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National Cancer Institute®
Ultima Vez Modificado: 21 de noviembre del 2001
UI - 21262941
AU - Rhee HW; Zhau HE; Pathak S; Multani AS; Pennanen S; Visakorpi T; Chung
TI - LW Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a three-dimensional rotating-wall vessel.
SO - In Vitro Cell Dev Biol Anim 2001 Mar;37(3):127-40
AD - Department of Urology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
A three-dimensional (3D) integrated rotating-wall vessel cell-culture system was used to evaluate the interaction between a human prostate cancer cell line, LNCaP, and microcarrier beads alone, or microcarrier beads previously seeded with either prostate or bone stromal cells. Upon coculture of LNCaP cells with microcarrier beads either in the presence or in the absence of prostate or bone stromal cells, 3D prostate organoids were formed with the expected hormonal responsiveness to androgen, increased cell growth, and prostate-specific antigen production. In this communication, we define permanent phenotypic and genotypic changes of LNCaP cells upon coculture with microcarrier beads alone, or with microcarrier beads previously seeded with either prostate or bone stromal cells. Most notably, we observed selective genetic changes, i.e., chromosomal losses or gains, as evaluated by both conventional cytogenetic and comparative genomic hybridization, in LNCaP sublines derived from the prostate organoids. Moreover, the derivative LNCaP cells appear to have altered growth profiles, and exhibit permanent and stable changes in response to androgen, estrogen, and growth factors. The derivative LNCaP sublines showed increased anchorage-independent growth rate, and enhanced tumorigenicity and metastatic potential when inoculated orthotopically in castrated athymic mice. Our results support the hypothesis that further nonrandom genetic and phenotypic changes in prostate cancer epithelial cells can occur through an event that resembles "adaptive mutation" such as has been described in bacteria subjected to nutritional starvation. The occurrence of such permanent changes may be highly contact dependent, and appears to be driven by specific microenvironmental factors surrounding the tumor cell epithelium grown as 3D prostate organoids.
UI - 21385143
AU - Kasahara K; Taguchi T; Yamasaki I; Karashima T; Kamada M; Yuri K; Shuin
TI - T Fluorescence in situ hybridization to assess transitional changes of aneuploidy for chromosomes 7, 8, 10, 12, 16, X and Y in metastatic prostate cancer following anti-androgen therapy.
SO - Int J Oncol 2001 Sep;19(3):543-9
AD - Department of Urology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
There have been few detailed studies conducted on the cell population in relation to cytogenetic changes between the pre- and post-treatment periods in patients with prostate cancer. We investigated numerical chromosome changes associated with anti-androgen therapy, using fluorescence in situ hybridization (FISH). FISH using chromosome-specific centromeric probes was used to assess transitional changes in the frequency of aneuploidy for chromosomes 7, 8, 10, 12, 16, X, and Y in prostate cancer during the pre- and post-treatment periods. Gains of chromosomes 7, 8 and 12 were notable in the pre-treatment samples (8 out of 9 cases in chromosome 7; 8 out of 9 cases in chromosome 8; 7 out of 9 cases in chromosome 12), while a notable reduction in the number of cells with extra copies of these chromosomes was observed in post-treatment specimens. Other chromosomes did not show noticeable change in their FISH signals at each phase of clinical treatment in all 9 cases. Changes in cell number with high ploidies of chromosome 7, 8 and 12 reflect the clinical effects of anti-androgen therapy at the early phase, which might explain the androgen dependency of metastatic prostate cancer cells.
UI - 21417714
AU - Gupta S; Hastak K; Ahmad N; Lewin JS; Mukhtar H
TI - Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols.
SO - Proc Natl Acad Sci U S A 2001 Aug 28;98(18):10350-5
AD - Department of Dermatology, Case Western Reserve University & The Research Institute of University Hospitals of Cleveland, Cleveland, OH 44106, USA.
Development of effective chemopreventive agents against prostate cancer (CaP) for humans requires conclusive evidence of their efficacy in animal models that closely emulates human disease. The autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human disease. Employing male TRAMP mice, we show that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits CaP development and increases survival in these mice. In two separate experiments, the cumulative incidence of palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of 20). In these mice, 95% (19 of 20), 65% (13 of 20), 40% (8 of 20), and 25% (5 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol) provided as the sole source of drinking fluid to TRAMP mice from 8 to 32 weeks of age resulted in (i) significant delay in primary tumor incidence and tumor burden as assessed sequentially by MRI, (ii) significant decrease in prostate (64%) and genitourinary (GU) (72%) weight, (iii) significant inhibition in serum insulin-like growth factor-I and restoration of insulin-like growth factor binding protein-3 levels, and (iv) marked reduction in the protein expression of proliferating cell nuclear antigen (PCNA) in the prostate compared with water-fed TRAMP mice. The striking observation of this study was that GTP infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significant apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.
UI - 21418977
AU - Vogel W; Maier C; Paiss T
TI - Prostate cancer and the problem of genotype phenotype correlation.
SO - Cytogenet Cell Genet 2001;93(3-4):162-7
AD - Department of Human Genetics, University of Ulm, Ulm, Germany. email@example.com
UI - 21427668
AU - Burchardt M; Burchardt T; Shabsigh A; Ghafar M; Chen MW; Anastasiadis A;
TI - de la Taille A; Kiss A; Buttyan R Reduction of wild type p53 function confers a hormone resistant phenotype on LNCaP prostate cancer cells.
SO - Prostate 2001 Sep 15;48(4):225-30
AD - The Department of Urology, The College of Physicians and Surgeons of Columbia University, New York, USA.
BACKGROUND: The protein encoded by the p53 gene is required for some forms of apoptosis and loss or mutations in this gene are found with increased frequency in advanced and hormone resistant human prostate cancers. In order to better appreciate whether reduction of wildtype p53 function in prostate cancer cells might contribute to the development of therapeutic-resistance by these cells, we created stable variants of the androgen-responsive, wild type p53-expressing human prostate cancer cell line, LNCaP, by transfection with expression vectors designed to reduce expression or function of wildtype p53 in them. These cells were then tested for their ability to form tumors in castrated male nude mice. METHODS: A conditional eukaryotic expression vector (under tetracycline regulation) expressing antisense p53 cDNA was constructed and either directly transfected into LNCaP cells or tranduced into these cells using recombinant retroviruses containing the vector. Stably transfected/transduced cells (LNCaP/Asp53) were evaluated by Western blot analysis for the ability of doxycycline to reduce p53 protein expression and for their ability to form tumors in castrated male nude mice treated or untreated with doxycycline. Additionally, we derived an LNCaP subline (LNCaP/DD) stably expressing a dominant-negative form of p53 and tested these cells for their ability to form tumors in castrated male nude mice. RESULTS: LNCaP/Asp53 cells showed reduced expression of p53 protein when cultured in a medium containing doxycycline and tested sublines were able to efficiently form tumors in castrated male nude mice only when the mice were treated with doxycycline. LNCaP/DD cells were readily able to form tumors in castrated male nude mice whereas parental LNCaP cells or control-transfected LNCaP cells were not. CONCLUSION: Loss of wildtype p53 function can contribute to the phenotype of hormone resistance of prostate cancer cells. Copyright 2001 Wiley-Liss, Inc.
UI - 21427669
AU - Olsson P; Bera TK; Essand M; Kumar V; Duray P; Vincent J; Lee B; Pastan
TI - I GDEP, a new gene differentially expressed in normal prostate and prostate cancer.
SO - Prostate 2001 Sep 15;48(4):231-41
AD - Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
BACKGROUND: The database of human expressed sequence tags (dbEST) is a potential source for the identification of tissue specific genes. The database contains sequences that originate from cDNA libraries from different tissues cell types and tumors. METHODS: Computer based analysis identified a cluster of sequence homologous ESTs, containing ESTs derived only from human prostate cDNA libraries. The tissue specificity was examined by multiple tissue RNA dot blots and RT-PCR. The new RNA transcript was characterized using northern blot analysis, RACE-PCR, and a ribonuclease protection assay. RESULTS: We have identified a gene differentially expressed in prostate using EST database analysis and experimental studies. We name the gene GDEP for gene differentially expressed in prostate. The major GDEP transcript is about 520 bp long. GDEP RNA was detected in nine prostate tissue samples, four normal and five cancer. Expression in prostate epithelial cells was established by in situ hybridization. Weak expression was detected in the prostate cancer cell line LNCaP. In vitro transcription/translation indicate that the RNA encodes a small 34 amino acid protein. The major transcript consists of two exons with one large intron (> 15 kb). The GDEP gene was mapped to chromosome 4q21.1 by radiation hybrid mapping. CONCLUSIONS: Our data proves that tissue specific genes can be identified by EST database mining. The prostate specificity of GDEP expression indicates that GDEP may be useful in the diagnosis or treatment of prostate cancer. Published 2001 Wiley-Liss, Inc.
UI - 21427671
AU - Kibel AS; Christopher M; Faith DA; Bova GS; Goodfellow PJ; Isaacs WB
TI - Methylation and mutational analysis of p27(kip1) in prostate carcinoma.
SO - Prostate 2001 Sep 15;48(4):248-53
AD - Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63105, USA. firstname.lastname@example.org
BACKGROUND: We have previously identified 12p12-13 as a region of frequent genetic loss in prostate carcinoma. A candidate tumor suppressor gene at this locus is the cyclin dependent kinase inhibitor p27(kip1), which has been implicated as a marker of aggressive prostate carcinoma. Herein, we examine metastatic prostate tumors, xenografts, and cell lines for gene inactivation via mutational inactivation or promoter hypermethylation. METHODS: Mutation analysis was performed on metastatic prostate tumors of 18 patients, eight prostate carcinoma cell lines, and 18 xenografts by PCR amplification of the entire open reading frame of p27(kip1). PCR products were sequenced directly using internal primers. Methylation analysis was performed on four cell lines and nine xenografts using direct sequencing of cloned PCR products of bisulfite treated DNA. Presence of a CpG was consistent with methylation of that cytosine in the original sample. RESULTS: With the exception of the previously reported homozygous deletion, no additional mutations were identified. Methylated CpG residues were identified in three xenografts (LuCAP23, LuCAP35, and PC82) and the methylated residues clustered at six sites; the cytosines 69, 149, 191, 286, 349, and 487 base pairs 5' of the ATG start codon. However, no sample demonstrated promotor methylation in all sequenced clones and the number of methylated base pairs ranged from seven to three, not the level usually associated with gene silencing. CONCLUSIONS: Mutational inactivation of p27(kip1) is a rare event in metastatic prostate carcinoma. While CpG methylation does occur, it is an infrequent event and does not appear to be the mechanism of p27(kip1) down regulation in prostate carcinoma. Copyright 2001 Wiley-Liss, Inc.
UI - 21427675
AU - Bonkhoff H; Fixemer T; Hunsicker I; Remberger K
TI - Progesterone receptor expression in human prostate cancer: correlation with tumor progression.
SO - Prostate 2001 Sep 15;48(4):285-91
AD - Institute of Pathology, University of the Saarland, Homburg/Saar, Germany. email@example.com
BACKGROUND: The recent discovery of the classical estrogen receptor alpha (ERalpha) in metastatic and recurrent prostatic adenocarcinoma suggests that estrogens are implicated in prostate cancer progression. METHODS: To get more insight into estrogen signaling in prostate cancer tissue, the current study has examined the immunoprofile of the estrogen-inducible progesterone receptor (PR), and evaluated its relation to ERalpha gene expression. RESULTS: In primary tumors, the PR was detectable in 36% of primary Gleason grade 3 (5 of 14 cases), 33% of primary Gleason grade 4 (5 of 15 cases), and in 58% of primary Gleason grade 5 tumors (7 of 12 cases). None of the 41 primary tumors investigated revealed significant PR expression in more than 50% of tumor cells. Conversely, moderate to strong receptor expression was observed in 60% of metastatic lesions (9 of 15 cases), and in 54% of androgen-insensitive tumors (38 of 71 cases). Irrespective of grades and stages, the presence of the PR was invariably associated with high steady state levels of ERalpha mRNA, whereas the ERalpha protein was undetectable by immunohistochemistry (IHC) in a significant number of cases (58 of 97 cases). CONCLUSIONS: The progressive emergence of the PR during tumor progression obviously reflects the ability of metastatic and androgen-insensitive tumors to use estrogens through a ERalpha-mediated pathway. The present data provide a theoretical background for studying the efficiency of antiestrogens and antigestagens in the medical treatment of advanced prostate cancer. Copyright 2001 Wiley-Liss, Inc.
UI - 21427676
AU - Peters MA; Janer M; Kolb S; Jarvik GP; Ostrander EA; Stanford JL
TI - Germline mutations in the p73 gene do not predispose to familial prostate-brain cancer.
SO - Prostate 2001 Sep 15;48(4):292-6
AD - Division of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. firstname.lastname@example.org
BACKGROUND: Analysis of high-risk prostate cancer (PC) families with at least one confirmed case of primary brain cancer (BC) has identified a region of genetic linkage on chromosome 1p36 termed CAPB. The p36 region of chromosome one has been reported to have frequent loss of heterozygosity (LOH) in brain and central nervous system (CNS) tumors and epidemiological studies have shown an increased relative risk of BC and tumors of the CNS in PC families. In 1997 a reported tumor suppressor with high homology to p53, termed p73, was mapped to the p36 region of chromosome one. Here, we examine the p73 gene as a potential candidate for CAPB. METHODS: Ninety-four members from the 12 prostate-brain cancer families in which linkage was originally found were examined. The complete coding region and intron-exon boundaries of the p73 gene were analyzed for germline mutations by Single Stranded Conformational Polymorphism analysis (SSCP) and direct DNA sequencing. RESULTS: Silent nucleotide substitutions only were detected within the coding regions of the gene in affected individuals. Nucleotide changes were detected in introns 1, 6, 8, 9, and 10, but all were located >or=16 base pairs from the splice site, and are thus unlikely to be deleterious mutations. CONCLUSIONS: Germline mutations in the p73 gene are unlikely to be critical for inherited susceptibility to PC in this specified subset of families. Copyright 2001 Wiley-Liss, Inc.
UI - 21427678
AU - Wu GJ; Varma VA; Wu MW; Wang SW; Qu P; Yang H; Petros JA; Lim SD; Amin
TI - MB Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues.
SO - Prostate 2001 Sep 15;48(4):305-15
AD - Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. email@example.com
BACKGROUND: Over expression of huMUC18, a cell adhesion molecule in the immunoglobulin gene superfamily, causes a non-metastatic human melanoma cell line to become metastatic in a nude mouse system. To determine if MUC18 expression correlates with the malignant progression of prostate cancer, we investigated differential expression of human MUC18 (huMUC18) in normal prostate epithelial cells, prostate cancer cell lines, and prostatic normal and cancer tissues. METHODS: RT-PCR and Western blot analyses were used to analyze the expression of MUC18 mRNA and protein in four human prostate cancer cell lines, cultured primary normal prostate epithelial cells, normal prostate and malignant prostate tissues. Immunohistochemistry was used to determine the expression of MUC18 antigen in prostatic tissues at different stages of malignancy. RESULTS: Human MUC18 mRNA and protein was expressed in three different prostate cancer cell lines (TSU-PR1, DU145, and PC-3), but not in one prostate cancer cell line (LNCaP.FGC). HuMUC18 protein was also expressed at high levels in extracts prepared from tissue sample sections containing high grade prostatic intraepithelial neoplasia (PIN), but weakly expressed in extracts prepared from either cultured primary normal prostatic epithelial cells or the normal prostate gland. Immunohistochemical analysis showed that huMUC18 was expressed at higher levels in the epithelial cells of high-grade PIN and prostatic carcinomas and in cells of a lymph node metastasis compared to that in normal or benign hyperplastic epithelium (BPH). CONCLUSIONS: We therefore conclude that MUC18 is expressed at higher levels in pre-malignant and malignant prostatic epithelium, including metastasis. We suggest that over-expression of MUC18 may be a new marker of human prostate cancer and also implicates its possible role in development and progression of prostate cancer. Copyright 2001 Wiley-Liss, Inc.
UI - 21439123
AU - Ghadersohi A; Sood AK
TI - Prostate epithelium-derived Ets transcription factor mRNA is overexpressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen.
SO - Clin Cancer Res 2001 Sep;7(9):2731-8
AD - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
PURPOSE: There is a need to identify novel breast tumor-associated molecules with a potential as diagnostic/prognostic markers of breast cancer as well as targets of vaccine and drug discovery against this cancer. EXPERIMENTAL DESIGN: We used a combination of digital differential display and reverse transcription-PCR (RT-PCR) methods to identify breast tumor-associated cDNAs. RESULTS: It was found that prostate epithelium-derived Ets transcription factor (PDEF) and five other cDNAs occur at high frequency in the cDNA libraries from normal human breast tissue and human breast tumors. In contrast, these cDNAs are either undetectable or present at low frequencies in the cDNA libraries from other normal human tissues. RT-PCR expression analysis of PDEF showed it to be overexpressed in 14 of 20 primary human breast tumors and in one metastases tested. Also, consistent with the digital differential display data, RT-PCR analysis of PDEF expression showed highly restricted expression in normal human tissues. Furthermore, we show that PDEF transcript levels are 192-fold higher in the peripheral blood of a breast cancer patient in comparison with two normal individuals and another breast cancer patient. In contrast to PDEF, RT-PCR analysis of the expression of the other three cDNAs, including MYL5, Hs.44017, and Hs.215937, showed that these cDNAs are expressed in several normal human tissues. CONCLUSIONS: These results suggest that PDEF is a breast tumor-associated cDNA and should be further evaluated for its potential as a breast tumor marker and a breast tumor antigen.
UI - 21439124
AU - Goode EL; Stanford JL; Peters MA; Janer M; Gibbs M; Kolb S; Badzioch MD;
TI - Hood L; Ostrander EA; Jarvik GP Clinical characteristics of prostate cancer in an analysis of linkage to four putative susceptibility loci.
SO - Clin Cancer Res 2001 Sep;7(9):2739-49
AD - Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, 98195-7236, USA.
PURPOSE: Hereditary prostate cancer is an etiologically heterogeneous disease with six susceptibility loci mapped to date. We aimed to describe a collection of high-risk prostate cancer families and assess linkage to multiple markers at four loci: HPC1 (1q24-25), PCaP (1q42.2-43), HPCX (Xq27-28), and CAPB (1p36). EXPERIMENTAL DESIGN: Medical record data on 505 affected men in 149 multiply-affected prostate cancer families were reviewed, and correlations of clinical traits within each family were calculated. Logarithm of odds (LOD) score and nonparametric (NPL) linkage analyses were performed; white families were stratified by age of diagnosis, grade and stage of disease, and evidence of linkage to the other loci to increase genetic homogeneity. RESULTS: Age at diagnosis was the most correlated clinical trait within families. A maximum NPL score of 2.61 (P = 0.007) appeared to confirm HPC1 linkage for families that had a prevalence of high-grade or advanced-stage prostate cancer and which were not likely to be linked to PCaP, HPCX, or CAPB. Because the NPL scores improved when families more likely to be linked to the other loci were excluded, HPC1 may act independently of the other loci. The relationship of HPC1 and aggressive disease was strongest in families with median age at diagnosis > or =65 years (NPL, 3.48; P = 0.0008). CONCLUSIONS: The current results suggest that HPC1 linkage may be most common among families with more severe prostate cancer. Stratification by clinical characteristics may be a useful tool in prostate cancer linkage analyses and may increase our understanding of hereditary prostate cancer.
UI - 21439150
AU - Hobisch A; Ramoner R; Fuchs D; Godoy-Tundidor S; Bartsch G; Klocker H;
TI - Culig Z Prostate cancer cells (LNCaP) generated after long-term interleukin 6 (IL-6) treatment express IL-6 and acquire an IL-6 partially resistant phenotype.
SO - Clin Cancer Res 2001 Sep;7(9):2941-8
AD - Department of Urology, University of Innsbruck, Innsbruck A-6020, Austria.
PURPOSE: The levels of interleukin-6 (IL-6) are frequently elevated in sera from patients with advanced prostate carcinoma. Our main objective was to investigate changes in responsiveness to IL-6 and/or androgen that occur in LNCaP cells after long-term treatment with IL-6. This in vitro model could be of clinical relevance because of its similarity with late-stage prostate carcinoma. EXPERIMENTAL DESIGN: LNCaP human prostate cancer cells were treated with IL-6 at a concentration of 5 ng/ml. After 20 passages, the new subline LNCaP-IL-6+ has been established. Passages 20-40 are referred to as low passages (LP) and passages 41-73 as high passages (HP). LNCaP cells passaged at the same time in the absence of IL-6 were used as controls (LNCaP-IL-6-). Cells were counted after treatment with either IL-6 or the synthetic androgen methyltrienolone (R1881), and cell cycle analysis was performed. Binding of IL-6 or R1881 was assessed by radioligand binding assays. Reporter gene activity was measured by chloramphenicol acetyltransferase assay. Prostate-specific antigen in LNCaP-IL-6+ supernatants was measured by an enzyme immunoassay. Expression of IL-6 mRNA and protein was assessed by reverse transcription-PCR and ELISA, respectively. RESULTS: The basal proliferation rate in HP LNCaP-IL-6+ cells was higher than that in LNCaP-IL-6- cells. IL-6 inhibited proliferation of LNCaP-IL-6- cells but not that of either LP or HP of LNCaP-IL-6+ cells. This inability to elicit a growth-inhibitory response was associated with lack of effect on cell cycle distribution in the LNCaP-IL-6+ subline. In parallel, IL-6 binding decreased gradually during long-term IL-6 treatment and, in HP, reached only 33% of the levels measured in controls. Binding of radiolabeled androgen increased 2-fold in HP LNCaP-IL-6+ cells. Reporter gene assays revealed that R1881, at nanomolar concentrations, was a more potent androgen receptor activator in LNCaP-IL-6+ than in LNCaP-IL-6- cells. However, androgen- and IL-6-induced prostate-specific antigen secretion decreased in long-term IL-6-treated cells. IL-6 cDNA fragments were detected by reverse transcription-PCR in HP LNCaP-IL-6+ cells but not in controls or LP. IL-6 protein was first detected in passage 36 of LNCaP-IL-6+ cells, and it increased in HP. CONCLUSIONS: Long-term treatment of LNCaP human prostate cancer cells with IL-6 leads to abolishment of inhibitory growth response. In contrast to control cells, the LNCaP-IL-6+ subline expresses IL-6 mRNA and protein.
UI - 21455238
AU - Latil AG; Azzouzi R; Cancel GS; Guillaume EC; Cochan-Priollet B; Berthon
TI - PL; Cussenot O Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways.
SO - Cancer 2001 Sep 1;92(5):1130-7
AD - Center for Research into Prostate Pathologies, Evry, France. firstname.lastname@example.org
BACKGROUND: Ethnicity, when it is used to mean shared genetic inheritance within a group, has become one of the most important factors in determining prostate carcinoma risk. Genetic polymorphisms were hypothesized to be the probable explanation for differences in risk among ethnic groups. The authors evaluated the association between polymorphisms in genes involved in the androgen biosynthesis and metabolism pathway and the risk of prostate carcinoma. METHODS: Two hundred twenty-six patients with the pathologic diagnosis of sporadic prostate tumor and 156 healthy matched (age, ethnic group) male controls from a large epidemiologic cohort were genotyped for previously described polymorphisms in the androgen receptor (AR), 5alpha-reductase type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The different polymorphisms in prostate carcinoma patients also were analyzed according to age of onset, preoperative prostate-specific antigen level, tumor stage, and tumor grade. RESULTS: The distribution of the tetranucleotide simple tandem repeat polymorphism (STRP) in intron 4 of CYP19 was significantly different in control and cancer patients (P = 0.012). The 171 allele and the 187 allele were associated with prostate carcinoma risk (P = 0.05 and P = 0.045, respectively). Conversely, no association was observed between prostate carcinoma risk and the other polymorphisms studied as follow: the CAG repeat in exon 1 of AR, the (TA)n dinucleotide repeat polymorphism in the 3' untranslated region, and the A49T or V89L substitutions in SDR5A2, the single base pair (bp) (a T to C transition) polymorphism that creates an additional Sp1-type (CCACC box) promoter site in CYP17. In prostate carcinoma patients, CAG repeats of AR, and TA repeats of SDR5A2 are associated with age of onset (P = 0.05 and P < 0.001, respectively). CONCLUSIONS: The association between the 171-bp allele of CYP19 and prostate carcinoma risk suggests that aromatase could be used as a new indicator for prostate carcinoma prevention in men of White French ethnogeographic origin. Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2) resulting in no overall difference in risk observed across the population. For these reasons, the development of a polygenic model, incorporating multiple loci from the individual genes may maximize the chance of identifying individuals with high-risk genotypes. Copyright 2001 American Cancer Society.
UI - 21423022
AU - Ranganathan S; McCauley RA; Dexter DW; Hudes GR
TI - Modulation of endogenous beta-tubulin isotype expression as a result of human beta(III)cDNA transfection into prostate carcinoma cells.
SO - Br J Cancer 2001 Sep 1;85(5):735-40
AD - Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Increases of individual beta tubulin isotypes in antimicrotubule drug resistant cell lines have been reported by several laboratories. We have previously described elevations in beta(III)and beta(IVa)isotypes in estramustine and paclitaxel resistant human prostate carcinoma cells. To investigate further the function of beta tubulin isotypes in antimicrotubule drug response, human prostate carcinoma cells that normally have very low to undetectable levels of beta(III)were stably transfected with beta(III)cDNA in pZeoSV system. An 18 bp haemagglutinin (HA) epitope tag was added at the 3' end prior to cloning into the vector. Cells were transfected with pZeoSV or pZeoSV-beta(III)plasmids and selected in the presence of Zeocin. Immunofluorescent staining of the transfectant cells have shown significant expression and incorporation of HA-tagged beta(III)tubulin into cellular microtubules. Quantitation of Western blots revealed the HA-tagged beta(III)levels to be approximately 7-fold higher than the vector control cells. RT-PCR analysis confirmed the increase at the transcript level and also revealed a collateral increase of beta(II)and beta(IVb)transcripts. Cell viability assays indicated that sensitivity of beta(III)transfected cells to various antimicrotubule agents was similar to vector transfected cells: IC50 values for estramustine, paclitaxel, colchicine and vinblastine were 4 microM, 4 nM, 22 nM and 2 nM, respectively for both cell lines. Thus, overexpression of beta(III)isotype in human prostate carcinoma cells by stable transfection failed to confer antimicrotubule drug resistance to these cells. Counterregulatory increases of endogenous beta(II)and beta(IVb)tubulin isotypes in these beta(III)transfected cells may be a compensatory mechanism used by the cells to overcome the effects of elevated beta(III)levels on the cellular microtubules. These results highlight the difficulty in isolating the contribution of single tubulin isotypes in drug response studies. Copyright 2001 Cancer Research Campaign.
UI - 21262974
AU - Kanazawa M; Ogata Y; Aoyagi K; Stearns ME; Shirouzu K
TI - Significance of cysteine rich transcription factor (CRTF) in the synthesis of tissue inhibitor of metalloproteinases 1 (TIMP-1) in gastrointestinal cancers.
SO - J Exp Clin Cancer Res 2001 Mar;20(1):145-51
AD - Dept. of Surgery, Kurume University School of Medicine, Fukuoka, Japan.
We previously reported that a novel promoter enhancer element "human tissue inhibitors of metalloproteinases 1 (TIMP-1) enhancer" (HTE) and a novel transacting protein "cysteine rich transcription factor" (CRTF) induced TIMP-1 synthesis in prostate cancer cells 2xN.I.PC-3. In the present study, to clarify the significance of CRTF in gastrointestinal cancers we measured the binding activity of CRTF to HTE using an electrophoretic mobility shift assay (EMSA), and the TIMP-1 concentration by ELISA after various stimulation of six cancer cell lines (KE-3, TE-9, MKN-28, MKN-45, KM12SM, SW620). In three cell lines (KE-3, MKN-45, SW620), both the binding activity of CRTF and TIMP-1 concentration significantly increased after IL-10 stimulation. Fetal bovine serum (FBS) did not affect the binding activity of CRTF, whereas FBS induced TIMP-1 synthesis in all cell lines. In KE-3 esophageal cancer cells and SW620 colon cancer cells, both the binding activity of CRTF and TIMP-1 concentration increased in the presence of a conditioned medium (CM) of fibroblasts which was isolated from human colon cancer tissues, but did not increase in MKN-45 cells. Moreover, in the fibroblasts, both the binding activity of CRTF and the TIMP-1 concentration increased in the presence of CM from KM12SM, SW620, and TE-9 cancer cell lines. These results suggested that IL-I0, and unknown factors in addition to IL-10, induced TIMP-1 synthesis via an increase in the binding activity of CRTF in gastrointestinal cancers, and that interaction between cancer cells and fibroblasts may play an important role in TIMP-1 synthesis through a signal transduction pathway consisting of CRTF phosphorylation and HTE activation.
UI - 21291363
AU - Strom SS; Spitz MR; Yamamura Y; Babaian RJ; Scardino PT; Wei Q
TI - Reduced expression of hMSH2 and hMLH1 and risk of prostate cancer: a case-control study.
SO - Prostate 2001 Jun 1;47(4):269-75
AD - Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
BACKGROUND: Although prostate cancer is the most common incident cancer in men, not much is known about its etiology. We tested the hypothesis that expression levels of hMSH2 and hMLH1 in unaffected (normal) tissue play a role in the etiology of prostate cancer. METHODS: Total RNA was extracted from peripheral blood lymphocytes of subjects ascertained by a case-control study (70 patients and 97 age- and ethnicity-matched controls). A multiplex reverse transcription-polymerase chain reaction assay was used to simultaneously evaluate the relative expression of hMSH2 and hMLH1, using beta-actin as the internal control. RESULTS: The relative gene expression levels of hMSH2 and hMLH1 were significantly lower in cases than in controls (P < 0.05 for both genes). When compared with the highest tertile of the controls, low expression levels (the middle and lowest tertiles) of hMLH1 were associated with significantly increased risk of prostate cancer in a dose-response relationship (ORs = 2.68, and 4.31; 95% confidence interval = 1.00-7.23 and 1.64-11.30, respectively) after adjustment for age, ethnicity, smoking status, and family history of prostate cancer. CONCLUSIONS: These results suggest that reduced expression of hMLH1 in peripheral lymphocytes may be a risk factor for prostate cancer. However, it cannot be ruled out that the reduced expression we observed may be caused by the disease status. Our findings and the factors that may affect the expression of hMLH1 need further confirmation in larger prospective studies. Copyright 2001 Wiley-Liss, Inc.
UI - 21291364
AU - Tieva A; Stattin P; Wikstrom P; Bergh A; Damber JE
TI - Gonadotropin-releasing hormone receptor expression in the human prostate.
SO - Prostate 2001 Jun 1;47(4):276-84
AD - Institute of Surgical and Perioperative Sciences, Urology & Andrology, Umea University, Umea, Sweden.
BACKGROUND: Inhibitory effects of gonadotropin-releasing hormone (GnRH) analogs on prostate cancer cell proliferation, both in vivo and in vitro, indicate the presence of specific binding sites for GnRH on prostate cancer cells. To investigate this issue further, we examined the expression of GnRH receptor (GnRH-R) mRNA and protein in human prostate biopsies as well as in other extrapituitary tissues. METHODS: The relative quantity of GnRH-R mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) in human prostate biopsies. Extrapituitary GnRH-R levels were determined by a semiquantitative PCR reaction. RESULTS: Using PCR, a relatively high expression level of GnRH-R mRNA was found in prostate tumor tissue followed by normal prostate, thymus, and kidney expression levels. The levels showed by heart, brain, placenta, lung, liver, skeletal muscle, pancreas, colon, ovary, small intestine, spleen, and testis were low but detectable, whereas peripheral blood leukocyte showed no demonstrable product. GnRH-R immunoreactivity was localized in both luminal and basal epithelial cells in benign and malignant prostate tissue, and GnRH-R were also observed in intraprostatic lymphocytes. The relative GnRH-R mRNA levels in prostate biopsies from 16 patients showed a wide range of individual differences, but these differences were not related to histological grade. Castration therapy did not significantly influence GnRH-R mRNA expression in normal and malignant prostate tissue. CONCLUSIONS: These results suggest that epithelial cells and infiltrating lymphocytes are targets for GnRH action in the human prostate. Comparative data show relatively high GnRH-R expression in human prostate tissue compared to other human tissues. Copyright 2001 Wiley-Liss, Inc.
UI - 21369698
AU - Goodarzi G; Mashimo T; Watabe M; Cuthbert AP; Newbold RF; Pai SK; Hirota
TI - S; Hosobe S; Miura K; Bandyopadhyay S; Gross SC; Balaji KC; Watabe K Identification of tumor metastasis suppressor region on the short arm of human chromosome 20.
SO - Genes Chromosomes Cancer 2001 Sep;32(1):33-42
AD - Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA.
Acquisition of metastatic ability by prostate cancer cells is the hallmark of their lethal trait and outcome. However, the genetic alterations underlying the clinical progression and pathogenesis of prostate cancer are not well understood. Several studies involving loss of heterozygosity (LOH) and comparative genomic hybridization analysis have identified distinctively altered regions on various human chromosomes, and genomic imbalance of chromosome 20 was implicated in progression and recurrence of prostate tumors. To examine the role of chromosome 20 in prostate neoplasms, we introduced this chromosome into highly metastatic rat prostate cancer cells using the microcell-mediated chromosome transfer technique. Introduction of the chromosome resulted in significant suppression of the metastatic ability of the hybrid cells, by as much as 98%, without any interference with the in vivo growth rate or tumorigenicity of primary tumor in SCID mice. Our STS-PCR analysis on 10 hybrid clones indicates that the suppressor activity of chromosome 20 is located in the p11.23-12 region. Further examination of the hybrid clones by experimental metastasis assay and histologic analysis as well as Matrigel invasion assay suggests the involvement of the suppressor region at an early stage of invasion and extravasation. We also investigated the status of the chromosome 20 suppressor region in pathology specimens from human prostate cancer patients and detected the frequent loss of this region in high-grade tumors. These results suggest the presence of a putative suppressor gene on human chromosome 20 that is functionally involved in development of prostate cancer metastases. Copyright 2001 Wiley-Liss, Inc.
UI - 21427142
AU - Andriani F; Nan B; Yu J; Li X; Weigel NL; McPhaul MJ; Kasper S; Kagawa
TI - S; Fang B; Matusik RJ; Denner L; Marcelli M Use of the probasin promoter ARR2PB to express Bax in androgen receptor-positive prostate cancer cells.
SO - J Natl Cancer Inst 2001 Sep 5;93(17):1314-24
AD - Department of Medicine, Baylor College of Medicine, and VA Medical Center, Houston, TX 77030, USA.
BACKGROUND: Adenovirus-mediated overexpression of the apoptosis-inducing protein Bax can induce apoptosis in prostate cancer cell lines. Constitutive overexpression of Bax could result in unwanted apoptosis in every site of accidental Bax accumulation in vivo. Therefore, we developed an adenoviral construct (Av-ARR2PB-Bax) in which the probasin promoter, modified to contain two androgen response elements, drives Bax expression. This promoter would be expected to limit expression of Bax to cells expressing the androgen receptor. METHODS: A variety of androgen receptor (AR)-positive and -negative cell lines of prostatic or nonprostatic origin were infected with Av-ARR2PB-Bax or a control virus, Av-ARR2PB-CAT, in which the same promoter drives expression of the chloramphenicol acetyl transferase-reporter gene. Bax expression and apoptosis in vitro were assessed by western blot analysis. Tumor size and apoptosis in vivo were assessed after four weekly injections of Av-ARR2PB-Bax or Av-ARR2PB-CAT into subcutaneous LNCaP xenografts growing in uncastrated male mice. All statistical tests were two-sided. RESULTS: Bax was overexpressed in an androgen-dependent way in AR-positive cell lines of prostatic origin but not in AR-positive cells of nonprostatic origin or in AR-negative cell lines of either prostatic or nonprostatic origin. The androgen dihydrotestosterone activated apoptosis in LNCaP cells infected with Av-ARR2PB-Bax but not in those infected with Av-ARR2PB-CAT. Av-ARR2PB-Bax-injected LNCaP xenograft tumors decreased in tumor size from 34.1 mm3 (95% confidence interval [CI] = 25.1 mm3 to 43.1 mm3) to 24.6 mm3 (95% CI = -2.5 mm3 to 51.7 mm3), but the difference was not statistically significant (P =.5). Tumors injected with Av-ARR2PB-CAT increased in size, from 28.9 mm3 (95% CI = 12.7 mm3 to 45.1 mm3) to 206 mm3 (95% CI = 122 mm3 to 290 mm3) (P =.002) and contained statistically significant more apoptotic cells (23.3% [95% CI = 21.1% to 25.6%] versus 9.5% [95% CI = 8.0% to 11.1]) (P<.001). CONCLUSIONS: Av-ARR2PB-Bax induces androgen-dependent therapeutic apoptosis in vitro and in vivo by activating apoptosis in AR-positive cells derived specifically from prostatic epithelium and does not affect nonprostatic cells.
UI - 21441842
AU - So MJ; Cheville JC; Katzmann JA; Riehle DL; Lohse CM; Pankratz VS; Sebo
TI - TJ Factors that influence the measurement of prostate cancer DNA ploidy and proliferation in paraffin embedded tissue evaluated by flow cytometry.
SO - Mod Pathol 2001 Sep;14(9):906-12
AD - Swarthmore College, Swarthmore, Pennsylvania, USA.
DNA ploidy and proliferation have been shown in several studies to be prognostic markers for prostate cancer. Flow cytometry (FCM) is often used in the determination of ploidy and proliferation. However, FCM cannot readily distinguish among benign epithelium, stromal and inflammatory cells, high grade prostatic intraepithelial neoplasia (HGPIN), and cancer cells. In this study, we evaluated H&E histologic features of 322 radical prostatectomy formalin-fixed, paraffin-embedded tissue blocks used for determining DNA ploidy, percent S-phase (%S), and %S + %G2M by FCM. The microscopic findings included Gleason score, extent of cancer and HGPIN in the tissue block, and presence of a needle track. The amount of cancer in the block was expressed as a percentage of the total tissue surface area in quartiles: < or =25%, 26-50%, 51-75%, and > or =76%. The extent of HGPIN was recorded in rough 5% intervals. Needle track effect was defined as a combination of fibrohistiocytic reaction, fibrin clot, granuloma formation, and chronic inflammation. The associations between these histologic features and DNA ploidy and proliferation (%S and %S + %G2M) were assessed. In multivariate analyses, Gleason score, the amount of tumor in the tissue block, and the extent of HGPIN were significantly associated with ploidy. Gleason score was the only parameter significantly associated with the proliferation measure of %S. If we included %G2M as part of the proliferative fraction of the histogram, however, both Gleason score and the amount of tumor in the block were significantly associated with this measure of proliferation. The presence of a needle track was not significantly associated with DNA ploidy, %S, or %S + %G2M. In summary, prostate cancer DNA ploidy and proliferation results assessed by FCM in paraffin-embedded tissue blocks were associated with the Gleason score, amount of cancer in the tissue block, and extent of HGPIN. However, the presence of a needle track was not associated with the FCM results.
UI - 21443291
AU - Warren P; Li L; Song W; Holle E; Wei Y; Wagner T; Yu X
TI - In vitro targeted killing of prostate tumor cells by a synthetic amoebapore helix 3 peptide modified with two gamma-linked glutamate residues at the COOH terminus.
SO - Cancer Res 2001 Sep 15;61(18):6783-7
AD - Oncology Research Institute of the Greenville Hospital System, Greenville, South Carolina 29605, USA.
Prostate-specific membrane antigen (PSMA) is a trans-membrane protein specifically expressed in LNCaP cells, malignant human prostate tissues, and the surrounding neovasculature. PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates. It can sequentially remove the poly-gamma-glutamyl termini. To target prostate tumor cells, a novel procytolytic peptide was designed with a backbone consisting of an amoebapore H3 domain modified by two gamma-linked glutamate residues at the epsilon-amino group of the COOH-terminal lysine residue. The strategy behind the design of this prolytic peptide was to inactivate the lytic amoebapore H3 peptide by replacing its functionally important COOH-terminal positive charge with negatively charged groups, which in turn might be selectively removed by the PSMA exopeptidase. This peptide exhibited little cytolytic activity toward PSMA-negative cells, such as PC-3 cells. On the other hand, this peptide exhibited strong cytolytic activity toward PSMA-positive LNCaP cells in a concentration-dependent manner. The carboxypeptidase inhibitor 4,4'-phosphonicobis (butane-1,3-dicarboxylic acid) can inhibit this activity. Moreover, this peptide also exhibited cytolytic activity toward PSMA cDNA-transfected PC-3 cells.
UI - 21443293
AU - Xie X; Zhao X; Liu Y; Zhang J; Matusik RJ; Slawin KM; Spencer DM
TI - Adenovirus-mediated tissue-targeted expression of a caspase-9-based artificial death switch for the treatment of prostate cancer.
SO - Cancer Res 2001 Sep 15;61(18):6795-804
AD - Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Clinical experience with suicide gene therapy for prostate cancer using first-generation approaches has provided a basis for developing improved strategies. Given the low proliferation rate exhibited by prostate cancer, one improvement would be to develop suicide genes that effectively kill both dividing and nondividing cells. A second
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