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)

Prostatic cancer typically produces osteoblastic metastases which are not attended by marrow fibrosis (i.e., osteoblast but not stromal fibroblast proliferation). In the present study we sought to test the hypothesis that prostatic cancer cells produce factor(s) which act selectively on human osteoblasts. Such a paracrine mechanism would explain the observed increase in osteoblasts, unaccompanied by an increase in marrow fibroblasts. To test this hypothesis we investigated the mitogenic activity released by the human prostatic tumor cell line, PC3. PC3 cells have been reported previously to produce mitogenic activity for cells that was relatively specific for rat osteoblasts compared to rat fibroblasts. However, the effects of this activity on human cells has not been examined previously. PC3-conditioned medium (CM) (5-50 micrograms CM protein/ml) stimulated human osteoblast proliferation by 200-950% yet did not stimulate human fibroblast proliferation [( 3H]thymidine incorporation). PC3 CM also increased cell numbers in human osteoblast but not fibroblast cell cultures. To determine whether the osteoblast-specific mitogenic activity could be attributed to known bone growth factors, specific assays for these growth factors were performed. PC3 CM contained 10 pg insulin-like growth factor (IGF) I, less than 2 pg IGF II, 54 pg basic fibroblast growth factor, and 16 pg transforming growth factor beta/microgram CM protein. None of these growth factors alone or in combination could account for the observed osteoblast-specific PC3 cell-derived mitogenic activity. Furthermore, when 5 micrograms/ml PC3 CM was tested in combination with maximally effective concentrations of either basic fibroblast growth factor, IGF I, IGF II, or transforming growth factor beta, it produced an additive effect suggesting that PC3 CM stimulates osteoblast proliferation by a mechanism independent of these bone mitogens. Biochemical characterization supported the hypothesis that the PC3 cell growth factor was unique from other growth factors. The PC3 growth factor did not bind to heparin and was resistant to acid as well as the reducing agent, dithiothreitol. Sephadex G-75 and fast protein liquid chromatography Mono S cation-exchange chromatography revealed the PC3-derived mitogen to be an Mr 26,000-30,000 basic protein. Therefore, we conclude that PC3 cells release a mitogen which exhibits higher specificity for human osteoblasts than human fibroblasts and is unique from other growth factors tested. Production of this mitogen by human prostatic carcinoma cells could play an etiological role in the intense osteoblast-specific stimulation that occurs at sites of bone metastases.
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PMID:Human prostatic cancer cells, PC3, elaborate mitogenic activity which selectively stimulates human bone cells. 169 44

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

Prostate-specific antigen (PSA) is a 33 kD protein synthesized in the epithelial cells of the prostate gland. It is a serine protease that belongs to the subgroup of kallikreins, among which it is very similar to a putative enzyme called human glandular kallikrein (hGK-1). Although the hGK-1 enzyme remains to be characterized in vivo, the hGK-1 gene is expressed in the same prostatic epithelial cells as the PSA gene. Expression of the PSA gene is under complex control and the steady-state level of PSA mRNA is increased by androgens, and decreased by epidermal growth factor and activation of protein kinase C. This suggests the existence of several regulatory elements within the cis-acting control elements of the PSA gene. As a seminal serine protease, PSA has been shown to digest the high molecular weight seminal vesicle protein, seminogelin. However, it is likely that this does not constitute the only natural substrate of PSA, as PSA has been shown to degrade insulin-like growth factor-binding protein-3. Serum PSA concentrations are frequently increased in patients with prostatic cancer, but this is also the case in patients with benign prostatic hyperplasia. Thus, PSA measurements alone are not useful as a screening tool for undiagnosed prostatic cancer. However, serum PSA concentrations can be successfully used together with other methods in diagnosing prostatic diseases and in monitoring the successfulness of treatments for prostatic cancer.
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PMID:Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate. 752 Nov 73

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

The effects of treatment with the luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and agonist [D-Trp6] LH-RH were investigated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R-3327-AT-1 prostatic adenocarcinoma implanted orthotopically into the ventral lobes of prostate glands. The LH-RH antagonist SB-75 and the LH-RH agonist [D-Trp6] LH-RH were administered from osmotic minipumps and the survival time of animals bearing this cancer was evaluated. Treatment with SB-75 and [D-Trp6] LH-RH significantly prolonged the mean survival time of rats by 4.1 days and 4.5 days, respectively. In cell cultures, proliferation of the AT-1 cell line was strongly inhibited by the antagonist SB-75, but only a moderate suppression of tumor cell growth in vitro was observed with the agonist [D-Trp6] LH-RH. Receptor assays on Dunning R-3327-AT-1 tumor membranes showed high-affinity binding sites for LH-RH, epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). Receptors for EGF were significantly down-regulated by treatment with SB-75. Therapy with SB-75 also decreased EGF levels in tumor tissue to non-detectable levels, as measured by specific RIA. Our results demonstrate that the LH-RH antagonist SB-75 and agonist [D-Trp6] LH-RH inhibit the growth of androgen-independent Dunning R-3327-AT-1 prostatic cancer in vivo and in vitro.
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PMID:Inhibitory effects of analogs of luteinizing hormone-releasing hormone on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer. 792 4

Prostate adenocarcinoma, the most common tumor occurring among North American men, preferentially metastasizes to bone, where it characteristically forms osteoblastic lesions. The following growth regulatory factors are expressed in some human prostate cancers and/or established cell lines: epidermal growth factor (EGF), transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor (bFGF), and insulin-like growth factor. Some of these, especially EGF, bFGF, and TGF-beta, are also implicated in growth regulation in normal and benign hyperplastic prostates. Although evidence from in vitro study of the small number of prostate cell lines available demonstrates that these growth regulatory pathways are exploited by some of these cells, direct in vivo evidence is limited. The development of human prostate cancer cell lines which grow and metastasize in immune-deficient rodents is an advance which now permits experimental analysis of the role of these growth factors in prostatic metastasis, particularly to bone. The progression and metastasis of human prostate cancer results from the complex interactions of multiple growth factors, androgens, and cellular communication, which form a dynamic network. Continued progress in the study and treatment of this disease will require new conceptual frameworks as well as successful application of the techniques of molecular and cellular biology.
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PMID:Growth factors and their receptors as determinants in the proliferation and metastasis of human prostate cancer. 828 14

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

Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer.
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PMID:Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. 869 80

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


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