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)

Transforming growth factor B (TGF-beta) is a potent immunosuppressive cytokine that is frequently associated with mechanisms of tumor escape from immunosurveillance. We report that transplantation of murine bone marrow (BM) expressing a dominant-negative TGF-beta type II receptor (TbetaRIIDN) leads to the generation of mature leukocytes capable of a potent antitumor response in vivo. Hematopoietic precursors in murine BM from donor mice were rendered insensitive to TGF-beta via retroviral expression of the TbetaRIIDN construct and were transplanted in C57BL/6 mice before tumor challenge. After i.v. administration of 5 x 10(5) B16-F10 murine melanoma cells into TbetaRIIDN-BM transplanted recipients, survival of challenged mice at 45 days was 70% (7 of 10) versus 0% (0 of 10) for vector-control treated mice, and surviving TbetaRIIDN-BM mice showed a virtual absence of metastatic lesions in the lung. We also investigated the utility of the TGF-beta-targeted approach in a mouse metastatic model of prostate cancer, TRAMP-C2. Treatment of male C57BL/6 mice with TbetaRIIDN-BM resulted in the survival of 80% (4 of 5) of recipients versus 0% (0 of 5) in green fluorescent protein-BM recipients or wild-type controls. Cytolytic T-cell assays indicate that a specific T-cell response against B16-F10 cells was generated in the TbetaRIIDN-BM-treated mice, suggesting that a gene therapy approach to inducing TGF-beta insensitivity in transplanted BM cells may be a potent anticancer therapy.
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PMID:Suppression of tumor metastasis by blockade of transforming growth factor beta signaling in bone marrow cells through a retroviral-mediated gene therapy in mice. 1249 44

Interleukin-6 (IL-6) is a multifunctional cytokine that activates the signaling pathways of Janus kinases-signal transducers and activators of transcription (STAT) and/or mitogen-activated protein kinases (MAPK) in various tumors. Thus, it modulates cell growth and apoptosis. IL-6 levels are elevated in tissues and sera from prostate cancer patients and IL-6 receptor expression has been detected in prostate cancer cell lines and clinical specimens. Continuous exposure of prostate cancer cells to IL-6 might alter their responsiveness to this cytokine. To gain more insight into the function of IL-6 in prostate carcinoma, we have inoculated LNCaP-IL-6+ cells, generated after prolonged treatment with IL-6, into nude mice (total n = 16, two independent experiments). Controls included animals bearing LNCaP-IL-6- cells, passaged at the same time as LNCaP-IL-6+ cells without supplementation of IL-6. LNCaP-IL-6+ tumor volumes were larger than those of their counterparts at all time points. There were no signs of cachexia in any of the experimental animals and all mice were free of metastases. To better understand the mechanisms responsible for accelerated growth of LNCaP-IL-6+ tumors, we have investigated the expression of cell-cycle regulatory molecules by Western blot analysis. The levels of cyclin-dependent kinase 2 were elevated in LNCaP-IL-6+ cells. There was a strong down-regulation of cyclins D1 and E in the LNCaP-IL-6+ subline. The cell-cycle inhibitor p27 was expressed at a low level in LNCaP-IL-6+ cells and could not be up-regulated by addition of IL-6. Most notably, LNCaP-IL-6+ cells exhibited a reduced expression of the hypophosphorylated form of the retinoblastoma protein (pRb). Accelerated tumor growth in our model system was also associated with alterations in IL-6-signaling pathways. The ability of IL-6 to induce tyrosine phosphorylation of STAT3 was abolished in the LNCaP-IL-6+ subline. In contrast, the levels of the MAPK extracellular signal-regulated kinases 1/2 increased in cells generated after long-term IL-6 treatment. The inhibitor of MAPK kinase PD 98059 retarded the proliferation of LNCaP-IL-6+ but not that of control cells. In summary, we show in the present study that chronic exposure of prostate cancer cells to IL-6 facilitates tumor growth in vivo by abolishment of the growth control by pRb and activation of the MAPK signaling pathway. These findings could be relevant to understand the role of IL-6 in prostate cancer progression.
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PMID:Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. 1254 23

Ligand-activated androgen receptors (ARs) occupy target genes and recruit histone modifiers that influence transcriptional competency. In LNCaP prostate cancer cells, the natural ligand 5alpha-dihydrotestosterone (DHT) activates transiently transfected AR-responsive promoter constructs; concurrent treatment with the protein kinase A activator forskolin enhanced AR stimulation induced by DHT. Additional treatment with the cytokine IL-6, purportedly an AR activator, markedly inhibited receptor activity. To assess AR activity on natural chromatin-integrated promoters/enhancers, we determined AR occupancy of the endogenous prostate specific antigen (PSA) promoter/enhancer as well as PSA expression in LNCaP cells treated with DHT; AR occupancy of the PSA enhancer was rapid (within 1 h of stimulation), robust (10-fold over background), and sustained (8-16 h). In contrast, AR occupancy of the PSA promoter was only increased by 2-fold. Histone H3 acetylation at both the enhancer and promoter was evident 1-2 h after DHT treatment. Detectable pre- and mature PSA mRNA levels appeared after 1 and 6 h treatment, respectively. Substantial qualitative and quantitative differences in PSA expression and AR occupancy of the PSA enhancer were observed when DHT-induced and ligand-independent activations of the AR were compared; forskolin stimulated PSA mRNA and protein expression, whereas IL-6 inhibited both DHT- and forskolin-stimulated expression. IL-6 did not diminish DHT-dependent AR occupancy of the PSA enhancer but inhibited CBP/p300 recruitment, histone H3 acetylation, and cell proliferation. These findings provide a contextual framework for interpreting the contribution of non-steroidal activation of the AR to signaling in vivo, and have implications for prostate cancer cell growth.
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PMID:Androgen receptor activity at the prostate specific antigen locus: steroidal and non-steroidal mechanisms. 1265 11

Macrophage inhibitory cytokine-1 (MIC-1) gene is a member of transforming growth factor-beta superfamily and was reported to be highly overexpressed in human prostate cancer using microarray technology. The aim of this study was to evaluate the quantitative expression of MIC-1 in malignant and benign prostate tissues and to associate expression levels with clinicopathological parameters of prostate cancer. Matched (paired) prostatic tissue samples from the cancerous and noncancerous parts of the same prostates were obtained from 66 patients who underwent radical prostatectomy. Quantitative RT-PCR was performed using SYBR Green I on the Roche LightCycler system. Macrophage inhibitory cytokine-1 gene overexpression in cancerous tissues was observed in 88% of cases, compared to noncancerous tissues (P<0.001). The expression level of MIC-1 in cancerous tissues was significantly higher than in noncancerous tissue (P<0.001). Higher expression of MIC-1 gene was significantly associated with higher Gleason score (P=0.004). The expression of the MIC-1 gene in prostate cancer is significantly higher than in noncancerous tissues, especially in more aggressive forms of the disease (Gleason score>5). This is in contrast to prostate-specific antigen that is downregulated in higher-grade tumours. The upregulation of MIC-1 in prostate cancer and in advanced and more aggressive prostatic tumours suggests that MIC-1 protein should be evaluated as a potential diagnostic and prognostic biomarker.
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PMID:Quantitative analysis of macrophage inhibitory cytokine-1 (MIC-1) gene expression in human prostatic tissues. 1267 11

Genes whose products play a critical role in regulation of the immune response include the human leucocyte antigen (HLA) and cytokine families of genes. The HLA genes are the most polymorphic found in the human genome, and the bulk of this polymorphism results in functional differences in expressed HLA molecules, resulting in inter-individual differences in presentation of peptide antigens to T-cells. In addition, a considerable number of cytokine-associated gene polymorphisms have been identified, the bulk of which occur in the upstream promoter sequences of these genes, which in many cases results in differential in vitro expression of the respective pro- or anti-inflammatory gene product. Particular HLA polymorphisms result in well-defined associations with a large number of immunologically-mediated diseases, including some diseases with known dietary risk factors. For example, individuals of HLA-DQA1*0501, DQB1*0201 genotype have a greater than 200-fold increased risk of developing intolerance to dietary wheat gluten (coeliac disease), and additional HLA-related factors may influence the development of malignant lymphoma within pre-existing coeliac disease. Similarly, HLA-DRB1 alleles sharing a common sequence motif constitute the primary known genetic risk factor for rheumatoid arthritis. The influence of polymorphisms associated with differential cytokine expression on disease susceptibility is currently of much interest. Most attention has been focused on associations with susceptibility to benign immunologically-mediated diseases, including a number of gut diseases. However, recent work from our laboratory indicates that cytokine polymorphisms may influence susceptibility to and prognosis in a number of different cancers, including malignant melanoma skin cancer and solid tumours which may be influenced by diet, such as prostate cancer (collaboration with the CRC/BPG UK Familial Prostate Cancer study). In addition, preliminary work suggests that dietary modulation of expression levels of certain cytokines in healthy human subjects may be genotype dependent.
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PMID:Gene polymorphisms, inflammatory diseases and cancer. 1269 Nov 74

To date, no effective treatment for patients with advanced androgen-independent prostate cancer is available, whereas androgen ablation therapy, surgery, and radiation therapy are effective in treating local, androgen-dependent tumors. The mechanisms underlying the differences between androgen-dependent and -independent prostate cancer remain elusive. Interleukin (IL)-6 is a pleiotropic cytokine whose expression under normal physiological conditions is tightly controlled. However, aberrant constitutive IL-6 gene expression has been implicated in prostate cancer progression and resistance to chemotherapy and has been directly linked to prostate cancer morbidity and mortality. Particularly striking is the large increase in the expression of IL-6 in hormone-refractory prostate cancer. IL-6, in addition to its role as an immunomodulatory cytokine, functions as a growth and differentiation factor for prostate cancer cells. To determine the molecular mechanisms that lead to deregulated IL-6 expression in advanced prostate cancer, we examined the regulatory elements involved in IL-6 gene expression in androgen-independent prostate cancer cells. We demonstrate that, in contrast to the androgen-sensitive LNCaP cells, androgen-insensitive PC-3 and DU145 cells express high levels of IL-6 protein and mRNA due to enhanced promoter activity. Deregulated activation of the IL-6 promoter is for the most part mediated by a combined constitutive activation of the nuclear factor (NF)-kappaB p50 and p65 and the activator protein 1 (AP-1) JunD and Fra-1 family members as demonstrated by electrophoretic mobility shift assays, site-directed mutagenesis, and transfection experiments. Mutation of the NF-kappaB and AP-1 sites drastically reduces IL-6 promoter activity in both androgen-independent prostate cancer cell lines. Additionally, inhibition of these transcription factors using adenovirus vectors encoding either the IkappaBalpha repressor gene or a dominant negative JunD mutant leads to a strong down-regulation of IL-6 gene expression at the mRNA and protein level as measured by real-time PCR and ELISA, respectively. Furthermore, the blockade of IL-6 gene expression results in drastic inhibition of the constitutively activated signal transducers and activators of transcription 3 signaling pathway in DU145 cells. Our data demonstrate for the first time that a combined aberrant activation of NF-kappaB p50 and p65 and AP-1 JunD and Fra-1 in androgen-independent prostate cancer cells results in deregulated IL-6 expression, suggesting a novel potential entry point for therapeutic intervention in prostate cancer.
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PMID:Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. 1272 41

The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
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PMID:Principles of interleukin (IL)-6-type cytokine signalling and its regulation. 1277 95

Prostate-specific antigen (PSA) is a valuable marker antigen for prostate cancer. Lately considerable interest has been generated in the prospect of developing a vaccine for prostate cancer with PSA-derived peptide epitopes to induce cytotoxic T-cell (CTL) response. We report here that T cells capable of exhibiting PSA epitope-specific effector function-in their native state, i.e, without having to be further stimulated, in vitro-are detectable in more than half of the prostate cancer patients we studied. Ex vivo cultured autologous dendritic cells (DC) were used to present four HLA-A2-binding PSA peptide epitopes to freshly isolated peripheral blood lymphocytes (PBL) from patients and healthy volunteers. Ten out of 14 patients' PBL recognized at least one of the four peptides and 6 out of 10 patients' PBL recognized more than one peptide antigen as measured by IFN-gamma secretion upon stimulation of the PBL with the peptide antigen. Intracytoplasmic cytokine analysis for IFN-gamma in purified CD8(+) cells after stimulation with peptide antigens was tested in 6 patients and this technique demonstrated a similar response. Freshly isolated and purified CD8(+) cells when tested, also recognized the epitopes, as measured by IFN assay, when presented by transporter associated with antigen-processing (TAP) deficient T2 cells in an MHC-I restricted fashion. PBL from 9 normal donors when tested in identical fashion did not show any IFN-gamma production in recognition to the peptide antigens. Interestingly, neither of these CD8(+) T cells having IFN-gamma-producing ability did show any cytolytic activity in their native state against peptide loaded target cells or tumor cells when tested in cytotoxicity assay. In long term cocultures stimulation of purified CD8(+) T cells with matured DC pulsed with PSA peptides generated a PSA-specific CTL response in 4 of 6 patients studied and in 2 of 9 normal donors. While our observations of CTL generation are consistent with the prior reports that have demonstrated that specific CD8(+) CTL could be generated which recognize PSA-derived epitopes by in vitro stimulation by one means or another, this observation that IFN-gamma-producing CD8(+) T cells are present in patients which are antigen experienced, and do not require in vitro stimulation, is novel and has major implications for prostate cancer vaccine preparation.
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PMID:Recognition of PSA-derived peptide antigens by T cells from prostate cancer patients without any prior stimulation. 1278 16

The development of effective cancer vaccines depends heavily on the ability to deliver target antigens to generate an immune response. Dendritic cells are the most potent antigen-processing cells, capable of sensitizing T cells to new and recall antigens. Dendritic cells express high levels of major histocompatibility complex class I and II antigens, which are crucial to cancer immunotherapy, as well as a variety of important immunomodulatory proteins, adhesins, and a potent cytokine. Dendritic cells must undergo activation to induce an immune response, and this can be achieved through the use of certain carrier proteins, adjuvants, cytokines, or genetically engineered viruses. Dendritic cells are scattered throughout many tissues of the body, as well as bone marrow and peripheral blood. Most studies have used dendritic cells from peripheral blood; however, these cells are not prevalent in peripheral blood mononuclear cells. The cytokine, granulocyte-macrophage colony-stimulating factor, has been found to induce the maturation and enhance the viability of dendritic cells isolated from peripheral blood. Numerous clinical trials of antigen-pulsed dendritic cells have been conducted in various types of cancer, including non-Hodgkin lymphoma, multiple myeloma, prostate cancer, malignant melanoma, colorectal cancer, and non-small cell lung cancer. These studies show that antigen-loaded dendritic cell vaccinations are safe and promising in the treatment of cancer. This review discusses the use of dendritic cells in immunotherapy and some of the clinical trials that have been conducted.
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PMID:Dendritic cell-based cancer immunotherapy. 1288 9

The lack of efficacy of chemotherapeutics, radiotherapy, and cytokine-based immunotherapy has catalyzed the preliminary enthusiasm for nonmyeloablative stem cell transplants as a novel investigational tool for treating metastatic RCC. The observation that cytokine-refractory metastatic RCC may regress following allogeneic transplantation attests to the powerful nature of the graft-versus-tumor effect that results from this treatment modality. Pilot trials and recent in vitro data provide the first clear evidence that the graft-versus-tumor effect mounted against RCC can produce clinically meaningful regression of a metastatic solid tumor. Given this observation, the authors have begun to expand the investigational use of nonmyeloablative stem cell transplants to other treatment-refractory genitourinary tumors, including metastatic bladder and prostate cancer. It is hoped that future demonstrations of graft-versus-tumor effects in other solid malignancies will lay the groundwork for the development of tumor-targeted strategies that use allogeneic transplantation of donor lymphocytes as an immunotherapeutic platform. Further advances in systemic and selective immunosuppressive agents that limit acute GVHD hold the potential to decrease the toxicity associated with nonmyeloablative stem cell transplants and may ultimately broaden the clinical applicability of this approach.
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PMID:Allogeneic stem cell transplantation as immunotherapy for renal cell carcinoma: from immune enhancement to immune replacement. 1295 59


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