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Peter S Nelson

Publications and source records attributed to Peter S Nelson.

At least 55 records · Page 3Linked to original sources
PubMed2003

LuCaP 35: a new model of prostate cancer progression to androgen independence.

BACKGROUND: Generation of suitable in vivo models is critical for understanding of processes associated with development and progression of prostate cancer (CaP). METHODS: Lymph nodes containing metastatic androgen-independent CaP were implanted into athymic mice. A xenograft designated LuCaP 35 and its hormone-independent variant LuCaP 35V were established and characterized. RESULTS: LuCaP 35 is an androgen-sensitive, prostate-specific antigen (PSA)-producing xenograft. It expresses the wild-type androgen receptor and exhibits deletions in chromosome 8p, but not in chromosome 10. The response of LuCaP 35 to androgen ablation is similar to that observed in man. Using recurring LuCaP 35 tumors we have also established an androgen-insensitive variant of LuCaP 35. CONCLUSIONS: The availability of hormone-dependent and -independent variants of LuCaP 35, which exhibit many properties analogous to those of CaP in man, provides an excellent model system to study the processes associated with development of androgen independence and to evaluate new treatment modalities.

Aged↗
PubMed2003

Molecular characterization of prostatic small-cell neuroendocrine carcinoma.

OBJECTIVES: A subset of prostate carcinomas is composed predominantly, even exclusively, of neuroendocrine (NE) cells. In this report, we sought to characterize the gene expression profile of a prostate small cell NE carcinoma by assessing the diversity and abundance of transcripts in the LuCaP 49 prostate small cell carcinoma xenograft. METHODS: We constructed a cDNA library (PRCA3) from the LuCap 49 prostate small cell xenograft. Single pass DNA sequencing of randomly selected cDNA clones followed by sequence assembly and annotation produced a library of Expressed Sequence Tags (ESTs) representing the LuCaP 49 transcriptome. Comparative sequence analysis with ESTs derived from prostate adenocarcinoma libraries was performed using statistical algorithms designed to identify differentially expressed sequences. Putative NE cell-specific genes were further examined by Northern analysis. RESULTS: Sequence assembly and analysis identified 1,447 distinct genes expressed in the LuCaP 49 cDNA library. These include cDNAs encoding the NE markers secretogranin (SCG2), CD24, and ENO2. Northern analysis revealed that three additional genes, ASCL1, INA, and SV2B are expressed in LuCaP 49 but not in various prostate cancer cell lines or xenografts. Fifteen genes were identified with a statistical probability (P > 0.9) of being up-regulated in LuCaP 49 small cell carcinoma relative to prostate adenocarcinoma (two primary prostate adenocarcinomas and the LNCaP prostate adenocarcinoma cell line). CONCLUSIONS: Prostate small cell carcinoma expresses a diverse repertoire of genes that reflect characteristics of their NE cell of origin. ASCL1, INA, and SV2B are potential molecular markers for small cell NE tumors and NE cells of the prostate. This small cell NE carcinoma gene expression profile may yield insights into the development, progression, and treatment of subtypes of prostate cancer.

Aged↗
PubMed2003

Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1.

Increased expression of mac25/insulin-like growth factor binding-protein related protein-1 (IGFBP-rP1) in human breast and prostate epithelial cell lines results in the suppression of tumor growth. CDNA expression array analysis revealed increased manganese superoxide dismutase (SOD-2) expression in the mac25/IGFBP-rP1-transfected M12 human prostate cancer cell line compared to M12 control cells. SOD-2 has been postulated to be a tumor suppressor. SOD-2 was also increased in LNCaP cells stably transfected with mac25/IGFBP-rP1, but not in mac25/IGFBP-rP1-transfected PC-3 cells. Mac25 LNCaP cells had a marked decrease in tumor growth in nude mice compared to controls, but there was no difference in tumor growth in mac25 PC-3 cells compared to control. Phosphorylated Erk and Akt were increased in the M12 and LNCaP transfected mac25/IGFBP-rP1 cells but not PC-3 mac25. Inhibition of PI-3 kinase results in a marked decrease in viability of the M12-mac25 cells compared to M12 controls. Cells treated with H(2)O(2) result in an increase in phospho-ERK. Transfection of SOD-2 in M12 cells markedly decreased tumor growth, apoptosis, G1 delay in the cell cycle, and expression of senescence associated beta-galactosidase. These results suggest that one of the downstream mediators of the senescence-associated tumor suppression effect of mac25/IGFBP-rP1 is SOD-2.

Adenocarcinoma↗
PubMed2003

Isolation and characterization of human and mouse WDR19,a novel WD-repeat protein exhibiting androgen-regulated expression in prostate epithelium.

Androgens regulate important processes involved in the normal development and function of the human and rodent prostate glands. Here we report the isolation and characterization of a new androgen-regulated gene, designated WDR19, that encodes repeating sequence motifs found in the WD-repeat family of proteins. The WD repeat is a conserved domain of approximately 40 amino acids that is typically bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. WD-repeat proteins are a large group of structurally related proteins that participate in a wide range of cellular functions, including transmembrane signaling, mRNA modification, vesicle formation, and vesicular trafficking. The WDR19 gene comprises 36 exons and is located on chromosome 4p15-4p11. The predicted protein contains six WD repeats, a clathrin heavy-chain repeat, and three transmembrane domains. Sequence analysis reveals that the WDR19 gene is conserved from Caenorhabditis elegans to human. WDR19 is expressed in normal and neoplastic prostate epithelium as demonstrated by RNA in situ hybridization and is regulated by androgenic hormones. WDR19 transcripts exhibit alternative splicing in which two isoforms appear to be prostate restricted, a property that could be exploited for designing diagnostic or therapeutic strategies for prostate carcinoma.

Alternative Splicing↗
PubMed2003

Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer.

The murine Pten prostate cancer model described in this study recapitulates the disease progression seen in humans: initiation of prostate cancer with prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma, and subsequent metastasis with defined kinetics. Furthermore, while Pten null prostate cancers regress after androgen ablation, they are capable of proliferating in the absence of androgen. Global assessment of molecular changes caused by homozygous Pten deletion identified key genes known to be relevant to human prostate cancer, including those "signature" genes associated with human cancer metastasis. This murine prostate cancer model provides a unique tool for both exploring the molecular mechanism underlying prostate cancer and for development of new targeted therapies.

Animals↗
PubMed2003

Differential expression of bikunin (HAI-2/PB), a proposed mediator of glioma invasion, by demethylation treatment.

Effective therapies for primary brain tumors continue to be elusive. Successful adjuvant therapies for CNS tumors will require a better understanding of their basic biology. Hepatocyte growth factor activator inhibitor type-2/placental bikunin (HAI-2/PB) is a serine proteinase inhibitor that has a broad inhibitory spectra against various serine proteinases. HAI-2/PB has anti-invasive effects thought to be mediated primarily by the inhibitory activity against serine proteinase-dependent matrix degradation. It has been previously demonstrated that the expression of HAI-2/PB is inversely related to degree of malignancy and possibly involved in the progression and invasion of human gliomas. Aberrant methylation patterns are an early change in glioma tumorigenesis, earlier than genetic changes. Methylation within 5' regulatory CpG islands by DNA methyltransferase is one of the most common epigenetic modifications. 5-Aza-2'-deoxycytidine (azacytidine) inhibits DNA methyltransferase and has been used in vitro to induce the expression of genes silenced by methylation. We have utilized azacytidine treatment and a micro-array system to investigate methylation influenced gene expression across several tumor cell lines of different lineage (brain, breast, prostate, liver). Using this system we have demonstrated that the expression of HAI-2/PB is under methylation control to a variable extent in glioma cell lines, in comparison to the other tested cell lines. Because the expression of HAI-2/B is inversely related to glioma invasiveness and degree of malignancy, this finding may provide insight into glioma initiation and progression as well as potentially providing new therapeutic targets.

Antimetabolites, Antineoplastic↗
PubMed2003

The role of cyclooxygenase-2 inhibition for the prevention and treatment of prostate carcinoma.

Experimental and epidemiologic studies have demonstrated that nonsteroidal antiinflammatory drugs (NSAIDs) are effective in the prevention of human cancers. Nonsteroidal antiinflammatory drugs inhibit the cyclooxygenase (COX) enzyme that functions to convert arachidonic acid to prostaglandins (PGs). Cyclooxygenase-2, a key COX isoenzyme, is rapidly induced in response to inflammatory stimuli, growth factors, cytokines, and promoters of neoplastic growth. Cyclooxygenase-2-catalyzed reactions may be involved in carcinogenesis via 2 distinct mechanisms: (1). DNA damage and (2). PG-mediated effects. Reactions mediated by COX-2 form reactive oxygen species that can directly induce the oxidation of DNA or instigate the bioactivation of carcinogens. Prostaglandin E2, a byproduct of COX-2-mediated arachidonic acid metabolism, exhibits several biologic actions that have been shown to promote tumorigenesis and tumor progression. These actions include increased cell proliferation, promotion of angiogenesis, and the elevated expression of the antiapoptotic protein Bcl-2. In addition, PGE2 decreases natural killer cell activity and alters immune surveillance. In vitro experimental studies find that COX-2 inhibitors decrease cellular proliferation, increase apoptosis, and modulate genes involved in cell cycle regulation. Evidence from animal studies supports a role for NSAIDs in prostate cancer (CaP) prevention. Population-based studies have observed a reduced incidence of CaP among men using NSAIDs. Because CaP evolves slowly and rarely strikes men before the sixth or seventh decade of life, any strategy to delay or lengthen the time to development of clinically evident CaP, such as chemoprevention strategies, would greatly impact the natural history of this disease. Recent progress and critical analyses in the roles of COX-2 inhibition on prostate carcinogenesis and CaP prevention will be presented.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Effects of the herbal extract PC-SPES on microtubule dynamics and paclitaxel-mediated prostate tumor growth inhibition.

BACKGROUND: PC-SPES is a botanical preparation shown to have efficacy in patients with androgen-dependent and androgen-independent prostate carcinoma. Several herbal constituents in PC-SPES inhibit tumor growth through cell cycle arrest and apoptosis, although the mechanisms of these activities are poorly defined. We sought to identify PC-SPES-induced changes in gene expression, specifically in those genes encoding cytoskeletal proteins that could be associated with PC-SPES-induced cytoxicity. METHODS: LNCaP prostate carcinoma cells were treated with PC-SPES, and changes in gene expression were determined by complementary DNA (cDNA) microarray hybridization and northern blot analyses. PC-SPES and paclitaxel, a microtubule-stabilizing drug, effects on microtubules were assessed by immunofluorescence of treated cells and by in vitro tubulin polymerization assays. In vivo effects of PC-SPES and paclitaxel were assessed using CWR22R androgen-independent prostate cancer xenografts. All statistical tests were two-sided. RESULTS: PC-SPES treatment of LNCaP cells for 24 hours altered the expression of 17 cytoskeletal genes. mRNA levels of alpha-tubulin decreased sevenfold. Although paclitaxel stabilized and PC-SPES treatment disrupted microtubule architecture in LNCaP cells, the combination of both agents had an intermediate effect. PC-SPES inhibited tubulin polymerization in vitro, even in the presence of paclitaxel. Compared with tumors in control mice (mean tumor volume = 2983 mm(3), 95% confidence interval [CI] = 2380 to 3586 mm(3)), tumors were statistically significantly smaller in mice that received PC-SPES (mean tumor volume = 2018 mm(3), 95% CI = 1450 to 2568 mm(3); P =.028), paclitaxel (mean tumor volume = 1340 mm(3), 95% CI = 697 to 1983 mm(3); P<.001), or the combination of PC-SPES and paclitaxel (mean tumor volume = 1955 mm(3), 95% CI = 1260 to 2650 mm(3); P =.034). CONCLUSION: PC-SPES may interfere with microtubule polymerization. This activity has implications for the clinical management of patients with advanced prostate cancer who may be taking PC-SPES concurrently with microtubule-modulating chemotherapeutic agents, such as paclitaxel.

Animals↗
PubMed2002

Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina.

Retinoids are chromophores involved in vision, transcriptional regulation, and cellular differentiation. Members of the short chain alcohol dehydrogenase/reductase superfamily catalyze the transformation of retinol to retinal. Here, we describe the identification and properties of three enzymes from a novel subfamily of four retinol dehydrogenases (RDH11-14) that display dual-substrate specificity, uniquely metabolizing all-trans- and cis-retinols with C(15) pro-R specificity. RDH11-14 could be involved in the first step of all-trans- and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor (RDH12) and retinal pigment epithelial cells (RDH11). The dual-substrate specificity of RDH11 explains the minor phenotype associated with mutations in 11-cis-retinol dehydrogenase (RDH5) causing fundus albipunctatus in humans and engineered mice lacking RDH5. Furthermore, photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. These newly identified enzymes add new elements to important retinoid metabolic pathways that have not been explained by previous genetic and biochemical studies.

Alcohol Oxidoreductases↗
PubMed2002

Ribozyme-targeting of a secreted FGF-binding protein (FGF-BP) inhibits proliferation of prostate cancer cells in vitro and in vivo.

Prostate cancer is one of the most common malignant tumors with increasing incidence rates in the aging male. Since locally advanced or metastatic prostate tumors are essentially incurable, identification of new target molecules and treatment strategies is of critical importance. Fibroblast growth factor-2 (FGF-2) acts as potent mitogen which is upregulated in prostate cancers modulating cancer cell proliferation and development of an invasive phenotype. Normally it is tightly bound to the extracellular matrix that quenches its biological activity. The FGF-binding proteins (FGF-BP, HBp17) is a secreted protein which is able to mobilize and activate FGF-2 from the extracellular matrix. Here we show that FGF-BP is highly expressed in prostate tumor cells. To study the functional role of FGF-BP, we use a ribozyme-targeting approach to selectively deplete FGF-BP in prostate cancer cells achieving a more than 50% reduction of FGF-BP mRNA and protein levels in two mass-transfected cell lines. FGF-BP depletion reduces proliferation of the cells in vitro without changes in cell cycle distribution or apoptosis. Using cDNA microarrays, Northern blotting and RT-PCR, we show a complex pattern of changes in the gene expression profiles upon FGF-BP depletion. Most strikingly, ribozyme-mediated reduction of FGF-BP levels completely abolishes the ability of the highly metastatic PC-3 prostate carcinoma cells to grow tumors in an athymic nude mouse in vivo model which is far beyond the effects of FGF-BP ribozyme targeting observed previously in cells from other tumors in the same model. Taken together, our study identifies FGF-BP as a potential rate-limiting factor for prostate cancer growth and, due to its restricted expression pattern in adults, a potentially attractive target for prostate cancer therapy.

Apoptosis↗
PubMed2002

The program of androgen-responsive genes in neoplastic prostate epithelium.

The human prostate gland is an important target organ of androgenic hormones. Testosterone and dihydrotestosterone interact with the androgen receptor to regulate vital aspects of prostate growth and function including cellular proliferation, differentiation, apoptosis, metabolism, and secretory activity. Our objective in this study was to characterize the temporal program of transcription that reflects the cellular response to androgens and to identify specific androgen-regulated genes (ARGs) or gene networks that participate in these responses. We used cDNA microarrays representing about 20,000 distinct human genes to profile androgen-responsive transcripts in the LNCaP adenocarcinoma cell line and identified 146 genes with transcript alterations more than 3-fold. Of these, 103 encode proteins with described functional roles, and 43 represent transcripts that have yet to be characterized. Temporal gene expression profiles grouped the ARGs into four distinct cohorts. Five uncharacterized ARGs demonstrated exclusive or high expression levels in the prostate relative to other tissues studied. A search of available DNA sequence upstream of 28 ARGs identified 25 with homology to the androgen response-element consensus-binding motif. These results identify previously uncharacterized and unsuspected genes whose expression levels are directly or indirectly regulated by androgens; further, they provide a comprehensive temporal view of the transcriptional program of human androgen-responsive cells.

Amino Acid Motifs↗
PubMed2002

Molecular effects of the herbal compound PC-SPES: identification of activity pathways in prostate carcinoma.

Clinical trials of the herbal preparation PC-SPES have demonstrated substantial responses in patients with advanced prostate cancer. Biochemical assays and clinical observations suggest that the effects of PC-SPES are mediated at least in part through estrogenic activity, although the mechanism(s) remains largely undefined. In this study, we used cDNA microarray analysis to identify gene expression changes in LNCaP prostate carcinoma cells exposed to PC-SPES and estrogenic agents including diethylstilbestrol. PC-SPES altered the expression of 156 genes after 24 h of exposure. Of particular interest, transcripts encoding cell cycle-regulatory proteins, alpha- and beta-tubulins, and the androgen receptor were down-regulated by PC-SPES. A comparison of gene expression profiles resulting from these treatments indicates that PC-SPES exhibits activities distinct from those attributable to diethylstilbestrol and suggests that alterations in specific genes involved in modulating the cell cycle, cell structure, and androgen response may be responsible for PC-SPES-mediated cytotoxicity.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Isolation and characterization of the murine prostate short-chain dehydrogenase/reductase 1 (Psdr1) gene, a new member of the short-chain steroid dehydrogenase/reductase family.

We report the isolation and characterization of a complementary DNA (cDNA) encoding a novel member of the short-chain dehydrogenase/reductase (SDR) gene family that we have designated murine prostate short-chain dehydrogenase/reductase 1 (Psdr1). Psdr1 was cloned as a 3.2 kbp transcript from mouse testis cDNA based on the sequence of the recently described androgen-regulated human PSDR1 gene (Cancer Res. 61 (2001) 1611). The putative protein encoded by Psdr1 consists of 316 amino acids with 85% identity to human PSDR1. A search against the BLOCKS database of conserved protein motifs indicates that Psdr1 retains features essential for SDR function. Northern analyses demonstrate that Psdr1 is highly expressed in the murine testis and liver and exhibits several isoforms. Cloning and sequence analysis of the putative Psdr1 promoter region identified motifs with homology to the consensus androgen response element and progesterone response element. The Psdr1 gene was mapped to mouse chromosome 12q31-34, which has synteny with the human PSDR1 chromosomal location (14q23-24.3). Together, these data describe a new member of the SDR gene family that may be involved in the tissue-specific metabolism of retinoids or steroid hormones.

Amino Acid Sequence↗
PubMed2002

Evidence that the human gene for prostate short-chain dehydrogenase/reductase (PSDR1) encodes a novel retinal reductase (RalR1).

All-trans-retinoic acid is a metabolite of vitamin A (all-trans-retinol) that functions as an activating ligand for a family of nuclear retinoic acid receptors. The intracellular levels of retinoic acid in tissues are tightly regulated, although the mechanisms underlying the control of retinoid metabolism at the level of specific enzymes are not completely understood. In this report we present the first characterization of the retinoid substrate specificity of a novel short-chain dehydrogenase/reductase (SDR) encoded by RalR1/PSDR1, a cDNA recently isolated from the human prostate (Lin, B., White, J. T., Ferguson, C., Wang, S., Vessella, R., Bumgarner, R., True, L. D., Hood, L., and Nelson, P. S. (2001) Cancer Res. 61, 1611-1618). We demonstrate that RalR1 exhibits an oxidoreductive catalytic activity toward retinoids, but not steroids, with at least an 800-fold lower apparent K(m) values for NADP+ and NADPH versus NAD+ and NADH as cofactors. The enzyme is approximately 50-fold more efficient for the reduction of all-trans-retinal than for the oxidation of all-trans-retinol. Importantly, RalR1 reduces all-trans-retinal in the presence of a 10-fold molar excess of cellular retinol-binding protein type I, which is believed to sequester all-trans-retinal from nonspecific enzymes. As shown by immunostaining of human prostate and LNCaP cells with monoclonal anti-RalR1 antibodies, the enzyme is highly expressed in the epithelial cell layer of human prostate and localizes to the endoplasmic reticulum. The enzymatic properties and expression pattern of RalR1 in prostate epithelium suggest that it might play a role in the regulation of retinoid homeostasis in human prostate.

Alcohol Oxidoreductases↗
PubMed2002

Human prostate epithelial cell-type cDNA libraries and prostate expression patterns.

BACKGROUND: Transcriptome analysis is a powerful approach to uncovering genes responsible for diseases such as prostate cancer. Ideally, one would like to compare the transcriptomes of a cancer cell and its normal counterpart for differences. METHODS: Prostate luminal and basal epithelial cell types were isolated and cell-type-specific cDNA libraries were constructed. Sequence analysis of cDNA clones generated 505 luminal cell genes and 560 basal cell genes. These sequences were deposited in a public database for expression analysis. RESULTS: From these sequences, 119 unique luminal expressed sequence tags (ESTs) were extracted and assembled into a luminal-cell transcriptome set, while 154 basal ESTs were extracted and assembled into a basal-cell set. Interlibrary comparison was performed to determine representation of these sequences in cDNA libraries constructed from prostate tumors, PIN, cell lines. CONCLUSIONS: Our analysis showed that a significant number of epithelial cell genes were not represented in the various transcriptomes of prostate tissues, suggesting that they might be underrepresented in libraries generated from tissue containing multiple cell types. Although both luminal and basal cell types are epithelial, their transcriptomes are more divergent from each other than expected, underscoring their functional difference (secretory vs. nonsecretory). Tumor tissues show different expression of luminal and basal genes, with perhaps a trend towards expression of basal genes in advanced diseases.

DNA, Complementary↗
PubMed2002

The human (PEDB) and mouse (mPEDB) Prostate Expression Databases.

The Prostate Expression Databases (PEDB and mPEDB) are online resources designed to allow researchers to access and analyze gene expression information derived from the human and murine prostate, respectively. Human PEDB archives more than 84 000 Expressed Sequence Tags (ESTs) from 38 prostate cDNA libraries in a curated relational database that provides detailed library information including tissue source, library construction methods, sequence diversity and sequence abundance. The differential expression of each EST species can be viewed across all libraries using a Virtual Expression Analysis Tool (VEAT), a graphical user interface written in Java for intra- and inter-library sequence comparisons. Recent enhancements to PEDB include (i) the development of a murine prostate expression database, mPEDB, that complements the human gene expression information in PEDB, (ii) the assembly of a non-redundant sequence set or 'prostate unigene' that represents the diversity of gene expression in the prostate, and (iii) an expanded search tool that supports both text-based and BLAST queries. PEDB and mPEDB are accessible via the World Wide Web at http://www.pedb.org and http://www.mpedb.org.

Animals↗
PubMed2002

A neuroendocrine/small cell prostate carcinoma xenograft-LuCaP 49.

The late stages of progression of prostate carcinoma are typically characterized by an androgen-insensitive, rapidly proliferative state. Some late-stage tumors are composed predominantly of neuroendocrine cells. Virtually no animal models of a neuroendocrine/small cell variant of prostate carcinoma are available for experimental studies. We report a human neuroendocrine/small cell prostate carcinoma xenograft that was developed from a nodal metastasis of a human prostate carcinoma and that has been propagated as serial subcutaneous implants in severe combined immunodeficient mice for >4 years. Designated LuCaP 49, all tumor passages exhibit a neuroendocrine/small cell carcinoma phenotype-insensitivity to androgen deprivation, expression of neuroendocrine proteins, lack of expression of prostate-specific antigen or androgen receptor, and an unusually rapid growth (a doubling time of 6.5 days) for prostate cancer xenografts. Genetically this tumor exhibits loss of heterozygosity for the short arm of chromosome 8 and has a complex karyotype. This xenograft should prove to be useful in the investigation of mechanisms underlying the androgen-insensitive state of progressive prostate carcinoma.

Aged↗