National Cancer Institute®
Last Modified: October 1, 2002
UI - 12006245
AU - Nasu Y; Kusaka N; Saika T; Tsushima T; Kumon H
TI - Suicide gene therapy for urogenital cancer: current outcome and prospects.
SO - Mol Urol 2000 Summer;4(2):67-71
AD - Department of Urology, Okayama University Medical School, Shikata, Okayama, Japan. email@example.com
Viral-mediated transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene has been demonstrated by several investigators to confer sensitivity to nucleoside analogs such as ganciclovir (GCV) in a variety of tumor cells including brain, prostate, bladder, kidney, ovary, head and neck, lung, pancreas, and liver cancers. Fourteen suicide gene clinical protocols using adenovirus vectors have been conducted, including four in prostate cancer. Two additional protocols for prostate cancer are in preparation in Japan and the Netherlands. A study conducted at Baylor College of Medicine was the first to demonstrate the safety of HSV-tk plus GCV therapy for human prostate cancer and the anticancer activity of gene therapy in this disease. However, it is still in the early stage of its development, with a number of problems to be overcome. Systemic delivery, specific introduction, and specific expression of the target gene are the major issues to be managed in order to establish a clinically relevant treatment strategy.
UI - 12006246
AU - Shirakawa T; Gotoh A; Wada Y; Kamidono S; Ko SC; Kao C; Gardner TA;
TI - Chung LW Tissue-specific promoters in gene therapy for the treatment of prostate cancer.
SO - Mol Urol 2000 Summer;4(2):73-82
AD - Department of Urology, Kobe University School of Medicine, Kobe, Japan. firstname.lastname@example.org
Delivery of therapeutic toxic genes to and their expression in tumor cells through the use of tissue-specific promoters could decrease their toxic effect on neighboring normal cells when virus-mediated gene delivery results in their infection. We have demonstrated the utility of two prostate cancer-specific promoters, long PSA and osteocalcin, for tissue-specific toxic gene therapy for prostate cancer. The two promoters were highly active in both androgen-dependent and androgen-independent prostate cancer cells. We also introduce the Phase I trial of osteocalcin promoter-based toxic gene therapy for bone metastases of prostate cancer, which is in progress at the University of Virginia.
UI - 12136249
AU - Anastasiadis AG; Ghafar MA; Salomon L; Vacherot F; Benedit P; Chen MW;
TI - Shabsigh A; Burchardt M; Chopin DK; Shabsigh R; Buttyan R Human hormone-refractory prostate cancers can harbor mutations in the O(2)-dependent degradation domain of hypoxia inducible factor-1alpha (HIF-1alpha).
SO - J Cancer Res Clin Oncol 2002 Jul;128(7):358-62
AD - The Department of Urology, College of Physicians and Surgeons, Columbia University, Atchley Pavilion, 11th Floor, 161 Fort Washington Avenue, New York, NY 10032, USA.
PURPOSE: Androgen ablation, the preferred therapy for advanced prostate cancer, reduces blood flow and induces hypoxia in androgen-dependent tissues. Given the transient effectiveness of this therapy, we must consider whether a hypoxia-resistance mechanism might be involved in the development of therapeutic resistance by prostate cancer cells. The transcription factor protein, hypoxia-inducible factor 1alpha (HIF-1alpha), helps increase the expression of gene products that enable cells to survive conditions of hypoxic stress. Enhanced HIF-1alpha expression during hypoxia results from a drastic reduction of its degradation rate within a critical region of the protein referred to as the "oxygen-dependent degradation (ODD) domain". We sequenced HIF-1alpha cDNAs amplified from human prostate cancer cell lines and from hormone resistant prostate cancer specimens to determine whether prostate cancer cells might harbor mutations within the HIF-1alpha ODD domain. METHODS: HIF-1alpha cDNAs were RT-PCR amplified from three prostate cancer cell lines (LNCaP, PC-3, and DU145), from five different human hormone-resistant prostate cancers and one normal prostate, all microdissected, and were sequenced to determine whether the HIF-1alpha gene products were wildtype or mutant. One specimen containing a hormone-resistant prostate tumor that expressed a mutated HIF-1alpha cDNA was further microdissected into benign and tumorous regions and DNAs extracted from these regions were directly amplified by PCR and sequenced to determine whether the HIF-1alpha mutation was specific to the tumor. RESULTS: Although the HIF-1alpha cDNAs of all cell lines, the normal prostate, and three of the tumors were found to have a wildtype sequence, HIF-1alpha cDNAs amplified from two hormone-resistant tumors had nucleic acid substitutions that resulted in significant amino acid changes within the ODD domain of the HIF-1alpha protein. Analysis of the DNA extracted from a benign or tumorous region of one of these specimens showed that only the wildtype (nonmutated) form of the HIF-1alpha gene was amplified from the normal DNA whereas only the mutated form of the HIF-1alpha gene was amplified from the tumor. CONCLUSIONS: Some human hormone-refractory prostate cancers have mutations in a critical regulatory domain of the HIF-1alpha protein. We believe that these mutations might enable expression of this protein under inappropriate conditions and contribute to the development of therapeutic resistance by the cancer cells. This hypothesis is currently being tested.
UI - 12241875
AU - Klein CA; Blankenstein TJ; Schmidt-Kittler O; Petronio M; Polzer B;
TI - Stoecklein NH; Riethmuller G Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer.
SO - Lancet 2002 Aug 31;360(9334):683-9
AD - Institut fur Immunologie, Ludwig-Maximilians-Universitat Munchen, D-80336 Munchen, Germany. email@example.com
BACKGROUND: Because cancer patients with small tumours often relapse despite local and systemic treatment, we investigated the genetic variation of the precursors of distant metastasis at the stage of minimal residual disease. Disseminated tumour cells can be detected by epithelial markers in mesenchymal tissues and represent targets for adjuvant therapies. METHODS: We screened 525 bone-marrow, blood, and lymph-node samples from 474 patients with breast, prostate, and gastrointestinal cancers for single disseminated cancer cells by immunocytochemistry with epithelial-specific markers. 71 (14%) of the samples contained two or more tumour cells whose genomic organisation we studied by single cell genomic hybridisation. In addition, we tested whether TP53 was mutated. Hierarchical clustering algorithms were used to determine the degree of clonal relatedness of sister cells that were isolated from individual patients. FINDINGS: Irrespective of cancer type, we saw an unexpectedly high genetic divergence in minimal residual cancer, particularly at the level of chromosomal imbalances. Although few disseminated cells harboured TP53 mutations at this stage of disease, we also saw microheterogeneity of the TP53 genotype. The genetic heterogeneity was strikingly reduced with the emergence of clinically evident metastasis. INTERPRETATION: Although the heterogeneity of primary tumours has long been known, we show here that early disseminated cancer cells are genomically very unstable as well. Selection of clonally expanding cells leading to metastasis seems to occur after dissemination has taken place. Therefore, adjuvant therapies are confronted with an extremely large reservoir of variant cells from which resistant tumour cells can be selected.
UI - 11956645
AU - Tayeb MT; Clark C; Sharp L; Haites NE; Rooney PH; Murray GI; Payne SN;
TI - McLeod HL CYP3A4 promoter variant is associated with prostate cancer risk in men with benign prostate hyperplasia.
SO - Oncol Rep 2002 May-Jun;9(3):653-5
AD - Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, UK.
Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been linked with PRCa. CYP3A4 may influence PRCa through its role in testosterone metabolism. This nested case-control study assessed a CYP3A4 single nucleotide polymorphism as a risk factor for developing PRCa in patients with BPH. The CYP3A4 variant allele identified men with BPH who are at increased risk of progressing to PRCa (odds ratio 6.3, 95% CI 2.3-17.3), providing a potential tool to assist prediction strategies for this disease.
UI - 12235003
AU - Calvo A; Xiao N; Kang J; Best CJ; Leiva I; Emmert-Buck MR; Jorcyk C;
TI - Green JE Alterations in gene expression profiles during prostate cancer progression: functional correlations to tumorigenicity and down-regulation of selenoprotein-P in mouse and human tumors.
SO - Cancer Res 2002 Sep 15;62(18):5325-35
AD - Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute/NIH, Building 41, Room C629, 41 Library Drive, Bethesda, MD 20892, USA.
To identify molecular changes that occur during prostate tumor progression, we have characterized a series of prostate cancer cell lines isolated at different stages of tumorigenesis from C3(1)/Tag transgenic mice. Cell lines derived from low- and high-grade prostatic intraepithelial neoplasia, invasive carcinoma, and a lung metastasis exhibited significant differences in cell growth, tumorigenicity, invasiveness, and angiogenesis. cDNA microarray analysis of 8700 features revealed correlations between the tumorigenicity of the C3(1)/Tag-Pr cells and changes in the expression levels of genes regulating cell growth, angiogenesis, and invasion. Many changes observed in transcriptional regulation in this in vitro system are similar to those reported for human prostate cancer, as well as other types of human tumors. This analysis of expression patterns has also identified novel genes that may be involved in mechanisms of prostate oncogenesis or serve as potential biomarkers or therapeutic targets for prostate cancer. Examples include the L1-cell adhesion molecule, metastasis-associated gene (MTA-2), Rab-25, tumor-associated signal transducer-2 (Trop-2), and Selenoprotein-P, a gene that binds selenium and prevents oxidative stress. Many genes identified in the Pr-cell line model have been shown to be altered in human prostate cancer. The comprehensive microarray data provides a rational basis for using this model system for studies where alterations of specific genes or pathways are of particular interest. Quantitative real-time reverse transcription-PCR for Selenoprotein-P demonstrated a similar down-regulation of the transcript of this gene in a subset of human prostate tumors, mouse tumors, and prostate carcinoma cell lines. This work demonstrates that expression profiling in animal models may lead to the identification of novel genes involved in human prostate cancer biology.
UI - 12181642
AU - Medeiros R; Morais A; Vasconcelos A; Costa S; Pinto D; Oliveira J; Lopes
TI - C The role of vitamin D receptor gene polymorphisms in the susceptibility to prostate cancer of a southern European population.
SO - J Hum Genet 2002;47(8):413-8
AD - Molecular Oncology Unit and Department of Urology, Laboratorios-PISO 4, Instituto Portugues de Oncologia, R. Dr. Ant. Bernardino Almeida 4200-072 Porto, Portugal. firstname.lastname@example.org
Epidemiological data indicate a relationship between ultraviolet radiation, vitamin D, and prostate cancer risk. Antiproliferative effects of vitamin D require the expression of the nuclear vitamin D receptor (VDR). A three-fold increase in prostate cancer risk associated with the less active vitamin D receptor allele (the T allele from VDR TaqI polymorphism at codon 352) was reported. The role of VDR genotypes in the susceptibility to prostate cancer has not yet been studied in populations of southern Europe. In the present study, we determined VDR TaqI genotypes in Portuguese prostate cancer cases ( n = 163) and controls ( n = 211), a southern European population. When cases were compared with controls, we found an association of VDR T allele with prostate cancer risk (odds ratio [OR] = 1.87, 95% confidence interval [CI] 1.02-3.37; P = 0.035). This association was confirmed using logistic regression analysis (OR = 2.11, 95% CI 1.15-3.88; P = 0.015) and in particular associated to risk of prostate cancer onset in men over the age of 66 years (OR = 2.36, 95% CI 1.05-5.29; P = 0.036). Fifty percent of cases older than 66 years could be attributed to the influence of this risk factor. Our results indicate that the contribution of VDR genotypes to prostate cancer susceptibility might depend on the population studied and its geographic localization, and that VDR genotypes are important in the definition of the genetic risk profile of populations of southern Europe.
UI - 12111700
AU - Dutta R; Sens DA; Somji S; Sens MA; Garrett SH
TI - Metallothionein isoform 3 expression inhibits cell growth and increases drug resistance of PC-3 prostate cancer cells.
SO - Prostate 2002 Jul 1;52(2):89-97
AD - Program in Genetics and Developmental Biology, West Virginia University, Morgantown, West Virginia 26506-9251, USA.
BACKGROUND: The third isoform of metallothionein (MT-3) is overexpressed in prostate cancers and PIN lesions. The expression of MT-3 is highly variable but appears to correlate to Gleason score. The goal of the present study was to determine the effect of MT-3 overexpression on the growth of the PC-3 prostate cancer cell line. METHODS: PC-3 cells were stably transfected with either the MT-3 or MT-1E gene. Cell growth was determined by counting DAPI-stained nuclei, drug resistance by the colony formation assay, MT mRNA expression by reverse transcriptase-polymerase chain reaction, and MT protein by immunoblot. RESULTS: PC-3 cells that overexpress the MT-3 gene are growth inhibited compared with either untransfected cells, cells with blank vector, or cells with similar overexpression of the MT-1E gene. Furthermore, increased chemotherapeutic drug resistance occurred in PC-3 clones derived from MT-3- and MT-1E-transfected cells. CONCLUSION: The overexpression of MT-3 can influence the growth and chemotherapeutic drug resistance of the PC-3 prostate cancer cell line. Copyright 2002 Wiley-Liss, Inc.
UI - 12200121
AU - Tanaka Y; Sasaki M; Kaneuchi M; Shiina H; Igawa M; Dahiya R
TI - Polymorphisms of the CYP1B1 gene have higher risk for prostate cancer.
SO - Biochem Biophys Res Commun 2002 Aug 30;296(4):820-6
AD - Department of Urology, University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA.
Various carcinogenic factors including estrogen metabolites play a role in malignant transformation. These metabolites are formed in part, as a result of the hydroxylation activity of cytochrome P450 (CYP) 1B1. Variant forms of this enzyme have been shown to enhance its activity, and thus, we hypothesize that single nucleotide polymorphisms of the CYP1B1 gene can be a risk factor for prostate cancer. To test this hypothesis, the genetic distribution of six different CYP1B1 polymorphisms at intron 1 (C-->T), codon 48 (C-->G), codon 119 (G-->T), codon 432 (C-->G), codon 449 (C-->T), and codon 453 (A-->G) was analyzed in 117 prostate cancer samples and 200 healthy normal subjects from a Japanese population. Results of these experiments demonstrate that the genotype at codon 119 is significantly different between prostate cancer patients and controls (P<0.001). The odds ratio of genotype T/T compared to G/G (reference) was calculated as 4.02 with a 95% confidence interval of 1.73-9.38. All other codons, except 453, showed polymorphisms but were not significantly different between cancer patients and controls. No association was found between stage and grade of cancer with any of the polymorphic sites. This is the first report that demonstrates the polymorphism at codon 119 of CYP1B1 to be associated with prostatic carcinogenesis. These results are important in understanding the role of CYP1B1 polymorphisms in the pathogenesis of prostate cancer.
UI - 11340636
AU - Chetcuti A; Margan S; Mann S; Russell P; Handelsman D; Rogers J; Dong Q
TI - Identification of differentially expressed genes in organ-confined prostate cancer by gene expression array.
SO - Prostate 2001 May 1;47(2):132-40
AD - Department of Medicine, University of Sydney, Sydney, NSW, Australia.
BACKGROUND: To understand the molecular mechanisms underlying prostate cancer, we have utilized the gene expression array to search for genes whose expression is altered in this disease. METHODS: RNA quality from manual microdissected tissue was compared with that from microselected tissue by electrophoresis. For array analysis, malignant and normal prostate epithelium was enriched using microselection technique from prostate cancer and the peripheral zone of a normal prostate. Identical array membrane was hybridized to labeled cancer and normal cDNA, respectively. The differentially expressed gene was further evaluated by RT-PCR. RESULTS: Microdissection, but not microselection, causes visible degradation to RNA. Of the 588 genes on the membrane, 87 genes yielded significant signals. Based on a three fold difference relative to normal prostate tissue, 1 gene was overexpressed and 12 genes underexpressed in prostate cancer. Of them, five showed statistically significant reduction in mRNA levels in six prostate cancer specimens compared with seven normal prostate specimens. These five genes are glutathione S-transferase M1 (GSTM1), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha receptor-1 (TNFR-1), transforming growth factor beta3 (TGF-beta3), and inhibitor of DNA binding-1 (ID-1). CONCLUSIONS: GST-based metabolism, cytokine MCP-1 and TNFR-1, and TGF-beta3 signaling pathways, and some helix-loop-helix nuclear proteins could be potentially important in organ-confined prostate cancer and deserve further investigation. Copyright 2001 Wiley-Liss, Inc.
UI - 11375906
AU - Ouyang XS; Wang X; Lee DT; Tsao SW; Wong YC
TI - Up-regulation of TRPM-2, MMP-7 and ID-1 during sex hormone-induced prostate carcinogenesis in the Noble rat.
SO - Carcinogenesis 2001 Jun;22(6):965-73
AD - Department of Anatomy, Faculty of Medicine, Li Shu Fan Building, 5 Sassoon Road, University of Hong Kong, Hong Kong, SAR, China.
Prostate cancer is the most frequently diagnosed malignancy in the Western world and changes in the ratio of testosterone and estrogens with advancing age is one of the potential risk factors in the development of this disease. However, the molecular mechanisms associated with hormone imbalance in prostate carcinogenesis are poorly understood. In this study we induced a high incidence of prostate hyperplasia, dysplasia and adenocarcinoma in the Noble rat using a combination of testosterone and estradiol-17beta. Using this animal model, we studied the gene expression profile during sex hormone-induced prostate carcinogenesis using a cDNA array technique; the results were further confirmed by RT-PCR, western blotting and immunohistochemical analyses. We found up-regulation of TRPM-2 (testosterone-repressed prostatic message-2), MMP-7 (matrix metalloproteinase-7) and Id-1 (inhibitor of differentiation or DNA binding) during development of sex hormone-induced prostate cancer. Increased expression of TRPM-2 and MMP-7 was observed in both premalignant and malignant tissues after sex hormone treatment, indicating their role in the early stages of hormone response and prostate cancer development. In contrast, Id-1 was expressed at relatively low levels in all premalignant samples but increased in malignant cells, suggesting its potential roles as a biomarker for prostate cancer cells. Furthermore, expression of Id-1 appeared to be stronger in poorly differentiated lesions than in well-differentiated carcinomas, suggesting that the levels of Id-1 expression may be correlated with the malignancy of tumors. Our results provide the first evidence of up-regulation of TRPM-2, MMP-7 and Id-1 during sex hormone-induced prostate carcinogenesis and strongly suggest their association with the development of prostate cancer.
UI - 12006534
AU - Zou Z; Zhang W; Young D; Gleave MG; Rennie P; Connell T; Connelly R;
TI - Moul J; Srivastava S; Sesterhenn I Maspin expression profile in human prostate cancer (CaP) and in vitro induction of Maspin expression by androgen ablation.
SO - Clin Cancer Res 2002 May;8(5):1172-7
AD - Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland 20852, USA.
PURPOSE: Expression of tumor suppressor gene, MASPIN, is associated with inhibition of tumor cell invasion and metastasis. Loss of or decreased expression of Maspin is found frequently in breast and prostate cancer cells. The objective of this study is to investigate Maspin expression in prostate tumor specimens and explore the mechanisms of hormonal regulation of Maspin expression in prostate tumors. EXPERIMENTAL DESIGN: Immunohistochemical staining of Maspin expression was performed on surgical whole-mounted prostate specimens. The expression of Maspin was scored on individual tumors. Correlation of Maspin expression with clinicopathological features was analyzed for statistical significance. Androgen ablation-induced Maspin expression was analyzed by Maspin promoter luciferase reporter assay and quantitative reverse transcription-PCR analysis of endogenous Maspin expression in LNCaP cells in vitro and in animal model. RESULTS: Comprehensive evaluation of Maspin expression profile in multiple tumor foci from whole mounted prostate specimens of prostate cancer patients revealed absence of Maspin expression in a significant fraction (63%). However, Maspin expression is significantly higher in tumor specimens (92%) of patients treated with neoadjuvant androgen ablation therapy before radical prostatectomy. LNCaP cells cultured in androgen-depleted medium show induction of Maspin promoter activity in a promoter luciferase reporter assay. In addition, Maspin expression is increased after castration in LNCaP prostate cancer cells derived tumors in nude mice. CONCLUSIONS: Maspin expression is frequently absent in primary prostate cancers. Up-regulation of MASPIN in response to androgen ablation strongly suggests a physiological role of Maspin in growth inhibition and/or apoptosis of prostate cancer cells during androgen ablation.
UI - 12163131
AU - Navarro D; Luzardo OP; Fernandez L; Chesa N; Diaz-Chico BN
TI - Transition to androgen-independence in prostate cancer.
SO - J Steroid Biochem Mol Biol 2002 Jul;81(3):191-201
AD - Department of Biochemistry, Instituto Canario de Investigacion del Cancer (ICIC), P.O. Box 550, 35080 Las Palmas de Gran Canaria, Canary Islands, Spain.
Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the western countries. Withdrawal of androgens or the peripheral blockage of androgen action remain the critical therapeutic options for the treatment of advanced prostate cancer. However, after initial regression, most of the prostate cancers become androgen-independent and progress further, with eventual fatal outcome. Understanding the mechanisms of transition to androgen independence and tumor progression in prostate cancer is critical to finding new ways to treat aged patients that are ineligible for conventional chemotherapy. A large number of different molecular mechanisms might be responsible for the transition to androgen-independence. Many of these involve the androgen receptor (AR) and its signalling pathways, but they might also include genetic changes that affect several genes, which results in the activation of oncogenes or the inactivation of tumor suppressor genes. Here, we discuss the most recent and relevant findings on androgen resistance in prostate cancer in order provide a comprehensive interpretation of the clinical behaviour of tumors at molecular levels.
UI - 12068172
AU - Halabi M; Oliva E; Mazal PR; Breitenecker G; Young RH
TI - Prostatic tissue in mature cystic teratomas of the ovary: a report of four cases, including one with features of prostatic adenocarcinoma, and cytogenetic studies.
SO - Int J Gynecol Pathol 2002 Jul;21(3):261-7
AD - Department of Pathology, General Hospital of Ried, Austria.
Four cases of mature cystic teratoma that contained prostatic tissue are reported. The ovarian tumors occurred in patients from 17 to 38 (mean 31) years of age and had no unusual clinical or gross aspects. The microscopic findings for the most part were typical of a mature cystic teratoma, but they also contained foci of prostatic tissue that ranged from 0.2 to 1.9 cm in greatest dimension. In these areas there was a lobular arrangement of medium-sized acini lined by cuboidal to columnar cells with pale cytoplasm and round nuclei with inconspicuous nucleoli except focally in one case as noted below. Basal cells were seen focally. The prostatic acini lay in a paucicellular fibromuscular stroma. In two cases thick layers of disorganized smooth muscle covered by transitional-like pseudostratified epithelium, resulting in an appearance resembling fetal bladder wall, were present next to the prostatic glands. One tumor also contained prostatic-type acini, which haphazardly infiltrated the stroma over an area approximately 5 mm in maximal dimension. The acini, a few of which contained intraluminal flocculent eosinophilic material, were lined by cells with eosinophilic to amphophilic focally granular cytoplasm and had nuclei that were enlarged compared with the benign-appearing, prostatic-type acini in the four cases and had focally prominent nucleoli. Basal cells were not identified in these infiltrating glands. Grading this focus according to the approach in the prostate, the morphology was that of a Gleason grade 3 of 5 adenocarcinoma. Immunohistochemical stains of the putative prostatic epithelial cells confirmed their nature by showing immunoreactivity for prostatic-specific antigen in the lining epithelial cells in all four cases and for prostatic-specific acid phosphatase in the one case tested. The high molecular cytokeratin stain, 34betaE12, highlighted basal cells to a variable extent in the three cases containing only benign prostatic tissue. Material was not available to immunostain for basal cells in the case with carcinoma. Cytogenetic studies were performed in two cases and showed that the great majority of the nuclei of the nonprostatic and prostatic tissue had an XX karyotype but from 3% to 5% of the nuclei displayed trisomy for the X chromosome. A small number of cases of prostatic tissue in ovarian teratomas have previously been documented but none had morphologic features of carcinoma.
UI - 12352406
AU - Jorda M; Morales A; Ghorab Z; Fernandez G; Nadji M; Block N
TI - Her2 expression in prostatic cancer: a comparison with mammary carcinoma.
SO - J Urol 2002 Oct;168(4 Pt 1):1412-4
AD - Department ofpathology, University of Miami-Jackson Memorial Medical Center, Miami, Florida, USA.
PURPOSE: There is growing interest in HER2 and its downstream signaling pathway molecules as treatment targets in human malignancies, including prostatic carcinoma. We used a standard Food and Drug Administration approved HER2 immunohistochemical kit to study HER2 expression in prostate cancer. We compared the results with those reported for mammary carcinoma. MATERIALS AND METHODS: For this study we selected 216 specimens obtained from patients who underwent radical prostatectomy for primary untreated prostatic carcinoma. Immunohistochemical staining was performed using the HercepTest kit (Dako Corp., Carpinteria, California) in strict fashion according to the technical and analytical protocols outlined in the kit. RESULTS: Of the tumors 33 (15%) were positive for HER2, including 31 (94%) that were only weakly positive (2+). Of the HER2 positive tumors 97% were Gleason grade 7 or higher. Of the 33 positive cases 22 (67%) showed only a focal positive reaction for HER2 in discrete tumor areas. CONCLUSIONS: HER2 is expressed in a minority of untreated primary prostatic carcinomas. Unlike in mammary carcinoma, HER2 positivity in prostatic cancer is usually weak in intensity and focal in distribution. While the former casts doubt on the usefulness of HER2 as a potential treatment target for most primary untreated prostatic cancer, the latter phenomenon may lead to false-negative results if the test is performed in small biopsies. Furthermore, HER2 staining of prostatic carcinoma can be technically and analytically reproducible provided that there is strict adherence to the outlined methodologies and interpretation.
UI - 12352461
AU - Venkateswaran V; Fleshner NE; Klotz LH
TI - Modulation of cell proliferation and cell cycle regulators by vitamin E in human prostate carcinoma cell lines.
SO - J Urol 2002 Oct;168(4 Pt 1):1578-82
AD - Division of Urology, Sunnybrook and Women's College Health Science Centre, Toronto, Ontario, Canada.
PURPOSE: Vitamin E has been identified as a candidate agent for the prevention of prostate cancer. We hypothesize that the mechanism for this effect is in part a result of cell cycle inhibition rather than only due to a reduction in reactive oxygen species. We tested whether vitamin E induces cell cycle arrest in prostate carcinoma, mediated by alterations in cell cycle regulatory proteins, including cyclin E, cdk2 and p27. MATERIALS AND METHODS: Cells were incubated with and without vitamin E (alpha-tocopherol succinate, 20 microg./ml.), fixed and stained with propidium iodide for flow cytometry analysis. In parallel experiments total protein was extracted, immunoprecipitated with cyclin E antibody and analyzed by Western blot for the expression of cell cycle markers. RESULTS: Flow cytometry analysis revealed a dramatic reduction in the S phase percent of LNCaP and PC3 cells in response to vitamin E (69% and 95%, respectively). It was accompanied by over expression of p27 (3-fold increase) with vitamin E treatment. CONCLUSIONS: This study demonstrates that at physiological concentrations vitamin E induced profound cell cycle arrest mediated by up-regulation of p27. This observation provides a theoretical basis for the putative chemopreventive effect of vitamin E.
UI - 12360410
AU - Liu L; Yoon JH; Dammann R; Pfeifer GP
TI - Frequent hypermethylation of the RASSF1A gene in prostate cancer.
SO - Oncogene 2002 Oct 3;21(44):6835-40
AD - Department of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, California, CA 91010, USA.
Recently, we have cloned and characterized the Ras association domain family 1A gene (RASSF1A) at 3p21.3, from which loss of genetic material is one of the most frequent events in several types of human solid tumors. The CpG island promoter region of this gene is highly methylated in several human cancers, most notably in small cell lung cancer, breast cancer, and renal cell carcinoma. In this study, we have analysed the methylation status of RASSF1A in primary prostate tumors and in the prostate cancer cell line LNCaP. In total, 37 out of 52 tumors (71%) were methylated at the promoter region of RASSF1A. The relative frequency of methylation was higher in more aggressive tumors compared with less malignant tumors. For instance, tumors with a Gleason score of 7-10 (25 out of 30, 83%) were significantly more methylated compared with Gleason 4-6 tumors (11 out of 20, 55%, P=0.032, Fisher's exact test). Coincident with a hypermethylated promoter, transcripts of RASSF1A were missing in LNCaP cells. Expression of RASSF1A was restored with 5-aza-2'-deoxycytidine, a DNA methylation inhibitor. In conclusion, our data suggest that epigenetic inactivation of RASSF1A by methylation is a very common event in prostate cancer and might be involved in the progression of the disease. Testing for RASSF1A methylation should become useful in prostate cancer early detection and diagnosis and might aid prognosis by gauging the potential status of progression.
UI - 12230620
AU - Mir K; Edwards J; Paterson PJ; Hehir M; Underwood MA; Bartlett JM
TI - The CAG trinucleotide repeat length in the androgen receptor does not predict the early onset of prostate cancer.
SO - BJU Int 2002 Oct;90(6):573-8
AD - Department of Surgery, Glasgow Royal Infirmary, UK.
OBJECTIVE: To relate the repeat length of the androgen-receptor CAG trinucleotide to the age of onset of prostate cancer, stage and grade of disease. PATIENTS AND METHODS: After obtaining ethical approval, 265 patients with locally confined or locally advanced/metastatic prostate cancer were identified and evaluated for age at diagnosis (< 65 years and > 75 years). DNA was extracted from peripheral blood lymphocytes and 1 micro g aliquots subjected to polymerase chain reaction using fluorescently labelled primers. Samples were then run on an ABI 377 gene scan analysis gel with an internal molecular weight marker. The length of the CAG repeat was determined by comparing the gene scan product size to samples where the CAG repeat length had been quantified using direct sequencing. The Kruskal-Wallis, Mann-Whitney and Wilcoxon two sample tests were used to analyse the data. RESULTS: The mean (range) length of the CAG repeat in the androgen receptor was 22.2 (10-31) in the younger and 22.5 (16-32) in the older group, and was not statistically different. There was no significant association between the CAG repeat length and the age of onset of prostate cancer (P = 0.568) or with stage (P = 0.577) and grade (P = 0.891) of prostate cancer. CONCLUSION: These results suggest that there is no correlation between the androgen receptor CAG repeat length and the age of onset, stage and grade of prostate cancer, confirming recent doubts from other similar studies of a suggested correlation between shorter androgen receptor CAG repeat and early onset and aggressiveness of prostate cancer.
UI - 12145743
AU - Rennert H; Bercovich D; Hubert A; Abeliovich D; Rozovsky U; Bar-Shira A;
TI - Soloviov S; Schreiber L; Matzkin H; Rennert G; Kadouri L; Peretz T; Yaron Y; Orr-Urtreger A A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews.
SO - Am J Hum Genet 2002 Oct;71(4):981-4
AD - Genetic Institute, Tel Aviv Sourasky Medical Center, Israel.
HPC1/RNASEL was recently identified as a candidate gene for hereditary prostate cancer. We identified a novel founder frameshift mutation in RNASEL, 471delAAAG, in Ashkenazi Jews. The mutation frequency in the Ashkenazi population, estimated on the basis of the frequency in 150 healthy young women, was 4% (95% confidence interval [CI] 1.9%-8.4%). Among Ashkenazi Jews, the mutation frequency was higher in patients with prostate cancer (PRCA) than in elderly male control individuals (6.9% vs. 2.4%; odds ratio = 3.0; 95% CI 0.6-15.3; P=.17). 471delAAAG was not detected in the 134 non-Ashkenazi patients with PRCA and control individuals tested. The median age at PRCA diagnosis did not differ significantly between the Ashkenazi carriers and noncarriers included in our study. However, carriers received diagnoses at a significantly earlier age, compared with patients with PRCA who were registered in the Israeli National Cancer Registry (65 vs. 74.4 years, respectively; P<.001). When we examined two brothers with PRCA, we found a heterozygous 471delAAAG mutation in one and a homozygous mutation in the other. Loss of heterozygosity was demonstrated in the tumor of the heterozygous sib. Taken together, these data suggest that the 471delAAAG null mutation is associated with PRCA in Ashkenazi men. However, additional studies are required to determine whether this mutation confers increased risk for PRCA in this population.
UI - 11225974
AU - Ichikawa T; Hosoki S; Suzuki H; Akakura K; Igarashi T; Furuya Y;
TI - Oshimura M; Rinker-Schaeffer CW; Nihei N; Barrett JC; Isaacs JT; Ito H Mapping of metastasis suppressor genes for prostate cancer by microcell-mediated chromosome transfer.
SO - Asian J Androl 2000 Sep;2(3):167-71
AD - Department of Urology, Chiba University School of Medicine, Japan. email@example.com
AIM: To identify the metastasis suppressor genes for prostate cancer. METHODS: A copy of human chromosomes was introduced into the highly metastatic Dunning R-3327 rat prostate cancer cells by the use of microcell-mediated chromosome transfer. Relationships between the size of human chromosomes introduced into microcell hybrid clones and the number of lung metastases produced by the clones were analyzed to determine which part of human chromosomes contained the metastasis suppressor gene(s) for prostate cancer. To determine portions of human chromosomes introduced, G-banding chromosomal analysis, fluorescence in situ hybridization analysis, and polymerase chain reaction analysis were performed. RESULTS: Each of microcell hybrid clones containing human chromosomes 7, 8, 10, 11, 12, or 17 showed decreased ability to metastasize to the lung without any loss of tumorigenicity. This demonstrates that these human chromosomes contain metastasis suppressor genes for prostate cancer. Spontaneous deletion of portions of human chromosomes was observed in the human chromosome 7, 10, 11, 12, and 17 studies. In the human chromosome 8 study, irradiated microcell-mediated chromosome transfer was performed to enrich chromosomal arm deletions of human chromosome 8. Molecular and cytogenetic analyses of microcell hybrid clones demonstrated that metastasis suppressor genes on human chromosomes were located on 7q21-22, 7q31.2-32, 8p21-12, 10q11-22, 11p13-11.2, 12p11-q13, 12q24-ter, and 17pter-q23. KAI1 and MKK4/SEKI were identified as metastasis suppressor genes from 11p11.2 and 17p12, respectively. CONCLUSION: This assay system is useful to identify metastasis suppressor gene (s) for prostate cancer.
UI - 11225981
AU - Hu WL; Li YQ; He HX; Li QR; Tian Y; Lai RQ; Mei H
TI - KAI1/CD82 gene expression in benign prostatic hyperplasia and late-stage prostate cancer in Chinese.
SO - Asian J Androl 2000 Sep;2(3):221-4
AD - Department of Urology, The General Hospital of Guangzhou Military Area, Chinese People's Liberation Army. firstname.lastname@example.org
AIM: To evaluate KAI1/CD82 expression in Chinese patients with benign prostatic hyperplasia (BPH) and late-stage carcinoma of prostate (CaP). METHODS: Thirty Chinese patients with benign prostatic hyperplasia and 34 with CaP (adenocarcinoma clinical stage C and D) were analyzed by means of immunohistochemical methods. RESULTS: The KAI1/CD82 expression in BPH tissue was all positive, which was uniformly located on the glandular cell membrane at the cell-to-cell borders, but KAI1/CD82 expression in metastasis CaP tissues was either significantly lower than that of BPH or negative, and the immunostaining pattern was not continuous. In late-stage CaP KAI1/CD82 expression was correlated inversely to the pathological grade ( P < 0.05), but not to clinical stage ( P > 0.05). CONCLUSION: The authors believe that decreased and negative KAI1/CD82 expression in late-stage CaP may be related to tumor progression and metastasis, and appears to be a prognostic marker.
UI - 12242728
AU - Bruckheimer EM; Kyprianou N
TI - Bcl-2 antagonizes the combined apoptotic effect of transforming growth factor-beta and dihydrotestosterone in prostate cancer cells.
SO - Prostate 2002 Oct 1;53(2):133-42
AD - Division of Urology, Department of Surgery, University of Maryland School of Medicine, Baltimore, USA.
BACKGROUND: We previously demonstrated that dihydrotestosterone (DHT) enhances transforming growth factor-beta (TGF-beta) -induced apoptosis in human prostate cancer cells (Endocrinology 2001;142:2419-2426). METHODS: In this study, the ability of the apoptosis suppressor bcl-2 to directly antagonize the combined apoptotic effect of TGF-beta and DHT in the androgen-sensitive LNCaP TbetaRII prostate cancer cells was examined. The previously cloned TGF-RbetaII receptor LNCaP cells, responsive to both TGF-beta and androgens, were engineered to overexpress the bcl-2 oncoprotein and the profile of apoptosis induction was analyzed in response to TGF-beta alone (5.0 ng/ml) or in combination with DHT (1 nM). RESULTS: Biological characterization of cloned LNCaP TbetaRII hygromycin/bcl-2 transfectants demonstrated that bcl-2 overexpression resulted in a significant inhibition of the combined TGF-beta and DHT apoptotic effect in prostate cancer cells (P < 0.01). Furthermore, molecular analysis indicated that this antagonistic effect of bcl-2 on apoptosis was due to partial suppression of TGF-beta and DHT-mediated induction of caspase-1 expression and activation in LNCaP TbetaRII-hygro/bcl-2 transfectants. These results support a potential bcl-2 interference with the TGF-beta and androgen apoptotic signaling in prostate cancer cells by means of an antagonistic effect on caspase-1 activation. CONCLUSION: This evidence may have mechanistic significance in understanding the contribution of bcl-2 overexpression in the development of androgen-independent prostate cancer by means of conferring resistance to TGF-beta-mediated apoptosis. Copyright 2002 Wiley-Liss, Inc.
UI - 12242730
AU - Koh E; Noda T; Kanaya J; Namiki M
TI - Differential expression of 17beta-hydroxysteroid dehydrogenase isozyme genes in prostate cancer and noncancer tissues.
SO - Prostate 2002 Oct 1;53(2):154-9
AD - Department of Urology, School of Medicine, Kanazawa University, Ishikawa, Japan. email@example.com
BACKGROUND: The adrenal steroids dehydroepiandrosterone and androstenediones are converted into active androgen testosterone in prostatic tissues. Different 17beta-hydroxysteroid dehydrogenase (17betaHSD) isozymes are characterized by either oxidation or reduction reactions. These redox reactions represent an important step in both biosynthesis and metabolism of androgens. This study presents the differential expression of 17betaHSD isozyme genes in cancerous and noncancerous prostate tissues of in vivo samples. METHODS: Thirty-four fresh specimens of transrectal prostatic needle biopsy were obtained; 11 were pathologically diagnosed as adenocarcinoma and 23 as without malignancy. The gene expression levels of five isozymes (type 1-5) of 17betaHSD were evaluated. The quantification of gene expression was assessed by means of the real-time polymerase chain reaction. RESULTS: The expression levels of the type 3 17betaHSD gene with malignancy were significantly higher than those in prostatic tissues without malignancy, and those of type 2 17betaHSD with malignancy were significantly lower than those in nonmalignant tissues. There were no significant differences in 17betaHSD type 1, type 4, and type 5 gene expression in cancerous and noncancerous tissues. CONCLUSION: Our results suggest that 17betaHSD type 2 and type 3 play an important role in the conversion of adrenal steroids into potential androgens in prostate cancer tissue. Copyright 2002 Wiley-Liss, Inc.
UI - 12365012
AU - Sanchez KM; Sweeney CJ; Mass R; Koch MO; Eckert GJ; Geary WA; Baldridge
TI - LA; Zhang S; Eble JN; Cheng L Evaluation of HER-2/neu expression in prostatic adenocarcinoma: a requested for a standardized, organ specific methodology.
SO - Cancer 2002 Oct 15;95(8):1650-5
AD - Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
BACKGROUND: Some evidence suggests a role for HER-2/neu overexpression in prostate carcinoma progression. Reported rates of HER-2/neu overexpression in patients with prostate carcinoma vary greatly. METHODS: The authors studied radical prostatectomy specimens from 38 patients who had biochemical failure after undergoing radical prostatectomy for prostate carcinoma. Immunohistochemistry for HER-2/neu overexpression using the HercepTest kit (Dako Corporation, Carpenteria, CA) was employed. Two different antigen-retrieval techniques were used: 1) the standard U.S. Food and Drug Administration (FDA)-approved HercepTest assay and 2) a modified HercepTest, which employed an alkaline citrate buffer, pH 9.0, for antigen retrieval and a 1-hour primary antibody incubation time. The level of HER-2/neu expression was evaluated on a scale from 0 (no staining) to 3+ according to the published guidelines. Fluorescent in situ hybridization for gene amplification was performed on all specimens. RESULTS: With the standard technique, only one specimen had 2+ staining, and no specimens had 3+ staining. With the modified technique, 10 specimens (26%) had 2+ staining, and 9 specimens (24%) had 3+ staining. There was a significant association between the level of HER-2/neu expression shown with the modified technique and tumor stage (P = 0.03) as well as Gleason grade (P = 0.01). None of the specimens had HER-2/neu gene amplification. CONCLUSIONS: The authors report a simple modification of the HercepTest that resulted in an increased rate of HER-2/neu expression, which was correlated with poor-risk pathologic findings. The findings suggest that adenocarcinoma of the prostate should be evaluated for HER-2/neu expression with a prostate specific immunohistochemical procedure that differs from the FDA-approved standard procedure. Copyright 2002 American Cancer Society.
UI - 7553490
AU - McLellan DL; Norman RW
TI - Hereditary aspects of prostate cancer.
SO - CMAJ 1995 Oct 1;153(7):895-900
AD - Dalhousie University, Halifax, NS.
OBJECTIVE: To review current literature on the hereditary aspects of prostate cancer and to evaluate the importance of family history in history taking and screening for prostate cancer. DATA SOURCES: MEDLINE was searched for articles in English or French published between Jan. 1, 1956, and Oct. 31, 1994, with the use of MeSH headings "prostatic neoplasms," "genetics" and "chromosomes." Additional references were selected from the bibliographies of articles found during the search. STUDY SELECTION: Case-control studies involving the incidence of prostate cancer and relative risk (RR) of such cancer in the families of men with this disease, compared with a control group, were included. Only studies in which prostate cancer was diagnosed on the basis of histologic tests were included. Animal investigations were excluded. DATA EXTRACTION: Ten case-control studies were evaluated critically in terms of design, case and control groups, the size of the samples and statistical results. The incidence of prostate cancer in the families of cases, compared with that in the families of controls, and differences in RR were reviewed. DATA SYNTHESIS: The lifetime risk of prostate cancer is 9.5% and of death from prostate cancer is 2.9% for a man 50 years of age. For first-degree male relatives of men with prostate cancer, the calculated RR ranges from 1.7 to 8.73. "Hereditary" prostate cancer is a term applied to a specific subset of patients with prostate cancer. This form of prostate cancer is transmitted by a rare, autosomal, dominant allele with high penetrance; it accounts for an estimated 43% of early-onset disease (affecting men less than 55 years of age) but only 9% of all prostate cancer in men up to 85 years of age. A greater number of affected family members and early onset among family members are the most significant predictors of risk. CONCLUSIONS: Recent confirmation of the familial clustering and Mendelian inheritance patterns of some prostate cancer has important implications. It increases the potential for directed research into the causes of prostate cancer and for refinements in the current screening practices to detect this common disease. Manoeuvres to detect prostate cancer should be started earlier among men with one or more first-degree relatives with the disease than among other men.
UI - 7553496
AU - Nickel JC
TI - The dilemma of hereditary prostate cancer.
SO - CMAJ 1995 Oct 1;153(7):935-8
The observation that a family history of prostate cancer significantly increases a man's risk of the disease (see pages 895 to 900 of this issue) highlights many of the ethical, emotional and pragmatic controversies in medical circles concerning the management of this common form of cancer. This editorial describes a patient's personal dilemma when he learns that his brother