National Cancer Institute®
Last Modified: March 1, 2002
UI - 11712084
AU - Kasahara K; Taguchi T; Inoue K; Shuin T; Kariya S; Yoshida S; Furihata M
TI - Early reduction in the aneuploidy at chromosomes 7 and 8 are significantly correlated with clinical effect in high-dose rate brachytherapy with external beam radiotherapy in localized prostate cancer.
SO - Int J Mol Med 2001 Dec;8(6):667-73
AD - Department of Urology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan. email@example.com
Although reduction in the serum prostate specific antigen (PSA) correlates with clinical outcome for high dose rate Iridium-192 (HDR Ir-192) brachytherapy, it takes a long latency period. We investigated numerical chromosome changes of prostatic cancer during the pre- and post-treatment periods of HDR Ir-192 brachytherapy (and external beam radiotherapy), using fluorescence in situ hybridization (FISH) to clear the effect of treatment in early phase. 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 were observed. Gains of chromosomes 7, 8 and 12 were noted in the pre-treatment samples (4 out of 12 cases in chromosomes 7 and 8; 1 out of 12 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. This change appears earlier than the reduction in the value of prostate specific antigen (PSA) and strongly reflects the effect of HDR brachytherapy with external beam radiotherapy in localized prostate cancer. Decrease in the number of cells with high ploidies of chromosomes 7, 8 and 12 at 12 weeks after treatment may predict clinical effects of radiation therapy, which may explain the radiation dependency of localized prostate cancer cells.
UI - 11748358
AU - Chung WB; Hong SH; Kim JA; Sohn YK; Kim BW; Kim JW
TI - Hypermethylation of tumor-related genes in genitourinary cancer cell lines.
SO - J Korean Med Sci 2001 Dec;16(6):756-61
AD - Department of Dental Microbiology, College of Dentistry, Kyungpook National University, Taegu, Korea. firstname.lastname@example.org
Hypermethylation of CpG island is a common mechanism for the inactivation of tumor-related genes. In the present study, we analyzed 13 genitourinary cancer cell lines for aberrant DNA methylation of 5 tumor-related genes using methylation- specific polymerase chain reaction (MSP). GSTP1 was methylated in 5 (38.5%), E-cadherin in 1 (8%), VHL in 1 (8%), and MGMT and hMLH1 in none (0%). Six out of thirteen genitourinary cancer cell lines had methylation of at least one of five genes; 5 had one gene methylated, and, 1 had two genes methylated. Methylation of these 5 genes was not detected in any of the bladder cancer cell lines. GSTP1 was methylated in all of the 3 prostate cancer cell lines. We conclude that aberrant hypermethylation may be an important mechanism for the inactivation of cancer-related genes in kidney and prostate cancer cell lines.
UI - 11813205
AU - Leube B; Drechsler M; Muhlmann K; Schafer R; Schulz WA; Santourlidis S;
TI - Anastasiadis A; Ackermann R; Visakorpi T; Muller W; Royer-Pokora B Refined mapping of allele loss at chromosome 10q23-26 in prostate cancer.
SO - Prostate 2002 Feb 15;50(3):135-44
AD - Institute of Human Genetics, University of Dusseldorf, Dusseldorf, Germany.
BACKGROUND: Allele loss of at least two segments in 10q, one mapping to the PTEN gene and one more distal were described in prostate cancer, with loss more frequent in advanced prostate cancer. METHODS: A 63 cM region from 10q23 to q26 was studied for allele loss (LOH) in 59 prostate cancer samples using a dense map of microsatellite markers. RESULTS: LOH of at least one marker in 10q was observed in 13/59 tumors. LOH increased with grade and stage. Detailed deletion mapping identified three regions of allele loss. The first region mapped to the site of the PTEN gene, the second is defined by loss of one marker, D10S1692, in one tumor, and the third is defined between markers D10S1757 and D10S587, including DMBT, with a subregion of approximately 1.2 Mb mapping between markers D10S209 and D10S1679, lost in one tumor. CONCLUSIONS: LOH at the PTEN gene is frequent but mutations in the remaining allele were not detected by SSCP-screening. There may be more than two tumor suppressor (TS) genes mapping more distal of PTEN. The site for these putative TS genes can now be mapped with a dense set of precisely localized markers in a larger series of advanced tumors. Copyright 2002 Wiley-Liss, Inc.
UI - 11813207
AU - Takahashi S; Suzuki S; Inaguma S; Ikeda Y; Cho YM; Nishiyama N; Fujita
TI - T; Inoue T; Hioki T; Sugimura Y; Ushijima T; Shirai T Down-regulation of human X-box binding protein 1 (hXBP-1) expression correlates with tumor progression in human prostate cancers.
SO - Prostate 2002 Feb 15;50(3):154-61
AD - First Department of Pathology, Nagoya City University Medical School, Mizuho-Cho, Mizuho-Ku, Nagoya, Japan. email@example.com
BACKGROUND: In our previous study, the gene encoding the human X-box binding protein 1 (hXBP-1) was isolated as a down-regulated gene in advanced prostate cancers using cDNA-representational difference analysis (RDA). In the present investigation, we characterized alterations of hXBP-1 in prostate cancer specimens. METHODS: Expression patterns of hXBP-1 in a series of human prostate cancers were examined by Northern blotting, mRNA in situ hybridization or immunohistochemistry. Loss of heterozygosity (LOH) analysis using microsatellite markers and gene mutation analysis in the hXBP-1 region were also performed. RESULTS: Expression of hXBP-1 was localized in epithelial and adenocarcinoma cells of the prostate. An inverse correlation between hXBP-1 expression and histological differentiation was found in a series of prostate cancers without hormonal therapy. Majority of refractory cancer cases exhibited weak hXBP-1 expression. No allelic loss or gene mutations were found in the hXBP-1 region and its open reading frame, respectively, in the prostate cancer examined. CONCLUSIONS: These results suggest that reduction of hXBP-1 expression may be a useful marker for prostate adenocarcinoma differentiation and progression. Copyright 2002 Wiley-Liss, Inc.
UI - 11813208
AU - Waltregny D; Alami Y; Clausse N; de Leval J; Castronovo V
TI - Overexpression of the homeobox gene HOXC8 in human prostate cancer correlates with loss of tumor differentiation.
SO - Prostate 2002 Feb 15;50(3):162-9
AD - Metastasis Research Laboratory, University Hospital of Liege, Liege, Belgium. David.Waltregny@ulg.ac.be
BACKGROUND: Homeobox (HOX)-containing proteins have been identified as regulators controlling the coordinated expression of genes involved in development and differentiation. Recent data also suggest a possible involvement of HOX genes in malignant transformation and/or progression. We have previously shown that HOXC8 expression was selectively turned on in human cervix cancer cells compared with normal keratinocytes, suggesting that HOXC8 may be involved in the process leading to the transformation of cervix keratinocytes [Alami et al.: Biochem Biophys Res Commun 257:738-745, 1999]. METHODS: RT-PCR and in situ hybridization experiments were performed to investigate the expression and cell type localization of HOXC8 transcripts in human prostate cancer cell lines and tissues. In situ hybridization was performed with the use of an HOXC8 anti-sense digoxigenin-labeled probe to investigate HOXC8 mRNA expression in 27 prostate cancer tissue specimens. RESULTS: Out of the three human prostate cancer cell lines tested, DU-145 and PC3 but not LNCaP cells expressed detectable amount of HOXC8 transcripts. Results from in situ hybridization experiments demonstrated that HOXC8 gene was expressed mainly in malignant epithelial cells. Furthermore, the staining intensity in epithelial cells was significantly increased in high Gleason score carcinomas (scores 7-9, n = 12; labeling intensity 2 + to 3 +) compared with the one observed in low and intermediate Gleason score tumors (scores 3-6, n = 15; labeling intensity 0 and 1 +) (ANOVA test, P < 0.0001). CONCLUSIONS: Our data showing that HOXC8 overexpression is associated with the loss of tumor differentiation in human prostate cancer suggests that HOXC8 may play a role in the acquisition of the invasive and metastatic phenotype of this malignancy. Copyright 2002 Wiley-Liss, Inc.
UI - 11813210
AU - July LV; Akbari M; Zellweger T; Jones EC; Goldenberg SL; Gleave ME
TI - Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy.
SO - Prostate 2002 Feb 15;50(3):179-88
AD - The Prostate Centre, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
INTRODUCTION AND OBJECTIVES: Progression of prostate cancer to androgen independence (AI) results in part from the upregulation of anti-apoptotic genes following androgen withdrawal, and androgen-independent disease remains the primary obstacle to improved survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the anti-apoptotic protein clusterin, which is upregulated in response to cellular compromise as observed in normal and malignant tissues undergoing apoptosis. Systemic administration of antisense clusterin oligonucleotides in prostate cancer xenograft models delays progression to AI and enhances chemosensitivity. The objective of this study was to define changes in clusterin expression following neoadjuvant hormone therapy (NHT) in prostate cancer patients. MATERIALS AND METHODS: Archival radical prostatectomy (RP) specimens were obtained for 128 patients who received either no NHT or treatment for 2-8 weeks, 3 months, or 8 months. Paired needle biopsy specimens were acquired for 30 patients and all tissues were subjected to clusterin immunohistochemistry. Western blot analysis was performed on frozen tissue from 5 untreated and 5 treated patients. RESULTS: Clusterin expression in malignant prostatic tissue was significantly greater in patients who underwent preoperative NHT (P < 0.001). Needle biopsies obtained prior to NHT consistently demonstrated lower staining intensity than corresponding RP specimens (P < 0.001). Western blot analysis confirmed clusterin levels increased 17-fold beginning within 4 weeks after androgen withdrawal. CONCLUSIONS: Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 11799394
AU - Carpten J; Nupponen N; Isaacs S; Sood R; Robbins C; Xu J; Faruque M;
TI - Moses T; Ewing C; Gillanders E; Hu P; Bujnovszky P; Makalowska I; Baffoe-Bonnie A; Faith D; Smith J; Stephan D; Wiley K; Brownstein M; Gildea D; Kelly B; Jenkins R; Hostetter G; Matikainen M; Schleutker J; Klinger K; Connors T; Xiang Y; Wang Z; De Marzo A; Papadopoulos N; Kallioniemi OP; Burk R; Meyers D; Gronberg H; Meltzer P; Silverman R; Bailey-Wilson J; Walsh P; Isaacs W; Trent J Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.
SO - Nat Genet 2002 Feb;30(2):181-4
AD - Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.
UI - 11830513
AU - Takaha N; Hawkins AL; Griffin CA; Isaacs WB; Coffey DS
TI - High mobility group protein I(Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells.
SO - Cancer Res 2002 Feb 1;62(3):647-51
AD - Department of Urology, The Johns Hopkins University School of Medicine, Marburg 121, 600 North Wolfe Street, Baltimore, MD 21287, USA.
The extent of chromosomal rearrangements correlates positively with the level of expression of the nuclear matrix high mobility group (HMG) proteins HMGI(Y) when tested in three human prostate cancer cell lines (PC-3 > DU-145 > LNCaP). HMGI(Y), topoisomerase II, and A-T-rich sequences have been reported to be located at the base of the DNA loop domains in both the nucleus and chromosome and are juxtapositioned for chromosomal rearrangement. Transfecting and expressing full-length HMG-I into the LNCaP cell markedly enhanced the presence and heterogeneity of unbalanced (nonreciprocal) chromosomal rearrangements but not of balanced rearrangements. Unbalanced chromosomal rearrangements are common in solid human tumors.
UI - 11830526
AU - Qi H; Fillion C; Labrie Y; Grenier J; Fournier A; Berger L; El-Alfy M;
TI - Labrie C AIbZIP, a novel bZIP gene located on chromosome 1q21.3 that is highly expressed in prostate tumors and of which the expression is up-regulated by androgens in LNCaP human prostate cancer cells.
SO - Cancer Res 2002 Feb 1;62(3):721-33
AD - Molecular Endocrinology and Oncology Research Center, Centre Hospitalier Universite Laval Research Center (CHUQ) and Laval University, Quebec G1V 4G2, Canada.
Androgens play an important role in the development and physiology of the normal prostate as well as in prostate cancer cell proliferation. Comparison of the mRNA expression profiles of control and R1881-treated cultures of LNCaP human prostate cancer cells using cDNA subtraction led to the identification of a novel transcription factor that we named Androgen-Induced bZIP (AIbZIP) protein. AIbZIP is a 395 aa protein with homology to cyclic AMP-responsive element binding protein/activating transcription factor transcription factors. It contains an NH(2)-terminal activation domain, a central bZIP domain, and a COOH-terminal transmembrane domain. The AIbZIP gene is localized on chromosome 1q21.3 and consists of 10 exons. A major 1.7-kb transcript was detected exclusively in the prostate as well as in breast and prostate cancer cell lines. Androgens up-regulate AIbZIP mRNA and protein levels in a dose-dependent manner. The kinetics of AIbZIP mRNA up-regulation and the results of experiments with cycloheximide suggest that AIbZIP may be a delayed response gene. Immunoreactive AIbZIP protein was primarily detected in the cytoplasm of prostatic luminal epithelial cells. Similarly, full-length AIbZIP-green fluorescent protein fusion proteins were localized in the cytoplasm of LNCaP cells, whereas a truncated form of AIbZIP lacking the putative transmembrane domain was exclusively nuclear. Examination of AIbZIP protein and mRNA expression in a series of transurethral resection of the prostate and needle biopsy specimens indicated that AIbZIP is expressed at higher levels in cancerous prostate cells compared with noncancerous prostate cells. The highly tissue-specific expression profile, androgen regulation, chromosomal localization, and expression profile of AIbZIP in prostate tumors suggest that AIbZIP may play an important role in prostate cancer and in androgen receptor signaling in prostate cells. Future studies will confirm a possible relationship between AIbZIP and prostate cancer.
UI - 11830536
AU - Rylova SN; Amalfitano A; Persaud-Sawin DA; Guo WX; Chang J; Jansen PJ;
TI - Proia AD; Boustany RM The CLN3 gene is a novel molecular target for cancer drug discovery.
SO - Cancer Res 2002 Feb 1;62(3):801-8
AD - Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Juvenile Batten disease is a neurodegenerative disease caused by accelerated apoptotic death of photoreceptors and neurons attributable to defects in the CLN3 gene. CLN3 is antiapoptotic when overexpressed in NT2 neuronal precursor cells. CLN3 negatively modulates endogenous ceramide levels in NT2 cells and acts upstream of ceramide generation. Because defects in regulation of apoptosis are involved in the development of cancer, we evaluated the expression of CLN3 on both mRNA and protein levels in a variety of cancer cell lines and solid colon cancer tissue. We also observed the effect of the blocking of CLN3 protein expression on cancer cell growth, survival, ceramide production, and apoptosis by using an adenovirus-bearing antisense CLN3 construct. We show that CLN3 mRNA and protein are overexpressed in glioblastoma (U-373G and T98g), neuroblastoma (IMR-32 and SK-N-MC), prostate (Du145, PC-3, and LNCaP), ovarian (SK-OV-3, SW626, and PA-1), breast (BT-20, BT-549, and BT-474), and colon (SW1116, SW480, and HCT 116) cancer cell lines but not in pancreatic (CAPAN and As-PC-1) or lung (A-549 and NCI-H520) cancer cell lines. CLN3 is also up-regulated in mouse melanoma and breast carcinoma cancer cell lines. We found CLN3 expression is 22-330% higher than in corresponding normal colon control tissue in 8 of 10 solid colon tumors. An adenovirus-expressing antisense CLN3 (Ad-AS-CLN3) blocks CLN3 protein expression in DU-145, BT-20, SW1116, and T98g cancer cell lines as seen by Western blot. Blocking of CLN3 expression using Ad-AS-CLN3 inhibits growth and viability of cancer cells. It also causes elevation in endogenous ceramide production through de novo ceramide synthesis and results in increased apoptosis as shown by propidium iodide and JC-1 staining. This suggests that Ad-AS-CLN3 may be an option for therapy in some cancers. More importantly these results suggest that CLN3 is a novel molecular target for cancer drug discovery.
UI - 11708878
AU - Rubinchik S; Wang D; Yu H; Fan F; Luo M; Norris JS; Dong JY
TI - A complex adenovirus vector that delivers FASL-GFP with combined prostate-specific and tetracycline-regulated expression.
SO - Mol Ther 2001 Nov;4(5):416-26
AD - Department of Microbiology and Immunology, Medical University of South Carolina, Charlestown, SC 29403, USA
Cell-type-restricted transgene expression delivered by adenovirus vectors is highly desirable for gene therapy of cancer, as it can limit cytotoxic gene expression to tumor cells. However, many tumor- and tissue-specific promoters are weaker than the constitutively active promoters and are thus less effective. To combine cell-type specificity with high-level regulated transgene expression, we have developed a complex adenoviral vector. We have placed the tetracycline transactivator gene under the control of a prostate-specific ARR2PB promoter, and a mouse Tnfsf6 (encoding FASL)-GFP fusion gene under the control of the tetracycline responsive promoter. We have incorporated both expression cassettes into a single construct. We show that FASL-GFP expression from this vector is essentially restricted to prostate cancer cells, in which it can be regulated by doxycycline. Higher levels of prostate-specific FASL-GFP expression were generated by this approach than by driving the FASL-GFP expression directly with ARR2PB. More FASL-GFP expression correlated with greater induction of apoptosis in prostate cancer LNCaP cells. Mouse studies confirmed that systemic delivery of both the prostate-specific and the prostate-specific/tet-regulated vectors was well tolerated at doses that were lethal for FASL-GFP vector with CMV promoter. This strategy should be able to improve the safety and efficacy of cancer gene therapy using other cytotoxic genes as well.
UI - 11857301
AU - Velasco A; Hewitt SM; Albert PS; Hossein M; Rosenberg H; Martinez C;
TI - Sagalowsky AI; McConnell JD; Marston W; Leach FS Differential expression of the mismatch repair gene hMSH2 in malignant prostate tissue is associated with cancer recurrence.
SO - Cancer 2002 Feb 1;94(3):690-9
AD - Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892-1501, USA.
BACKGROUND: Mismatch repair (MMR) genes are responsible for coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating mutations in MMR genes have been described in sporadic cancers and a hereditary cancer predisposition syndrome. Mismatch repair deficiency causes instability at microsatellites and increased mutation rates. Although microsatellite instability (MSI) has been described in high-grade and lymph node positive prostate carcinoma specimens, an analysis comparing hMSH2 expression, MSI, and outcome in clinically organ confined prostate carcinoma has not been reported. METHODS: Immunohistochemical analysis of benign and malignant prostate tissue from 101 patients was performed using a monoclonal antibody specific for the hMSH2 protein. Expression was correlated with MSI using dinucleotide repeat markers and laser-captured microdissected DNA from normal and tumor cells. hMSH2 protein expression and MSI were assessed with respect to pathologic stage, Gleason score, and time to detectable serum prostate specific antigen (PSA) after prostatectomy in patients with clinically localized prostate carcinoma. RESULTS: In normal glands, hMSH2 staining was minimal to low and confined to the basal cell layer. In 32% of benign prostatic hyperplasia cases, hMSH2 staining was increased in the basal and luminal cell layers whereas 71% of cancer specimens had uniform moderate to high staining. Microsatellite instability was detected in 60% of absent to low staining and 26% of moderate to high staining prostate carcinoma specimens. Differential staining in benign versus malignant prostate tissues was statistically significant (P < 0.001) as was the correlation between absent to low hMSH2 staining and presence of MSI (P = 0.028). Decreased risk for PSA recurrence after radical prostatectomy correlated with absent to low hMSH2 staining in malignant prostate tissue but was only marginally significant (P = 0.05 for 24 month recurrence and P = 0.08 for overall time to PSA recurrence). CONCLUSIONS: The results of the current study demonstrate differential hMSH2 expression in benign and malignant prostate tissue. Moreover, hMSH2 expression is altered in a subset of clinically localized prostate carcinoma specimens independent of pathologic stage and Gleason pattern. A statistically significant correlation between hMSH2 immunohistochemical staining intensity and MSI also was identified in prostate carcinoma specimens. Furthermore, the time to cancer recurrence as determined by detectable serum PSA after prostatectomy was associated with hMSH2 staining intensity. Taken together, our results suggest that hMSH2 gene expression in prostate carcinoma may be a useful prognostic marker for outcome in men with clinically organ confined prostate carcinoma. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10247
UI - 11838717
AU - Weinrich S; Royal C; Pettaway CA; Dunston G; Faison-Smith L; Priest JH;
TI - Roberson-Smith P; Frost J; Jenkins J; Brooks KA; Powell I Interest in genetic prostate cancer susceptibility testing among african American men.
SO - Cancer Nurs 2002 Feb;25(1):28-34
AD - School of Nursing, University of Louisville, KY 40292, USA. firstname.lastname@example.org
Six regions for prostate cancer genes have been identified, and it is anticipated that prostate cancer susceptibility testing will be available in the future. This correlational study identified predictors for interest in prostate cancer susceptibility testing among African American men. Participants were 320 African American men from the African American Hereditary Prostate Cancer Study and the South Carolina Prostate Cancer Education and Screening Study participated. Two questions measured interest in genetic prostate cancer susceptibility testing and family history of prostate cancer. Chi-square analyses by family history as well as demographics (age, education, marital status) were performed. Most of the men (277 [87%]) indicated an interest in genetic prostate cancer susceptibility testing. Interest in undergoing testing did not vary by family history, age, or education. Marital status was the only significant demographic predictor. Men who were married were significantly more likely to respond with a "yes" to interest in prostate cancer susceptibility testing than were men who were not married. The high "yes" response rate and the men's confusion between the genetic prostate cancer susceptibility testing and prostate cancer screening highlight the need for public education once prostate cancer genes are identified and available for public testing.
UI - 11848465
AU - Honda T; Gjertsen BT; Spurgers KB; Briones F; Lee SJ; Hobbs ML; Meyn RE;
TI - Roth JA; Logothetis C; McDonnell TJ Restoration of bax in prostate cancer suppresses tumor growth and augments therapeutic cell death induction.
SO - Anticancer Res 2001 Sep-Oct;21(5):3141-6
AD - Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND: Cancer cells are characterized by multiple genetic defects which result in altered rates of cell division, cell death and ability to differentiate. These same molecular alterations may also contribute to therapeutic resistance. We examined the potential contribution of the pro-apoptotic gene, bax, to suppressing the growth of prostate cancer cells. MATERIALS AND METHODS: The bax-deficient DU145 prostate cancer cell line was transfected with a hemagluttinin-tagged bax (HA-bax) vector to generate stable expressing bax clones. RESULTS: Ha-bax clones exhibited a significant reduction in tumor growth compared to vector control and parental cells when xenografted into nude mice. HA-bax clones were significantly more sensitive to cell death induction by cis-diamminedichloroplatinum, etoposide, doxorubicin and gamma-radiation than vector control cells. Sensitivity to paclitaxel remained unaltered in the Ha-bax cells. CONCLUSION: These findings suggest that bax may possess a tumor suppressor function in prostatic glandular epithelial cells and be an important determinant of sensitivity to therapeutic cell death induction.
UI - 11865006
AU - Oxley JD; Winkler MH; Gillatt DA; Peat DS
TI - Her-2/neu oncogene amplification in clinically localised prostate cancer.
SO - J Clin Pathol 2002 Feb;55(2):118-20
AD - Department of Cellular Pathology, Southmead Hospital, Westbury on Trym, Bristol BS10 5NB, UK. email@example.com
AIM: To examine the incidence of Her-2/neu oncogene amplification in clinically localised prostate cancer using in situ hybridisation. METHODS: One hundred and seventeen patients, who had undergone radical prostatectomy, were identified and in situ hybridisation was performed on formalin fixed, paraffin wax embedded tissue using the Quantum Appligene probe for Her-2/neu. The enzyme peroxidase was used to detect the probe because this enabled a permanent record to be kept. Tumours in which there were five or more signals in each nucleus in > 20% of the tumour cells were considered to have a significantly increased copy number. A serial section from these tumours was then hybridised with the chromosome 17 alpha satellite probe. The ratio of the percentage of cells showing an increase in Her-2/neu copy number to the number showing polysomy for chromosome 17 was calculated. A ratio above 2 was considered amplified. RESULTS: Biochemical recurrence occurred in 50 (43%) patients and 24 (21%) had clinical recurrence. In situ hybridisation for Her-2/neu was accessible in 114 (97%) patients. A significant increase in copy number was present in two patients (1.75 %), but chromosome 17 hybridisation showed that the increase was the result of polysomy rather than true amplification. Both these patients had a Gleason score of 7 and stage T3; they also had recurrent clinical disease with distal metastasis within two and 19 months. CONCLUSIONS: Increased Her-2/neu oncogene copy number appears to be rare in clinically localised prostatic adenocarcinoma and is related to chromosome 17 polysomy rather than true amplification. As a result, it would not be a useful biomarker for identifying those patients who will have recurrences after radical prostatectomy.
UI - 11176509
AU - Wullich B; Verelst S; Rohde V; Moll V; Lensch R; Retz M; Loch T; Zwergel
TI - T; Seitz G; Forster S; Stockle M High frequency microsatellite instability in mucinous adenocarcinoma of the prostate.
SO - J Urol 2001 Mar;165(3):912-3
AD - Clinic of Urology and Pediatric Urology, University of Saar, Homburg/Saar, Institute of Pathology, Clinic of Bamberg, Bamberg, Germany.
UI - 11825111
AU - Al-Maghrabi J; Vorobyova L; Toi A; Chapman W; Zielenska M; Squire JA
TI - Identification of numerical chromosomal changes detected by interphase fluorescence in situ hybridization in high-grade prostate intraepithelial neoplasia as a predictor of carcinoma.
SO - Arch Pathol Lab Med 2002 Feb;126(2):165-9
AD - Ontario Cancer Institute, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, Canada M5G 2M9.
CONTEXT: High-grade prostate intraepithelial neoplasia (HPIN) is the most likely precursor of prostate cancer. The condition of many patients with a diagnosis of HPIN in prostate needle core biopsy could, if left untreated, progress to invasive cancer. Currently there is no available clinical, immunohistochemical, or morphologic criteria that are predictive of this progression. OBJECTIVE: To determine whether chromosomal instability in these precursor lesions could increase their predictive value for cancer detection. DESIGN: Dual-color interphase fluorescence in situ hybridization analysis was performed on archived prostate needle core biopsies from 54 patients with initial diagnosis of isolated HPIN and follow-up of 3 years or more. We used commercially available centromere probes for chromosomes 4, 7, 8, and 10. We had interpretable results in 44 patients as follows: (1) group A: 24 HPIN patients with persistent HPIN and/or benign lesions in the follow-up biopsies, and (2) group B: 20 HPIN patients with progression to prostate carcinoma. RESULTS: Twenty-five percent of the patients in group B displayed numeric chromosomal aberrations. Only 8.3% of the patients from group A had chromosomal abnormalities (P =.1). The observed overall chromosomal changes in HPIN were higher than those in normal or hyperplastic epithelium, with a statistically significant difference (P <.05). All aberrations were detected in the form of chromosomal gain. Overall, the commonest aberration was gain of chromosome 8, followed by gains of chromosomes 7 and 10. CONCLUSION: These results indicated that although no single numeric chromosomal abnormality could be assigned as a predictor of HPIN progression to carcinoma, the overall level of numeric chromosomal abnormalities shows a trend of elevation in HPIN patients whose condition subsequently progressed to carcinoma.
UI - 11673464
AU - Miyamoto H; Rahman M; Takatera H; Kang HY; Yeh S; Chang HC; Nishimura K;
TI - Fujimoto N; Chang C A dominant-negative mutant of androgen receptor coregulator ARA54 inhibits androgen receptor-mediated prostate cancer growth.
SO - J Biol Chem 2002 Feb 15;277(7):4609-17
AD - George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA.
The ligand-bound androgen receptor (AR) regulates target genes via a mechanism involving coregulators such as androgen receptor-associated 54 (ARA54). We investigated whether the interruption of the AR coregulator function could lead to down-regulation of AR activity. Using in vitro mutagenesis and a yeast two-hybrid screening assay, we have isolated a mutant ARA54 (mt-ARA54) carrying a point mutation at amino acid 472 changing a glutamic acid to lysine, which acts as a dominant-negative inhibitor of AR transactivation. In transient transfection assays of prostate cancer cell lines, the mt-ARA54 suppressed endogenous mutated AR-mediated and exogenous wild-type AR-mediated transactivation in LNCaP and PC-3 cells, respectively. In DU145 cells, the mt-ARA54 suppressed exogenous ARA54 but not other coregulators, such as ARA55-enhanced or SRC-1-enhanced AR transactivation. In the LNCaP cells stably transfected with the plasmids encoding the mt-ARA54 under the doxycycline inducible system, the overexpression of the mt-ARA54 inhibited cell growth and endogenous expression of prostate-specific antigen. Mammalian two-hybrid assays further demonstrated that the mt-ARA54 can disrupt the interaction between wild-type ARA54 molecules, suggesting that ARA54 dimerization or oligomerization may play an essential role in the enhancement of AR transactivation. Together, our results demonstrate that a dominant-negative AR coregulator can suppress AR transactivation and cell proliferation in prostate cancer cells. Further studies may provide a new therapeutic approach for blocking AR-mediated prostate cancer growth.
UI - 11713582
AU - Wu SQ; Hafez GR; Zhang J; Newton M; Chen A; Lange J; Wilding G
TI - Identification of the prostate cancer micro-foci with chromosome 8p deletion at the tumor interface area by histopathological-FISH parallel examination.
SO - Int J Oncol 2001 Dec;19(6):1143-7
AD - Division of Medical Genetics, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. firstname.lastname@example.org
We used a histopathological-fluorescence in situ hybridization (histo-FISH) parallel examination technique to identify the micro-foci of prostate cancer with chromosome 8p deletion at the interface area adjacent to the tumor. The archival paraffin embedded prostate tissue sections from 27 prostate cancer patients were evaluated. Seventy-eight percent of the patients showed chromosome 8p deletion in the tumor sections. Eight of the 27 patients (30%) had been found positive for tumor micro-foci with chromosome 8p deletion at the tumor interface area. There is a strong trend for patients with late stage tumors to have positive findings for tumor micro-foci at the interface area (p<0.002). Our data suggests that the formation of tumor micro-foci with chromosome 8p deletion and ploidy change at the interface area is a significant development in the advanced prostate cancer, and identification of these micro-foci may serve as a prognostic parameter in the clinical assessment of prostate cancer patients.
UI - 11713598
AU - Verdorfer I; Hobisch A; Culig Z; Hittmair A; Bartsch G; Erdel M; Duba
TI - HC; Utermann G Combined study of prostatic carcinoma by classical cytogenetic analysis and comparative genomic hybridization.
SO - Int J Oncol 2001 Dec;19(6):1263-70
AD - Institut fur Medizinische Biologie und Humangenetik der Universitat Innsbruck, A-6020 Innsbruck, Austria.
Conventional cytogenetic analysis of prostatic carcinoma (PC) is characterized by inefficient growth of tumor cells during in vitro culture, leading to a lack of aberrant karyotypes in many of investigated tumors. In this study we have combined a modified short-term tissue culture method for conventional banding analysis and comparative genomic hybridization (CGH) to examine genetic changes in PC, and to evaluate the effect of the in vitro culture on chromosomal changes by comparing results of the two methods. Cytogenetic analysis was performed on 34 PCs using both, conventional and molecular methods. Tumor tissues were obtained predominantly from untreated primary tumors from 48 patients. For karyotyping all tumor samples were short-term cultured using a feeder layer technique. Additionally DNA from uncultured tumor material from 17 of those patients was isolated and screened for copy number changes using CGH. Conventional banding analysis: clonal aberrations were detected in 65% of the tumor samples. Most of the chromosomal findings were numerical changes, including loss of chromosomes Y (32%), 18, 19 and 21 (each 12%). Less frequent, trisomy of chromosome 7 and monosomy of chromosomes 9, 12 and 22 (each 9%) was found. Additionally an inversion of chromosome 9p and a deletion at chromosome 7q was found in two cases. In 35% no clonal aberrations could be detected. CGH: DNA copy number changes were detected in 65% of the analyzed tumors. Predominantly losses of DNA sequences were found. The most common losses were found at chromosome regions 13q21q33 (29%), 6q11q23 (24%), 16q, and 18 (each 18%), and the most common gains at 19 (18%). In six tumors no copy number changes were found. Both methods showed a similar aneuploidy rate, suggesting that the feeder layer technique is quite a suitable method for in vitro culture of PC cells. However, the two techniques produced substantially differing results for most of the tumor samples, and in some cases the discrepancies are quite striking. Therefore eventual culture effects need to be taken into account when comparing results from conventional cytogenetics and CGH. Some contrary findings from the two methods are discussed.
UI - 11783090
AU - Li C; Dong J; Guan W
TI - [CAG microsatellite polymorphisms of androgen receptor gene and the stage and grade of prostate cancer]
SO - Zhonghua Zhong Liu Za Zhi 2001 May;23(3):217-9
AD - Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.
OBJECTIVE: To explore the relationship between the CAG microsatellite in androgen receptor (AR) gene and the stage and grade of prostate cancer(PC). METHODS: The number of CAG repeats in exon 1 of the AR gene was measured in 37 PC tissues by PCR-SSCP analysis, and its association with stages and grades of PC determined. RESULTS: The average number of CAG repeats of AR gene differed significantly between PC in stage B (25.04 +/- 1.88) and in stage C-D (24.14 +/- 2.64) (P = 0.002). The frequency of short CAG(< 22) was 13.0% (3/23) in stage B and 28.6%(4/14) in stage C-D, while that of long CAG(> or = 22) was 87.0% (20/23) and 71.4% (10/14) (P = 0.029), respectively. The average number of CAG repeats increased with the decrease in tumor cell differentiation. The frequency of short CAG repeats dropped with the increase in tumor cell differentiation while the opposite was true for that of long CAG repeats. CONCLUSION: The number of CAG repeats in AR gene may be one of the factors determining the biologic characteristics PC. Short CAG repeats may signify aggressiveness of PC.
UI - 11856117
AU - Wolter H; Gottfried HW; Mattfeldt T
TI - Genetic changes in stage pT2N0 prostate cancer studied by comparative genomic hybridization.
SO - BJU Int 2002 Feb;89(3):310-6
AD - Department of Pathology, University of Ulm, Ulm, Germany.
OBJECTIVE: To identify chromosomal regions important for progression in clinically organ-confined prostate cancer, as the genetic changes underlying the development and progression of prostate cancer are poorly understood. MATERIALS AND METHODS: Comparative genomic hybridization (CGH) was used to search for DNA sequence copy-number changes in a series of 50 primary organ-confined prostate adenocarcinomas (pT2N0) removed by radical prostatectomy. RESULTS: CGH analysis indicated that 23 (46%) of the primary prostate adenocarcinomas showed chromosome alterations. The percentage of tumours with losses (38%) was higher than with gains (28%). Losses of 13q (24%), 8p (18%), 6q (10%), 16q (8%), 18q (6%) and 5q (6%) and gains of 17q (12%), 20q (12%), 9q (10%), 17p (8%) and 8q (6%) were the most frequent alterations. Amplifications were found at 8q24-qter. Minimal overlapping regions of loss, indicative of the presence of tumour-suppressor genes, were mapped to 13q21.1-q21.3 and 8p21.2, and minimal overlapping regions of gain, indicative of the presence of oncogenes, were found at 9q34.4-qter, 17q25-qter and 20q13.3-qter. There was a significant association between Gleason score and losses and gains (P = 0.003), and an association between chromosomal imbalance and high histological grade (P = 0.008). CONCLUSION: These results suggest that losses or gains of DNA in these regions are important for prostate cancer progression, and document the spectrum of chromosomal alterations in stage pT2N0 of clinically organ-confined prostate cancer.
UI - 11880477
AU - Sasaki M; Tanaka Y; Perinchery G; Dharia A; Kotcherguina I; Fujimoto S;
TI - Dahiya R Methylation and inactivation of estrogen, progesterone, and androgen receptors in prostate cancer.
SO - J Natl Cancer Inst 2002 Mar 6;94(5):384-90
AD - Department of Urology, University of California, San Francisco 94121, USA.
BACKGROUND: Prostate cancer development is initially steroid hormone dependent. Estrogen receptors (ERs), androgen receptors (ARs), and progesterone receptors (PRs) have been identified in normal and cancerous prostate tissues. We investigated whether the promoter regions of these steroid receptor genes are methylated and inactivated in prostate cancer cells and tissues. METHODS: The expression and promoter methylation status of three ERalpha isoforms (ERalpha-A, ERalpha-B, and ERalpha-C), ERbeta, two PR isoforms (PR-A and PR-B), and AR were investigated in five prostate cancer cell lines (ND1, DU145, PC3, LNCaP, and DUPro) and in pairs of normal and cancerous prostate tissues from 38 patients with prostate cancer. Methylation-specific polymerase chain reaction, reverse transcription--polymerase chain reaction, and 5' rapid amplification of complementary DNA ends were used. All statistical tests were two-sided. RESULTS: ERalpha-C was expressed in all cell lines, but ERalpha-A and ERalpha-B were not expressed in any cell line. ERalpha-A and ERalpha-B promoters were methylated, but ERalpha-C was unmethylated. Promoters for ERbeta, AR, PR-A, and PR-B were methylated and thus inactivated in some cell lines but not in others. Treating cells with the demethylating reagent 5-aza-2'-deoxycytidine restored expression of all steroid receptor genes with previously methylated promoters. All 38 pairs of cancer and normal tissues had unmethylated ERalpha-C promoters. Thirty-six (95%) of 38 cancers had methylated ERalpha-A, 35 (92%) of 38 cancers had methylated ERalpha-B, but all normal tissues had unmethylated ERalpha-A and ERalpha-B (both P<.001). ERbeta was methylated in 30 (79%) of 38 cancers but unmethylated in all normal tissues. AR was methylated in three (8%) of 38 cancers but unmethylated in all normal tissues. PR-A and PR-B were unmethylated in all tissues. CONCLUSION: Certain steroid receptor genes appear to be inactivated by CpG methylation in prostate cancer tissue and cell lines.
UI - 11737226
AU - Finnstrom N; Bjelfman C; Soderstrom TG; Smith G; Egevad L; Norlen BJ;
TI - Wolf CR; Rane A Detection of cytochrome P450 mRNA transcripts in prostate samples by RT-PCR.
SO - Eur J Clin Invest 2001 Oct;31(10):880-6
AD - Department of Medical Laboratory Sciences and Technology, Clinical Pharmacology, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, Sweden. email@example.com
BACKGROUND: The expression of cytochrome P450 (CYP)-dependent mono-oxygenases in the prostate is important, as it will determine the rate of activation of potential carcinogens as well as the metabolism of hormones with implications in diseases of the prostate. In addition, the levels of cytochromes P450 in prostatic tumours may well be determinants of the outcome of therapy involving P450 substrates such as anti-androgens. METHODS: The gene expression of 12 different CYP genes was measured by reverse transcription-polymerase chain reaction (RT-PCR) in a total of 28 human prostatic tumour and nontumour samples. RESULTS: Intriguingly, a large number of CYP mRNAs were detected in the prostate samples, including CYP1A2, -1B1, -2C19, -2D6, -3A4, -3A5, -3A7 and -4B1. CYP1B1 was consistently expressed and CYP3A5 and CYP4B1 were expressed in a majority of the samples tested. CONCLUSIONS: These data demonstrate a wide range of CYP genes being expressed in the prostate. The relative importance of these enzymes in the pathogenesis and treatment of prostatic disease remains an important theme for further study.
UI - 11870798
AU - Jongsma J; Oomen MH; Noordzij MA; Van Weerden WM; Martens GJ; van der
TI - Kwast TH; Schroder FH; van Steenbrugge GJ Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation.
SO - Prostate 2002 Mar 1;50(4):203-15
AD - Department of Experimental Urology, Josephine Nefkens Institute, Erasmus University, Rotterdam, Netherlands. firstname.lastname@example.org
BACKGROUND: Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310. METHODS: Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation. RESULTS: Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively. CONCLUSIONS: Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells in the progression of clinical prostate cancer. Copyrig