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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

Using monolayer cultures of clonally isolated C3 and T5 rat prostate cancer cells, we determined that acidic (aFGF) and basic (bFGF) fibroblast growth factors profoundly enhanced T5 cell thymidine incorporation with half-maximum stimulation at 0.53 and 0.35 ng/ml, respectively. In contrast, aFGF or bFGF enhancement of C3 cell thymidine incorporation was about 5% of that of T5 cells, and effects were principally mitogen concentration independent. Saturation analyses and cross-linking studies established that both C3 and T5 cells contained high-affinity FGF receptors of 120 and 145 kilodaltons and that receptor content and Kd of C3 and T5 cells were comparable. aFGF or bFGF stimulation of T5 cell thymidine incorporation profoundly decreased as cell plating density was reduced from 1.5 x 10(5) to 1.0 x 10(4) cells/well. The modest response of C3 cells to either aFGF or bFGF also decreased as cell plating density was reduced. Because heparin preserves FGF biological activity and enhances bFGF binding to high-affinity FGF receptors, we examined the effect of heparin on FGF stimulation of C3 cell thymidine incorporation. We found that changes in cell plating density and/or medium heparin concentration had variable, inconsistent effects. These were C3 cell plating density associated and included inhibition or modest enhancement of FGF effects. Binding analyses established that high-affinity bFGF binding of C3 and T5 cells immediately prior to assessing FGF-stimulated thymidine incorporation was comparable and independent of cell plating density, implying that C3 cell FGF insensitivity was not attributable to differences in C3 and T5 cell FGF receptor content at the time of mitogen stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Signal transduction defect appears to be the cause of rat prostate cancer cell fibroblast growth factor insensitivity. 144 1

Growth of the normal and malignant prostate is known to be regulated by androgens. Part of their effect has been suggested to be mediated through coordinated regulation of secreted growth factors with autocrine function. We now examine the biological role of preferentially paracrine acting factors in growth control of prostate cancer, i.e. fibroblast growth factor(s) (FGF). Coculture experiments using the androgen-responsive human prostate carcinoma cell line LNCaP as feeder cells and the FGF-dependent human adrenal carcinoma SW-13 cell line as target cells show that (i) LNCaP cells induce growth of SW-13 cells, (ii) even higher stimulation of SW-13 cells is seen in the presence of androgen treated LNCaP cells and (iii) a specific anti-bFGF antibody inhibits growth of SW-13 cells induced by androgen treated LNCaP cells; no proliferation of SW-13 cells occurs in the absence of LNCaP cells. Partial purification of the secretory products of LNCaP cells was performed by affinity chromatography using a heparin sepharose column. Fractions were tested for biological activity in a soft agar assay with SW-13 cells. Several activities could be detected, the main activity was eluted with about 1.5 M NaCl. These data suggest that androgen treatment of LNCaP cells leads to enhanced secretion of proteins which belong to the FGF-family.
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PMID:Regulation of fibroblast growth factor-like protein(s) in the androgen-responsive human prostate carcinoma cell line LNCaP. 156 38

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

Peptide growth factors play a role in the maintenance of normal prostatic growth and differentiation (Fig. 2). It seems likely that the androgen sensitivity of human prostate is mediated by the production of peptide growth factors from stromal cells which act as the direct intermediate of androgen action on epithelial cells. TGF-beta 1 inhibition of epithelial cells is opposed by the stimulatory action of EGF, IGF and FGFs to maintain an equilibrium of epithelial cell numbers. The indirect mitogenic action of androgens appear to act by down-regulation of TGF-beta 1 and possibly EGF receptors. There is also interaction with the effects of IGF-II, produced by prostatic stromal cells and acting on epithelial cells to increase proliferation. The growth of normal prostatic fibroblasts is under the control of bFGF and TGF-beta 1. However, although our understanding of the actions of these growth factors in the normal prostate has improved over the last decade, their role in the development and maintenance of prostate cancer is less clearly defined. TGF-beta 1, classically considered to be inhibitory for epithelial cells, may be up-regulated in prostatic tumours, stimulating growth. Alternatively, autocrine production of such growth factors by tumour cells may lead to loss of inhibitory effects from exogenous TGF-beta 1, a mechanism also witnessed with TGF-alpha and bFGF. The role of EGF in the development of prostate cancer is confusing because results from the use of different cell types and experimental conditions is contradictory. It may be that a switch in the production of the predominant EGFr ligand from EGF to TGF-alpha is an important feature in the development and maintenance of the malignant phenotype. The presence of TGF-alpha autocrine loops has been shown clearly in some tumour cell lines. This switch in the production of a particular ligand may also be a feature of IGFs in prostate cancer. IGF-II may be replaced by IGF-I during malignant progression, both of which are able to act via the type 1 receptor. This change in IGF expression appears to be accompanied by altered expression of the IGF-BP2, with less detectable within prostatic tissues but elevated serum levels [58]. Basic FGF is normally produced by prostatic fibroblasts but is also produced by some prostatic cancer cell lines [64]. However, as with all growth factors, the expression of the bFGF protein and its receptor is dependent on the cell line examined. The autocrine and paracrine control of normal and abnormal prostatic growth by growth factors is important in determining their role in the development and maintenance of prostate cancer. Better understanding of such mechanisms is essential for the development of novel therapeutic strategies in the control and treatment of prostate cancer.
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PMID:Peptide growth factors in the prostate as mediators of stromal epithelial interaction. 868 1

Progress in prostate cancer research has been hindered by the lack of well characterized, immortalized, human prostatic epithelial cell lines that express markers of normal prostatic epithelial cells and mimic normal growth and differentiation responses to androgens. The objectives of this study were to: (i) establish immortalized cell lines from non-neoplastic, adult human prostatic epithelium using adenovirus-12/simian virus-40 (Ad12-SV40) hybrid virus; (ii) establish their prostatic epithelial origin; (iii) demonstrate androgen responsiveness; and (iv) examine response to growth factors. Primary epithelial cell cultures derived from a non-neoplastic, adult human prostate were infected with the Ad12-SV40 virus. Several immortalized clones were isolated. Single cell cloning of one clone, free of cytopathic effects, gave rise to the PWr-1E cell line. An immortalized cell line PWR-1E, which expresses many characteristics of normal prostatic epithelial cells was established. Immunostaining showed that cells express cytokeratins 8 and 18 normally expressed by differentiated, secretory prostatic epithelial cells. The most remarkable characteristics of PWR-1E cells are growth stimulation, increased expression of androgen receptor and induction of prostate specific antigen (PSA) expression in response to androgens, which indisputably establish their prostatic epithelial origin. They are positive for SV40 large-T antigen and show strong nuclear staining for p53. Cells from passages 23 and 40 were not tumorigenic in nude mice even when co-injected with Matrigel. They grow in a serum-free defined medium and respond to EGF, bFGF and TGF-beta. Passage 42-cells showed a human male (XY), hyperdiploid karyotype. The PWR-1E cell line is the only known Ad12-SV40-immortalized human prostatic epithelial cell line. PWR-1E cells can be used to study (i) the etiology and the multistep process of carcinogenesis and tumor progression in the human prostate; (ii) normal prostate physiology and differentiation; and (iii) potential prostate cancer chemopreventive agents.
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PMID:Prostate specific antigen and androgen receptor induction and characterization of an immortalized adult human prostatic epithelial cell line. 876 20

RT-PCR analysis of total RNA prepared from the prostate cancer cell lines DU145 and PC3 and from primary epithelial cells indicated the presence of endothelin-1 (ET-1) messenger RNA (mRNA). Neither the LNCaP cell line nor primary prostatic stromal cells possess ET-1 mRNA transcripts. Seventy-two-hour-conditioned media derived from DU145, PC3, and primary epithelia contain immunoreactive ET concentrations equivalent to 0.814 +/- 0.048, 0.330 +/- 0.050, and 0.856 +/- 0.055 fmol/mL/10(6) cells after 72 h, respectively. Basal immunoreactive ET secretion was exhibited by LNCaP (0.029 +/- 0.009 fmol/mL/10(6) cells after 72 h) and stromal cells (0.067 +/- 0.007 fmol/ mL/10(6) cells after 72 h). Examination of ETA and ETB gene expression by RT-PCR demonstrates that ET receptor mRNA is almost completely undetectable in the prostate cancer cell lines. Both ETA and ETB mRNAs are detectable in primary cultures of prostatic epithelia and stroma. Competitive binding studies demonstrate a single class of binding site in both primary benign epithelia (dissociation constant = 1.85 x 10(-10) mol/L; maximal binding capacity = 2.7 x 10(4) binding sites/cell), and stroma (dissociation constant = 1.93 x 10(-10) mol/L; maximal binding capacity = 3.7 x 10(5) binding sites/cell). Use of selective ET receptor antagonists confirmed that the predominant stromal receptor subtype expressed in vitro is ETB. This receptor seems not to be coupled to mitogenic pathways because no growth response to exogenous ET-1 or cooperation between ET-1 and bFGF could be observed. Similarly, no effect of ET-1 or the ET-converting enzyme inhibitor, phosphoramidon, on benign epithelial cells could be observed over a 4-day period.
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PMID:In vitro expression of endothelin-1 (ET-1) and the ETA and ETB ET receptors by the prostatic epithelium and stroma. 902 45

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

Prostate cancer and benign tumors of the prostate are the two most common neoplastic diseases in men in the United States, however, research on their causes and treatment has been slow because of the difficulty in obtaining fresh samples of human tissue and a lack of well characterized cell lines which exhibit growth and differentiation characteristics of normal prostatic epithelium. Non-neoplastic adult human prostatic epithelial cells from a white male donor were immortalized with human papillomavirus 18 which resulted in the establishment of the RWPE-1 cell line. Cells from the RWPE-1 cell line were further transformed by v-Ki-ras to establish the RWPE-2 cell line. The objectives of this study were to: (1) establish the prostatic epithelial origin and androgen responsiveness of RWPE-1 and RWPE-2 cell lines; (2) examine their response to growth factors; and (3) establish the malignant characteristics of the RWPE-2 cell line. Immunoperoxidase staining showed that both RWPE-1 and RWPE-2 cells express cytokeratins 8 and 18, which are characteristic of luminal prostatic epithelial cells, but they also coexpress basal cell cytokeratins. These cell lines show growth stimulation and prostate specific antigen (PSA) and androgen receptor (AR) expression in response to the synthetic androgen mibolerone, which establishes their prostatic epithelial origin. Both cell lines also show a dose-dependent growth stimulation by EGF and bFGF and growth inhibition when exposed to TGF-beta, however, the transformed RWPE-2 cells are less responsive. RWPE-1 cells neither grow in agar nor form tumors when injected into nude mice with or without Matrigel. However, RWPE-2 cells form colonies in agar and tumors in nude mice. In the in vitro invasion assay, RWPE-1 cells are not invasive whereas RWPE-2 cells are invasive. Nuclear expression of p53 and Rb proteins was heterogeneous but detectable by immunostaining in both cell lines. The RWPE-1 cells, which show many normal cell characteristics, and the malignant RWPE-2 cells, provide useful cell culture models for studies on prostate growth regulation and carcinogenesis.
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PMID:Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. 921 5

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


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