited at a 1-microM concentration. Any growth responses to aFGF, bFGF, KGF, IGF1 and PDGF by DU-145 and PC-3 cells were unaffected by the inhibitor at concentrations of 1 microM or less. Additionally, the distribution of immunoreactive EGF-R varied between DU-145 and PC-3 cells, with EGF-R being predominately located on the cell membrane and in the cytoplasm, respectively.
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PMID:New EGF-R selective tyrosine kinase inhibitor reveals variable growth responses in prostate carcinoma cell lines PC-3 and DU-145. 918 5

Cellular interactions between stroma and epithelium are important in the growth and proliferation of prostate cancer. Peptide growth factors may facilitate the progression of prostate cancer as autocrine and/or paracrine factors. Keratinocyte Growth Factor (KGF or FGF7) has a differentiative and proliferative effect on the epithelium of the developing rat prostate. We investigated if KGF may act as a paracrine agent in human prostate cancer and examined the expression of KGF and Fibroblast Growth Factor Receptors (FGFRs) (IIIb and IIIc isoforms of the FGFR1 and FGFR2 genes). Sixty-five percent (11 out of 17 informative cases) of prostate cancers (CaP) expressed KGF mRNA by RT-PCR, while KGF expression was not detected in benign prostatic hyperplasia (BPH) (n = 6). Upregulation of KGF expression was related to hormone insensitive tumours (P<0.05). Tumour grade and stage were not associated with KGF expression. The source of KGF expression was further characterised using an in vitro primary culture model, showing its restriction to the prostatic stroma. The FGFR1IIIb isoform was expressed in all cases of prostate cancer (n = 17), and FGFR1IIIc mRNA was not detected. In the BPH group, FGFR1IIIb transcripts were detected in four out of six cases. FGFR2IIIb expression was detected in five of six cases of BPH and twelve out of seventeen (71%) cases of prostate cancer. In CaP, though not reaching statistical significance, the persistence of FGFR2IIIb expression appeared to be associated with hormone insensitive tumours (P=0.052). FGFR2IIIc expression was present in eleven of seventeen tumours but was absent in all six cases of BPH. Functional assessment of recombinant KGF in a proliferation assay demonstrated a mitogenic effect of up to 100% on cultured prostatic epithelial cells.
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PMID:Keratinocyte growth factor expression in hormone insensitive prostate cancer. 928 67

Prostate growth factor (PGF) was the first growth factor isolated from the prostate. Because of its proliferative effect on fibroblasts and its affinity for heparin, it was first recognized as belonging to the family of fibroblastic growth factors then identified as bFGF (basic fibroblast growth factor) by Story in 1980. The presence of paracrine signals between the fibromuscular stroma and the epithelial tissue in the prostate were first demonstrated in 1970 by the incapacity of epithelial cells to grow without the presence of mesenchymal tissue. These paracrine relations are established during embryogenesis of the prostate and are required for its development and functional control in the adult. Keratinocyte growth factor (KGF), also called FGF-7, could be a stomal androgen mediator with a mitogenic paracrine effect on the epithelium. Dysregulation of growth factors has been suggested to be involved in the development of prostate tumors in elderly men (benign hypertrophy and cancer of the prostate). FGFs probably play an important role in benign prostate hypertrophy. Several studies have demonstrated an important rise in mRNA levels for these factors in benign hyperplastic tissue compared with "normal" tissue. This increased level would be associated with fibromuscular proliferation in periglandular tissue and could explain, at least in prat, the epithelial hyperplasia often associated with the paracrine stimulating effect. In prostate cancer, different families of growth factors have been associated with acquisition of aggressive tumor functions. The EGF receptor and its ligands, the IGF family, beta TGF and certain neuropeptides could be partially implicated in androgen-independent autocrine growth. Heparin-related growth factors (FGFs, Midkine family), VEGF or endothelin could be more particularly implicated in metastatic progression by stimulating cell motility, angiogenesis and metastatic implantation by a two-way cooperation between the tumor and the stroma in which it is implanted. Several of these factors are found in the blood stream and have been proposed as biological markers of poor prognosis. Knowledge of peptides regulating prostate growth or of growth factor antagonists has led to the concept of antipeptidergic therapy as an adjuvant in antiprostate tumor regiments.
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PMID:[Growth factors and prostatic tumors]. 968 95

Increasing evidence indicates that endothelin 1 (ET-1) is implicated in prostate tumour progression. However, data on ET-1 regulation in human prostate and prostate cancer cell lines are lacking. In this study, regulation of ET-1 and its precursor big ET-1, using PC3 cells, a human bone metastatic prostatic carcinoma cell line, was addressed. ET-1 and big ET-1 assays demonstrated greater secretion of both peptides in the presence of 10% fetal calf serum (FCS) as compared with 0.5% FCS. Incubation of PC3 cells in the absence and presence of various cytokines and growth factors known to be implicated in prostate stroma-epithelium interactions, revealed that IL-6, FGF7/KGF and FGF2/bFGF had no effect on ET-1 and big ET-1 secretion, whereas interleukin 1beta (IL-1beta), tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) stimulated their secretion in a concentration-dependent manner. Binding experiments indicated the presence of specific ET-1 receptors in PC3 cells: Kdapp = 1.1 x 0.2 x 10(-10)M, Bmax = 2660 +/- 390 sites/cell. Data analysis demonstrated the presence of only the ETA receptor subtype in PC3 cells. In conclusion, our results indicate that the implication of ET-1 in prostate cancer is likely to be mediated via paracrine/autocrine control of cell factors.
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PMID:Upregulation of endothelin 1 and its precursor by IL-1beta, TNF-alpha, and TGF-beta in the PC3 human prostate cancer cell line. 1008 38

In prostate cancer, a distinct series of alterations in the fibroblast growthfactor (FGF) family occurs during the progression from a hormone-dependent to independent state that disrupts communication between stroma and epithelium and results in autonomy of cancer cells. Changes include (i) loss of FGFR2IIIb, whichbinds stromal-derived FGF-7, which promotes growth, growth limitation and differentiation and (ii) activation of FGFR1, the expression of which is normally limited to stroma, along with activation of FGFs that act on FGFR1 in an autocrine manner. Transfection of the FGFR2IIIb isoform into hormone-independent prostate cancer cells not only causes growth inhibition, but also induces differentiation. However, introduction of FGFR1 by transfection in hormone-dependent prostate cancer cells accelerates their progression to malignancy. These results suggest distinct targets for therapy aimed at both inhibition of the malignant phenotype and restoration of homeostasis.
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PMID:Hormone Refractory Prostate Cancer and Fibroblast Growth Factor Receptor. 1109 37

Expression of the fibroblast growth factor (FGF) axis was examined during prostate cancer progression in the autochthonous Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model, including TRAMP derived cell lines. Transcripts for FGF-7 and FGF-10 that are normally expressed by the stroma were detected in all samples, including the epithelial cell lines, suggesting that elaboration of these factors by the epithelium may be an essential event during transformation. Interestingly FGFR2iiib, the FGF-7 and FGF-10 receptor, was downregulated during tumor progression whereas a novel FGFR1iiic (Phi) inframe splice form was found to be expressed. These observations support the hypothesis that specific changes in FGF axis correlate with, and probably facilitate, tumor progression.
Prostate Cancer Prostatic Dis 1999 Mar
PMID:Characterization of the FGF axis and identification of a novel FGFR1iiic isoform during prostate cancer progression in the TRAMP model. 1249 42

This study was performed to develop an experimental model in which expression of estrogen receptors (ER) by human prostatic stromal cells could be reproducibly enhanced relative to similar cells with low ER expression. The second aim was to characterise changes in expression of ER, androgen receptor (AR), FGF-2 and FGF-7 in stromal cells exposed to high and low concentrations of estradiol and testosterone mimicking the different sex hormone levels between young and elderly men. Five strains of human prostatic stromal cells, isolated from BPH resections, were grown in steroid-free medium plus 1 micromol 17beta-estradiol. After 10 days, cells were passaged and grown in the same medium without estradiol until confluent. In a second study four cell strains were exposed to high and low concentrations of 17beta-estradiol and testosterone for 10 days. Cells were labelled with fluorescent antibodies to ERalpha, AR, FGF-2 and FGF-7 and the fluorescence intensity measured by flow cytometry. Following exposure to 1 micromol estradiol, stromal cells showed reduced expression of AR and ERalpha but after passage without estradiol they showed a 25% increase in both receptors over controls. Different combinations of sex hormones induced inconsistent changes with respect to expression of ER, AR and FGFs in the various cell-strains. However, there was a highly significant correlation between AR, ER and FGF-2 and FGF-7, which was cell strain-specific. Thus, changes in sex hormone balance per se may not be solely responsible for the observed increases in prostatic ER levels in BPH. Since expression of ER is correlated with synthesis of FGF-2 and FGF-7, it is likely that increases in stromal ER may mediate the synthesis of stromally-derived growth factors which contribute to the aetiopathogenesis of benign prostatic hyperplasia.
Prostate Cancer Prostatic Dis 2002
PMID:Upregulation of estrogen and androgen receptors modulate expression of FGF-2 and FGF-7 in human, cultured, prostatic stromal cells exposed to high concentrations of estradiol. 1249 97

This study investigated the hypothesis that, in benign prostatic hyperplasia (BPH), upregulated oestrogen receptors (ER) and the action of androgens differentially regulate expression of stromal growth factors. Eight human prostatic stromal cell strains were subjected to a procedure to upregulate their ER by exposing them to 1 micromol 17beta-estradiol for 10 days followed by passage and growth in the absence of steroids. Four of the cell strains instead received 100 nmol dihydrotestosterone for 48 h. Immunoexpression of ERalpha, AR and six growth factors was quantified by flow cytometry in each case. Expression of ERalpha was significantly increased in six of eight cell strains. Expressions of six growth factors (FGF-2, FGF-7, IGF-1, TGF-beta1 NGF and e NOS) were elevated but only for FGF-7 was it significant. There was a significant positive correlation between the change in ERalpha and the change in FGF-2 and FGF-7, but not the other growth factors. Exposure to dihydrotestosterone reduced expression of ERalpha and all six growth factors, compared with oestrogen-treated cells but not significantly. It is concluded that upregulated ERalpha in prostatic stroma may have a greater modulating influence on synthesis of certain growth factors than the direct action of androgens and, by enhancing synthesis of FGF-2 and FGF-7, could play a significant role in the development of BPH.
Prostate Cancer Prostatic Dis 2004
PMID:Relationship between upregulated oestrogen receptors and expression of growth factors in cultured, human, prostatic stromal cells exposed to estradiol or dihydrotestosterone. 1499 40


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