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

PA-III is one of the four transplantable cell lines propagated in vitro in cell monolayer cultures from four spontaneously developed prostate cancer tumors in aged germfree and conventional Lobund-Wistar (L-W) rats (Pollard Model). Our data documented the presence of IGF-I and glucocorticoid but the absence of IGF-II, insulin and androgen receptors in PA-III cells. Activation of IGF-I receptors by IGF-I, IGF-II and insulin stimulated the proliferation of PA-III cells. Activation of glucocorticoid receptors by dexamethasone inhibited the proliferation of PA-III cells. PA-III cells contained urokinase-like activity and expressed the mRNA for urokinase gene which was negatively regulated by glucocorticoids. The above results suggest that PA-III cells could be a useful model for the study of glucocorticoid effects on prostate cancer cells. In addition, these data are discussed in relationship to the capacity of PA-III cells to produce the osteoblastic reaction when transplanted on L-W rat skeleton. A model outlining the putative paracrine interactions between PA-III cells and rat osteoblasts is proposed.
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PMID:PA-III rat prostate adenocarcinoma cells (review). 132 42

Insulin-like growth factor binding protein-3 (IGFBP-3), the major serum carrier protein for the IGFs, is absent from Western ligand blots of seminal plasma, but is detectable by RIA. IGFBP-3 protease activity has recently been described in pregnancy serum. We investigated the possibility that seminal plasma contains an IGFBP-3 protease, by incubating seminal plasma with 125I-labeled human IGFBP-3. Seminal plasma was found to have potent IGFBP-3 protease activity with a cleavage pattern different from that of pregnancy serum. Prostate-specific antigen (PSA) is a serine protease found in semen. Autoradiographs measuring IGFBP-3 protease activity demonstrated that purified PSA cleaved IGFBP-3, yielding a cleavage pattern identical to that of seminal plasma. IGFBP-2 and -4 in seminal plasma were not degraded by PSA. Cleavage of IGFBP-3 by PSA resulted in a marked reduction in the binding affinity of the fragments to IGF-I, but not IGF-II. We speculate that PSA may serve to modulate IGF function within the reproductive system or in prostate cancer by altering IGF-IGFBP-3 interactions.
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PMID:Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. 138 55

Four transplantable cell lines (PA-I, II, III, and IV) derived from four Lobund-Wistar (L-W) rats that manifested spontaneous prostate cancer have demonstrated metastatic capacity in visceral organs. Interestingly, PA-III cells, when deposited over the scapula or calvarium of the Lobund-Wistar rat, could produce lytic and blastic reactions on rat skeleton. Since growth factors and growth factor receptors have been implicated in bone remodeling, cancer biology, and metastatic growth of cancer cells, we have examined 1) the effects of insulin and insulin-like growth factors (IGF-I and IGF-II) on the proliferation of PA-III cells; and 2) the presence of specific receptors for these peptides. IGF-I (0.5 to 100 ng/ml), IGF-II (0.5 to 100 ng/ml), and insulin (0.5 to 10 micrograms/ml) stimulated tritiated thymidine uptake and increased the number of PA-III cells in culture. Receptor studies demonstrated the presence of specific bindings sites for IGF-I and II but not for insulin. The number and affinity of the receptor sites were: IGF-I (nb = 675 fmol/100 g protein, Kd = 0.56 nmol) and IGF-II (nb = 225 fmol/100 g protein, Kd = 0.71 nmol). Molecular characterization of IGF binding sites by polyacrylamide gel electrophoresis under denaturing conditions indicated only the presence for the type I IGF receptor. The presence of the IGF-I receptor and the absence of IGF-II and insulin receptors are discussed in relation to the capacity of PA-III cells to produce bone lesions on the L-W rat.
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PMID:Mitogenic effects of insulin and insulin-like growth factors on PA-III rat prostate adenocarcinoma cells: characterization of the receptors involved. 166 15

The DU145 human prostate cancer cell line was shown to possess type I insulin-like growth factor receptors (IGFR). The addition of either IGF-I or IGF-II, but not insulin, to serum-free culture medium increases the rate of thymidine incorporation by the cells, a response which is suppressed by specific blockade of the previously described epidermal growth factor (EGF) autocrine growth regulatory loop. The DU145 cells secrete into conditional medium a specific IGF-binding protein (IGFBP) precipitated by an antibody to IGFBP-1, and whose secretion is also suppressed by interruption of the EGF autocrine loop. This IGFBP may modulate the bioactivity of IGFs arising from endocrine or paracrine sources in vivo. After removal of IGFBPs from the conditioned medium, no secretion of either IGF-I or IGF-II by this prostate cancer cell line is detected by radioimmunoassay and radioreceptor assay, respectively.
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PMID:Regulation of DU145 human prostate cancer cell proliferation by insulin-like growth factors and its interaction with the epidermal growth factor autocrine loop. 751 2

The network of androgen-dependent growth factors regulating the growth and function of normal or neoplastic prostate epithelium is largely unknown. To facilitate studies directed at investigating this issue, androgen receptor-negative (AR-) PC3 prostate carcinoma cells were stably transfected with the expression plasmid CMV3 containing a constitutively active AR construct that is truncated at its hormone-binding domain (CMV-ARCA). The major characteristic of the resulting cell line (PC3-ARCA) was a growth rate approximately 35% slower than that of a control mock-transfected cell line (PC3-Neo). Of the several growth factors known to be present in the prostate, the current studies focused on the insulin-like growth factor (IGF) axis, specifically the IGF-binding proteins (IGFBPs), several of which are known to be abnormally produced by prostate cancer. Northern analysis showed that IGFBP-1 and -5 are not expressed by PC3-ARCA and -Neo cells. Western ligand and immunoblot analysis of medium conditioned by PC3-Neo and PC3-ARCA cells revealed that equal amounts of IGFBP-2, -4, and -6 were secreted. In contrast, IGFBP-3 was undetectable in the conditioned medium of PC3-ARCA cells, but normally produced by the AR- cell line PC3-Neo. IGFBP-3 disappearance from the conditioned medium of PC3-ARCA cells was transcriptionally regulated, as a marked decrement in IGFBP-3 messenger RNA was detected by S1 protection analysis. We investigated the responses of these cells to exogenously added IGF-I, IGF-II, or IGFBP-3. IGF-I and IGF-II stimulated the proliferation of PC3-ARCA cells, but not of PC3-Neo cells. IGFBP-3 had no effect when given alone. When IGFBP-3 was administered together with IGF-I or IGF-II, it further increased the mitogenic response observed in PC3-ARCA cells, but no effect on PC3-Neo cells was observed. In conclusion, our studies suggest that the presence of an active AR modulates the proliferation of transfected PC3 prostate cancer cells, and that this phenomenon occurs at least in part through the regulation of IGFBP-3 production.
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PMID:Altered growth and insulin-like growth factor-binding protein-3 production in PC3 prostate carcinoma cells stably transfected with a constitutively active androgen receptor complementary deoxyribonucleic acid. 753 76

We have previously documented the presence of specific insulin-like growth factor (IGF)-binding protein (IGFBPs) in seminal plasma and prostate epithelial cell-conditioned medium IGFBP-2 is the prevalent IGFBP in both fluids. To assess whether patients with prostate carcinoma have alterations in serum IGFP levels related to the production of IGFBPs by their tumors, we performed Western ligand blots (WLB) and IGFBP-2 RIA on serum samples from 32 patients with prostate carcinoma of various degrees of clinical severity and compared them to results in 16 healthy age-matched controls. We have also measured serum IGF-I and -II by RIA. The mean level of IGFBP-2 in the prostate cancer patients was 170% of control levels by WLB analysis and 195% of control levels by RIA (P < 0.01). The degree of elevation of IGFBP-2 was related to the stage of the tumor and the levels of the serum tumor marker, prostate-specific antigen. Serum IGFBP-3 levels determined by WLB and serum IGF-I and IGF-II levels measured by RIA after acid chromatography were not different among the subjects with cancer and the normal controls. We conclude that IGFBP-2, which is the main IGFBP produced by prostate epithelial cells, is elevated in the serum of patients with prostate carcinoma, and that the degree of this elevation is related to serum prostate-specific antigen levels and the stage of the tumor. We speculate that prostate-derived IGFBPs may be secreted by prostate tumors and could e of value in understanding the pathophysiology of prostatic tumor growth as well as provide potential diagnostic markers.
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PMID:Elevated levels of insulin-like growth factor-binding protein-2 in the serum of prostate cancer patients. 768 60

In this study, we examined the expression of insulin-like growth factor (IGF) ligands, receptors, (IGFR1, IGFR2), and binding proteins (IGFBPs) in the human prostate cancer cell line DU145, as well as its mitogenic response to the IGFs. Using RNase protection assays, we found expression of IGF-II, IGFR1, and IGFR2 but failed to detect IGF-I messenger RNA. Distinct binding protein species as well as immunoreactive IGF-II were detected in conditioned media using radioligand and immunoblotting assays. Compared with controls, treatment with exogenous IGF-I and IGF-II resulted in stimulation of monolayer and anchorage-independent growth. Recombinant human IGFBP-1, which binds IGF-II with high affinity, inhibited IGF-II-induced monolayer growth and both baseline and IGF-II-induced anchorage-independent growth in this cell line. Our data suggest IGF-II is as an autocrine growth factor in DU145 cells, and that inhibition of IGF-II-dependent growth of human prostate cancer cells may represent a new therapeutic strategy for this disease.
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PMID:Proliferation of cultured human prostate cancer cells is inhibited by insulin-like growth factor (IGF) binding protein-1: evidence for an IGF-II autocrine growth loop. 853 May 86

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

The insulin-like growth factor (IGF) system has been demonstrated to be important for proliferation and differentiation in tissues. This system has also been demonstrated to be an important regulator of the growth of normal prostate epithelium and has been implicated in the process of transformation to human epithelial prostate cancer. This study examined the function of the various components of the IGF system in benign prostate epithelium (BPE), simian virus-40 (SV40)-T antigen-immortalized prostate epithelial cells, P69SV40-T (P69), and two sublines generated from the parental line by serial passage through athymic mice: one tumorigenic (M2182) and one metastatic (M12). IGF-II messenger ribonucleic acid (mRNA) and protein were detected in BPE cells, and each of the three P69 cell lines. IGF-II protein levels were significantly higher in medium collected from the P69, M2182, and M12 cells than in BPE. Proliferation in response to IGF was P69 > BPE > M2182 > M12. The proliferative responses in the four cell types were paralleled by an increase in c-jun. In addition, as the cells became progressively more tumorigenic, the basal level of c-jun mRNA increased. IGF-binding protein-2 (IGFBP-2), -3, -4, -5, and -6 could be detected in the primary epithelial cell medium; however, as the cells became progressively more tumorigenic, there was a decrease in IGFBP-2, -3, -5, and -6 in the medium. The type 1 IGF receptor (IGFr) also decreased as the cells became more tumorigenic. The M12 cells had 80% fewer receptors than the P69 cells and 70% fewer than M2182 cells. There was no change in the Kd for IGF between the cell lines. Based on these data it would appear that the difference in proliferation between the BPE cells and P69s may be due to an increased concentration of inhibitory IGFBPs in the P69 medium. The decrease in proliferation seen in response to IGF in M2182 and M12 cells compared to the P69s would appear at least in part to be due to a decreased IGFr number. IGFr mRNA is represented by 11.0- and 7.0-kilobase bands in the BPE and P69 cells, but only by an 11.0-kilobase band in M2182 and M12 cells. These data indicate that there are significant changes that occur in the IGF system during the process of malignant transformation of the prostate epithelium. The changes described in the P69 cell system are similar to those seen in vivo and suggest that an intact IGF system may be important in maintaining a differentiated epithelial cell.
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PMID:The effect on the insulin-like growth factor system in human prostate epithelial cells of immortalization and transformation by simian virus-40 T antigen. 885 27

Insulin-like growth factors (IGFs) and the type 1 IGF receptor (IGF-R) are involved in normal growth and development of the human prostate. Changes in levels of IGF-R and IGFs have been shown for several malignancies. Immunohistochemistry and in situ hybridization were performed to compare the expression of IGF-R and IGF-II in vivo in prostate tissue containing benign epithelium, high grade prostate intraepithelial neoplasia (PIN), and adenocarcinoma. Messenger ribonucleic acid (mRNA) hybridization signals and immunoreactivity for IGF-R were localized primarily to epithelial cells, with less signal in stroma. IGF-R mRNA was significantly decreased by 42% in PIN and 35% in cancer cells compared to that in benign epithelium (P < 0.0001). IGF-R immunostaining was significantly decreased by 32% in PIN and by 42% in malignant epithelium compared to that in benign epithelium (P < 0.004). IGF-II mRNA was also localized primarily to epithelial cells. IGF-II mRNA was significantly increased by 30% in adenocarcinoma compared to that in benign epithelium (P < 0.03). Immunoreactivity for IGF-II was localized to both stroma and epithelium. Protein levels for IGF-II were not significantly increased in cancer cells compared to those in benign epithelium. The decrease in the type 1 IGF receptor and increase in IGF-II mRNA may affect prostate cancer proliferation and differentiation.
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PMID:Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium. 885 37


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