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)

Despite evidence implicating the insulin-like growth factor (IGF) system in the pathogenesis of prostate cancer, its precise role remains unclear. In this study we investigated the differential expression of IGF-I, IGF-II and their type I receptor (IGFR-I) in the epithelium and stroma of prostate neoplastic tissues. Using immunohistochemistry and in situ hybridization techniques, we analyzed 43 paraffin-embedded prostatic samples and compared prostatic cancer (Pca) with prostatic intraepithelial neoplasia (PIN) and its normal adjacent prostate (NAP) counterpart. We then determined a possible correlation of the immunohistochemical and in situ findings with two known prognostic clinical-pathological indices: Gleason score histological tumor grade and TNM clinical stage. In 22 of the 43 frozen prostatectomy specimens, IGF-I, IGF-II and IGFR-I mRNA expression were also evaluated by semiquantitative RT-PCR. Non neoplastic and neoplastic tissues examined contained detectable amounts of epithelial and stromal IGF-I, IGF-II and IGFR-I protein and mRNA; all levels increased significantly from normal tissue to PIN to Pca. In all three areas examined, IGFR-I expression was invariably higher in epithelium than in stroma, whereas expression of IGF ligands differed. In normal prostatic tissue, IGF-I and IGF-II expression was higher in stroma than in epithelium. Conversely, in Pca tissue, both factors were more strongly expressed in epithelial malignant cells. PIN areas showed IGF-I lowest, and IGF-II and IGFR-I levels highest in the epithelium. IGF-II protein and mRNA reached their highest levels in prostate tumors with high Gleason scores. These findings indicate that the IGF system changes as prostate tissue progresses from a normal to a malignant state. Differential expression of certain IGF system components in Pca may be associated with the malignant phenotype and more aggressive tumor behavior. Hence IGFs could serve to predict the outcome of prostatic cancer.
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PMID:Insulin-like growth factor (IGF)-I, IGF-II and IGF type I receptor (IGFR-I) expression in prostatic cancer. 1466 84

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

Dietary intake of many fruits and vegetables has been shown to be associated with reduced risk of cancer. We investigated the in vivo efficacy of grape seed extract (GSE, patented as Traconol) against prostate cancer (PCA) and associated molecular events. Athymic nude mice were implanted with hormone-refractory human prostate carcinoma DU145 cells and fed with 100 and 200 mg/kg/day (5 days/week) doses of GSE for 7 weeks. At the end of experiment, tumors were immunohistochemically analyzed for cell proliferation, apoptosis and angiogenesis. Our data show that GSE feeding strongly inhibited tumor growth that accounted for 59-73% (p < 0.001) inhibition in tumor volume and 37-47% (p < 0.05) decrease in tumor weight at the end of the experiment. It did not show any significant change in body weight gain profile and diet consumption. Immunohistochemical analysis of tumors showed that GSE decreases proliferation index by 51-66% (p < 0.001) and increases apoptotic index by 3-4-fold (p < 0.001). CD31 staining for endothelial cells, showed decrease in intratumoral microvasculature in GSE-fed group of mice. Control tumors showed 64.0 +/- 1.6 CD31 positive cells/400x field compared to 23.2 +/- 0.9 and 15.7 +/- 0.08 (p < 0.001) CD31 positive cells in 100 and 200 mg/kg doses of GSE-treated tumors, respectively. GSE strongly inhibited (47-70%, p < 0.05) vascular endothelial growth factor (VEGF) secretion in conditioned medium by DU145 cells. Recently, the circulating level of insulin-like growth factor binding protein (IGFBP)-3 is shown to inversely related with PCA risk, growth and prognosis. Consistent with this, we observed 6-7-fold (p < 0.001) increase in tumor-secreted levels of IGFBP-3 after GSE feeding. In other immunohistochemical studies, compared to controls, tumor xenografts from GSE-fed groups of mice showed a moderate decrease in VEGF but an increase in IGFBP-3 levels. These findings suggest that GSE possesses in vivo anticancer efficacy against hormone-refractory human PCA, which is associated with its antiproliferative, proapoptotic and antiangiogenic activities together with upregulation of IGFBP-3.
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PMID:Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. 1469

Prostate-specific antigen (PSA) is a serine protease and one of the most abundant proteins secreted by the human prostate epithelium. PSA is used as a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3), providing increased local levels of IGF-1, leading to tumor growth. Separately, there are data that suggest an enzymatic regulatory role for dietary boron, which is a serine protease inhibitor. In this study we have addressed the use of boric acid as a PSA inhibitor in an animal study. We have previously reported that low concentrations (6 ug/mL) of boric acid can partially inhibit the proteolytic activity of purified PSA towards a synthetic fluorogenic substrate. Also, by Western blot we have followed the degradation of fibronectin by enzymatically active PSA and have found significant inhibition in the presence of boric acid. We proposed that dietary supplementation with boric acid would inhibit PSA and reduce the development and proliferation of prostate carcinomas in an animal model. We tested this hypothesis using nude mice implanted subcutaneously with LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric acid solutions (1.7, 9.0 mgB/kg/day) by gavage. Control group received only water. Tumor sizes were measured weekly for 8 weeks. Serum PSA and IGF-1 levels were determined at terminal sacrifice. The size of tumors was decreased in mice exposed to the low and high dose of boric acid by 38% and 25%, respectively. Serum PSA levels decreased by 88.6% and 86.4%, respectively, as compared to the control group. There were morphological differences between the tumors in control and boron-dosed animals, including a significantly lower incidence of mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were not different among groups, though expression of IGF-1 in the tumors was markedly reduced by boron treatment, which we have shown by immunohistochemistry. These data indicate that low-level dietary boron supplementation reduced tumor size and content of a tumor trophic factor, IGF-1. This promising model is being evaluated in further studies.
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PMID:Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice. 1471 51

The primary hurdle to improved survival of advanced prostate cancer is our failure to prevent or treat the tumor's progression to its lethal and untreatable stage of androgen independence. Novel treatment modalities designed to prevent androgen-independent progression including prostate cancer metastasis are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anticancer agents that specifically inhibit a progression-relevant target. Antisense oligonucleotides, short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene, promise to show enhanced specificity for malignant cells with a favorable side-effect profile due to well-defined and tailored modes of action. Although not all of the challenges have been met to date, emerging clinical evidence supports the premise that antisense oligonucleotides stand a realistic chance of emerging as major partners of rationally designed anticancer regimens. The rationale and status of antisense targeting of the treatment resistance factor clusterin and of insulin-like growth factor binding protein (IGFBP) 2 and 5 are discussed.
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PMID:Clusterin and IGFBPs as antisense targets in prostate cancer. 1475 27

Several epigenetic alterations leading to constitutively active mitogenic and cell-survival signaling, and loss of apoptotic response are causally involved in self-sufficiency of prostate cancer (PCA) cells toward uncontrolled growth, and increased secretion of pro-angiogenic factors. Therefore, one targeted approach for PCA prevention, growth control and/or treatment could be inhibition of epigenetic molecular events involved in PCA growth, progression and angiogenesis. In this regard, silibinin/silymarin (silibinin is the major active compound in silymarin) has shown promising efficacy. Our extensive studies with silibinin/silymarin and PCA cells have shown the pleiotropic anticancer effects leading to cell growth inhibition in culture and nude mice. The underlying mechanisms of silibinin/silymarin efficacy against PCA involve alteration in cell cycle progression, and inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling. Silibinin also synergizes the therapeutic effects of doxorubicin in PCA cells, making it a strong candidate for combination chemotherapy. Silibinin/ silymarin also inhibits the secretion of proangiogenic factors from tumor cells, and causes growth inhibition and apoptotic death of endothelial cells accompanied by disruption of capillary tube formation on Matrigel. More importantly, silibinin inhibits the growth of in vivo advanced human prostate tumor xenograft in nude mice. Recently, due to its non-toxic and mechanism-based strong preventive/therapeutic efficacy, silibinin has entered in phase I clinical trial in prostate cancer patients.
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PMID:Prostate cancer prevention by silibinin. 1496 63

To study the levels of vascular endothelium growth factor (VEGF), insulin-like growth factor of type I and II (IGF-I and IGF-II), prostate-specific antigen (PSA) and their correlations in prostatic cancer (PC) and benign prostatic hyperplasia (BPH), we examined 38 PC patients (mean age 66.6 +/- 5.5 years) and 80 BPH patients (mean age 60.3 +/- 2.5 years). Serum concentrations of VEGF, IGF-I and IGF-II were measured using kits made by R&D (USA), PSA by Boehringer Mannheim (Germany). Sensitivity and specificity of the tests were analysed by plotting the curves. The serum VEGF concentration in PC patients was 518.9 +/- 60.7 pkg/ml, in BPH patients--267.9 +/- 99.9 pkg/ml (p < 0.001). The IGF-I and IGF-II it was 178 +/- 19 and 136 +/- 9 ng/ml (p < 0.05), 400 +/- 31 and 351 +/- 23 ng/ml (p < 0.05), respectively. The ratio of growth factor concentration to PSA concentration in the blood serum in BPH patients was higher than in PC patients (p < 0.01). Sensitivity and specificity of PSA (4 ng/ml) made up 85.7 and 57%, VEGF (151.5 pg/ml)--76.2 and 57.6%, IGF-I (157 ng/ml)--57.6 and 50%; IGF-II (392 ng/ml)--57.5 and 50%, respectively. Sensitivity and specificity VEGF/PSA was 85.7 and 70%; IGF-I/PSA--84.2 and 75%; IGF-II/PSA--84.2 and 79.6%, respectively. Thus, the ratio of concentrations of IGF-I, IGF-II and VEGF to PSA level in blood serum has high sensitivity and specificity for PC detection. Clinical implications of serum levels of VEGF, IGF-I and IGF-II for prediction of PC course and detection is to be elicited.
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PMID:[Vascular endothelial growth factor and insulin-like-growth factors in prostate cancer. ]. 1502 38

Laser microdissection is a valuable tool to prepare pure cell populations from complex tissues for further analyses. Gene expression studies by real-time RT-PCR and cDNA arrays of microdissected tissues are becoming widely used methods. The integrity and quantity of prepared RNA must be proven to ensure reliable results in subsequent applications such as quantitative RT-PCR and cDNA-arrays. In the present study we used RNAlater trade mark protected prostate tissue for laser microdissection of tumor and tumor-free tissues. RNA quality and quantity was assessed using automated capillary gel electrophoresis. By using quantitative real time-RT-PCR before and after mRNA amplification the insulin-like growth factor binding protein-3 (IGFBP-3) gene expression was shown to be down-regulated in three out of five cases and DD3 was up-regulated in cancer tissues in all cases. The up-regulation of DD3 and the down-regulation of IGFBP-3 gene expression in cancer tissue were conserved after RNA amplification. A cDNA microarray also revealed an IGFBP-3 down-regulation in cancer tissue as well as several genes known to be differerentially expressed in prostate cancer. Taken together, we present a novel method for the isolation of intact RNA from laser microdissection-derived prostate cancer tissue useful for downstream applications of real-time RT-PCR and cDNA microarrays.
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PMID:cDNA microarray analysis with amplified RNA after isolation of intact cellular RNA from neoplastic and non-neoplastic prostate tissue separated by laser microdissections. 1506 29

We previously discovered that a fat-metabolizing enzyme, 15-lipoxygenase-1 (15-LO-1), is high in human prostate cancer (PCa) and correlates with disease progression. The biologic link between the aberrant 15-LO-1/linoleic acid (LA) metabolism and fat (which is a rich source of growth factors) in PCa is unknown. Therefore, we tested the hypothesis that the metabolic product of the polyunsaturated fatty acid LA (i.e., 13-S-hydroxyoctadecadienoic acid or 13-(S)-HODE) affects the proliferation status of PCa cells through one or more growth factors. We used parental prostate cancer cell line-3 (PC-3) and engineered PC-3 cell lines [PC3-Zeo (mock-transfected), PC3-15LOS (15-LO-1-overexpressing), and PC3-15LOAS (15-LO-1-blocked)] to test our hypothesis. Of the growth factors examined, only insulin-like growth factor-1 (IGF-1) exhibited a two-fold to three-fold increase in growth response on PC3-15LOS cells compared to PC3-Zeo (control) cell line (P <.01). Insulin-like growth factor-1 receptor (IGF-1R) immunohistochemical analyses of human normal and adenocarcinoma prostate tissues, as well as levels in tumors derived from nude mice injected with PC-3 cells, demonstrated that elevated IGF-1R expression correlated with 15-LO-1 levels. Radioligand binding assays demonstrated two-fold higher IGF-1 binding sites in PC3-15LOS cells (P <.05 vs PC3-Zeo cells). IGF-1R promoter reporter assay and affinity-purified IGF-1R receptor levels demonstrated a four-fold higher activity in PC3-15LOS cells (P <.01 vs PC3-Zeo cells). IGF-1R promoter activation is 13-(S)-HODE-dependent. IGF-1R blockade with a dominant-negative adenovirus caused significant growth inhibition in PC-3 cells (P <.0001; PC3-15LOAS versus PC3-15LOS cells), as well as affected the IGF-1-stimulated mitogen-activated protein (MAP) kinase (Erk1/2) and Akt activation levels. Our study suggests that overexpression of 15-LO-1 in PCa contributes to the cancer progression by regulating IGF-1R expression and activation.
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PMID:15-lipoxygenase-1 expression upregulates and activates insulin-like growth factor-1 receptor in prostate cancer cells. 1506 70

Patients with hormone refractory prostate cancer have limited treatment options and new therapies are urgently needed. Advances in the understanding of the molecular mechanisms implicated in prostate cancer progression have identified many potential therapeutic gene targets that are involved in apoptosis, growth factors, cell signalling and the androgen receptor (AR). Antisense oligonucleotides are short sequences of synthetic modified DNA that are designed to be complimentary to a selected gene's mRNA and thereby specifically inhibit expression of that gene. The antisense approach continues to hold promise as a therapeutic modality to target genes involved in cancer progression, especially those in which the gene products are not amenable to small molecule inhibition or antibodies. The current status and future direction of a number of antisense oligonucleotides targeting several genes, including BCL-2, BCL-XL, clusterin, the inhibitors of apoptosis (IAP) family, MDM2, protein kinase C-alpha, c-raf, insulin-like growth factor binding proteins and the AR, that have potential clinical use in prostate cancer are reviewed.
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PMID:Antisense approaches in prostate cancer. 1517 74


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