Table of Contents
CancerMail from the National Cancer Institute
UI - 21198521
AU - Allen NE; Forrest MS; Key TJ
TI - The association between polymorphisms in the CYP17 and 5alpha-reductase (SRD5A2) genes and serum androgen concentrations in men.
SO - Cancer Epidemiol Biomarkers Prev 2001 Mar;10(3):185-9
AD - Imperial Cancer Research Fund Cancer Epidemiology Unit, Oxford, United Kingdom. firstname.lastname@example.org
Prospective studies suggest that prostate cancer risk may be increased in association with high serum concentrations of free testosterone and androstanediol glucuronide (A-diol-g). Polymorphisms have been identified in the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5alpha-reductase type II gene (SRD5A2), two genes that are involved in the biosynthesis and metabolism of androgens in men. The CYP17 MspA1 I polymorphism has been associated with increased prostate cancer risk, and the SRD5A2 V89L polymorphism has been associated with low A-diol-g in Asian men, a serum marker of 5alpha-reductase activity. The purpose of this study was to investigate the association between these two polymorphisms and serum sex hormone concentrations in 621 British men. In particular, we wanted to test the hypotheses that the A2 allele in the CYP17 gene is associated with increased serum testosterone concentrations, and the L allele in the SRD5A2 gene is associated with reduced A-diol-g concentrations. Mean hormone concentrations were evaluated in each genotype and adjusted for age and other relevant factors. We found no evidence that the CYP17 MspA1 I polymorphism was associated with higher testosterone levels. The L/L genotype of the SRD5A2 V89L polymorphism was associated with a 10% lower A-diol-g concentration, but this was not significant at the 5% level. However, the L/L genotype of the V89L polymorphism was associated with significantly lower concentrations of testosterone and free testosterone (by 12% and 16%, respectively) and an 8% higher sex hormone-binding globulin concentration. These results suggest that the CYP17 MspA1 I polymorphism is not associated with testosterone concentrations and that the SRD5A2 V89L polymorphism is not a strong determinant of A-diol-g concentration in Caucasian men.
UI - 21198535
AU - Nathanson KL; Omaruddin R; Malkowicz SB; Rebbeck TR
TI - An intronic variant in PTEN is not associated with prostate cancer risk.
SO - Cancer Epidemiol Biomarkers Prev 2001 Mar;10(3):277-8
AD - Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA.
UI - 21378031
AU - de Pinieux G; Legrier ME; Poirson-Bichat F; Courty Y; Bras-Goncalves R; Dutrillaux AM; Nemati F; Oudard S; Lidereau R; Broqua P; Junien JL; Dutrillaux B; Poupon MF
TI - Clinical and experimental progression of a new model of human prostate cancer and therapeutic approach.
SO - Am J Pathol 2001 Aug;159(2):753-64
AD - Section de Recherche, Institut Curie, UMR-147-CNRS, 26 rue d'Ulm, 75231 Paris, France.
We report the clinical evolution of a prostate cancer, metastasizing to lungs and bones, recurring locally, and escaping from anti-androgen therapy. Key event of biological progression of the patient's tumor was the coincidence of allelic imbalance accumulation and of bone metastases occurrence. The recurrent tumor was established as the transplantable xenograft PAC120 in nude mice, where it grew locally. PAC120 displayed the same immunophenotype of the original tumor (positive for keratin, vimentin, prostatic acid phosphatase, and Leu-7) and expressed human HOXB9, HOXA4, HER-2/neu, and prostate-specific antigen genes, as detected by reverse transcriptase-polymerase chain reaction. It formed lung micrometastases detected by mRNA expression of human genes. Cytogenetic analysis demonstrated numerous alterations reflecting the tumor evolution. PAC120 was still hormone-dependent; its growth was strongly inhibited by the new gonadotropin-releasing hormone antagonist FE 200486 but weakly by gonadotropin-releasing hormone superagonist D-Trp(6)-luteinizing-hormone releasing hormone (decapeptyl). Tumor growth inhibition induced by anti-hormone therapy was linked to the hormone deprivation degree, more important and more stable with FE 200486 than with D-Trp(6)-luteinizing-hormone releasing hormone. Surgical castration of mice led to tumor regressions but did not prevent late recurrences. Transition to hormone-independent tumors was frequently associated with a mucoid differentiation or with a neuroendocrine-like pattern. Independent variations of mRNA expression of HER-2/neu and prostate-specific antigen were observed in hormone-independent tumors whereas HOXB9 gene expression was constant. In conclusion, PAC120 xenograft, a new model of hormone-dependent prostate cancer retained the progression potential of the original tumor, opening the opportunity to study the hormone dependence escape mechanism.
UI - 21397931
AU - Yasunaga Y; Nakamura K; Ewing CM; Isaacs WB; Hukku B; Rhim JS
TI - A novel human cell culture model for the study of familial prostate cancer.
SO - Cancer Res 2001 Aug 15;61(16):5969-73
AD - Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Research into molecular and genetic mechanisms underlying familial prostate cancer would be greatly advanced by in vitro models of prostate tumor cells representing primary tumors. We have successfully established an immortalized human prostate epithelial cell culture derived from primary tumors of familial prostate cancer patients with telomerase. The actively proliferating early-passaged 957E cells were transduced through infection with a retrovirus expressing the human telomerase catalytic subunit, human telomerase reverse transcriptase (hTERT). A high level of telomerase activity was detected in 957E/hTERT cells, but not in 957E cells. 957E/hTERT cells are currently growing well at passage 40, whereas 957E cells senesced at passage 5. 957E/hTERT cells exhibit epithelial morphology. Expression of an androgen-regulated prostate specific homeobox gene NKX3.1 and an epithelial cell-specific cytokeratin 8, but not prostate specific antigen or androgen receptor, was detected in 957E/hTERT cells. Prostatic stem cell antigen and p16 were also expressed in this line. 957E/hTERT cells showed growth inhibition when exposed to retinoic acid and transforming growth factor beta1, potent inhibitors of prostate epithelial cell growth. Chromosome analysis showed that the 957E/hTERT cell line (passage 10) was near diploid human male (XY), with most chromosome counts in the 44-46 range. However, there was random loss of chromosomes 8, 13, X, Y, and alteration in chromosome 4q. The late passage 957E/hTERT cell line (passage 32) was karyologically similar to the early passage 957E/hTERT cell line (passage 10) and also had the same alteration of 4q observed in the early passage 957E/hTERT cell line (passage 10) as well as a trisomy of chromosome 20. The well-characterized human cancer lines derived from such patients will be useful for the identification and characterization of prostate cancer susceptibility genes. This is the first documented case of an established human prostate cancer cell line from primary tumor of a familial prostate cancer patient.
UI - 21397932
AU - Welsh JB; Sapinoso LM; Su AI; Kern SG; Wang-Rodriguez J; Moskaluk CA; Frierson HF Jr; Hampton GM
TI - Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer.
SO - Cancer Res 2001 Aug 15;61(16):5974-8
AD - Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
Detection, treatment, and prediction of outcome for men with prostate cancer increasingly depend on a molecular understanding of tumor development and behavior. We characterized primary prostate cancer by monitoring expression levels of more than 8900 genes in normal and malignant tissues. Patterns of gene expression across tissues revealed a precise distinction between normal and tumor samples, and revealed a striking group of about 400 genes that were overexpressed in tumor tissues. We ranked these genes according to their differential expression in normal and cancer tissues by selecting for highly and specifically overexpressed genes in the majority of cancers with correspondingly low or absent expression in normal tissues. Several such genes were identified that act within a variety of biochemical pathways and encode secreted molecules with diagnostic potential, such as the secreted macrophage inhibitory cytokine, MIC-1. Other genes, such as fatty acid synthase, encode enzymes known as drug targets in other contexts, which suggests new therapeutic approaches.
UI - 21397939
AU - Matsubara S; Wada Y; Gardner TA; Egawa M; Park MS; Hsieh CL; Zhau HE; Kao C; Kamidono S; Gillenwater JY; Chung LW
TI - A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone stroma in an experimental model of androgen-independent prostate cancer bone metastasis.
SO - Cancer Res 2001 Aug 15;61(16):6012-9
AD - Department of Urology, Molecular Urology and Therapeutics Program, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Prostate cancer has a high propensity to metastasize to bone, which often resists hormone, radiation, and chemotherapies. Because of the reciprocal nature of the prostate cancer and bone stroma interaction, we designed a cotargeting strategy using a conditional replication-competent adenovirus to target the growth of tumor cells and their associated osteoblasts. The recombinant Ad-OC-E1a was constructed using a noncollagenous bone matrix protein osteocalcin (OC) promoter to drive the viral early E1a gene with restricted replication in cells that express OC transcriptional activity. Unlike Ad-PSE-E1a, Ad-OC-E1a was highly efficient in inhibiting the growth of PSA-producing (LNCaP, C4-2, and ARCaP) and nonproducing (PC-3 and DU145) human prostate cancer cell lines. This virus was also found to effectively inhibit the growth of human osteoblasts and human prostate stromal cells in vitro. Athymic mice bearing s.c. androgen receptor-negative and PSA-negative PC-3 xenografts responded to a single intratumoral administration of 2 x 10(9) plaque-forming unit(s) of Ad-OC-E1a. In SCID/bg mice, intraosseous growth of androgen receptor-positive and PSA-producing C4-2 xenografts responded markedly to i.v. administrations of a single dose of Ad-OC-E1a. One hundred percent of the treated mice responded to this systemic Ad-OC-E1a therapy with a decline of serum PSA to an undetectable level, and 80% of the mice with PSA rebound responded to the second dose of systemic Ad-OC-E1a. Forty percent of the mice were found to be cured by systemic Ad-OC-E1a without subsequent PSA rebound or tumor cells found in the skeleton. This cotargeting strategy shows a broader spectrum and appears to be more effective than systemic Ad-PSE-E1a in preclinical models of human prostate cancer skeletal metastasis.
UI - 21397941
AU - Malins DC; Johnson PM; Wheeler TM; Barker EA; Polissar NL; Vinson MA
TI - Age-related radical-induced DNA damage is linked to prostate cancer.
SO - Cancer Res 2001 Aug 15;61(16):6025-8
AD - Molecular Epidemiology Program, Pacific Northwest Research Institute, Seattle, Washington 98122, USA. email@example.com
We measured concentrations and ratios of mutagenic (8-OH) lesions to putatively nonmutagenic formamidopyrimidine (Fapy) lesions of adenine (Ade) and guanine (Gua) to elucidate radical (.OH)-induced changes in DNA of normal, normal from cancer, and cancer tissues of the prostate. The relationship between the lesions was expressed using the mathematical model log(10)[(8-OH-Ade + 8-OH-Gua)/(FapyAde + FapyGua)]. Logistic regression analysis of the log ratios for DNA of normal and cancer tissues discriminated between the two tissue groups with high sensitivity and specificity. Correlation analysis of log ratios for normal prostates revealed a highly significant increase in the proportion of mutagenic base lesions with age. Data from correlation analysis of the log ratios for normal tissues from cancer were consistent with an age-dependent, dose-response relationship. The slopes for both correlations intersected at approximately 61 years, an age when prostate cancer incidence is known to rise sharply. The age-related increase in the proportion of.OH-induced mutagenic base lesions is likely a significant factor in prostate cancer development.
UI - 21397944
AU - Rokman A; Ikonen T; Mononen N; Autio V; Matikainen MP; Koivisto PA; Tammela TL; Kallioniemi OP; Schleutker J
TI - ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer.
SO - Cancer Res 2001 Aug 15;61(16):6038-41
AD - Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33101 Tampere, Finland. firstname.lastname@example.org
The ELAC2/HPC2 gene at 17p11 is the first candidate gene identified for human prostate cancer (PRCA) based on linkage analysis and positional cloning (S. V.Tavtigian et al. Nat. Genet., 27:172-180, 2001). A truncating mutation was found in one hereditary prostate cancer (HPC) family, whereas two missense variants, Ser217Leu and Ala541Thr, were reported to be associated with increased PRCA risk in the general population. Here, we screened for mutations of the ELAC2/HPC2 gene in 66 Finnish HPC families. Several sequence variants, including a new exonic variant (Glu622Val) were found, but none of the mutations were truncating. We then analyzed the frequency of the three found missense variants in 1365 individuals, including hereditary (n = 107) and unselected (n = 467) PRCA, benign prostatic hyperplasia (n = 223), and population controls (568 healthy male blood donors). Ser217Leu and Ala541Thr variants carried no significantly elevated risk for HPC or PRCA, although the latter variant was associated with benign prostatic hyperplasia. The previously undescribed Glu622Val variant had a 1.0% population prevalence, but a significantly higher frequency in PRCA cases (3.0% odds ratio, 2.94; 95% confidence interval, 1.05-8.23). We conclude that ELAC2/HPC2 truncating mutations are rare in HPC, but that rare variants of the ELAC2/HPC2 require additional study as risk factors for PRCA in the general population.
UI - 21397948
AU - Yehia G; Razavi R; Memin E; Schlotter F; Molina CA
TI - The expression of inducible cAMP early repressor (ICER) is altered in prostate cancer cells and reverses the transformed phenotype of the LNCaP prostate tumor cell line.
SO - Cancer Res 2001 Aug 15;61(16):6055-9
AD - Department of Obstetrics, Gynecology and Women's Health, New Jersey Medical School, Newark, New Jersey 07103, USA.
Inducible cAMP early repressor (ICER) has been shown to be an important mediator of cAMP antiproliferative activity. In this report, it was found that cAMP retards LNCaP cell growth; in contrast, cAMP inhibits the growth of PC-3 and DU-145 cells. ICER protein levels were markedly reduced in prostate cancer epithelial cells and undetectable and uninducible by cAMP in LNCaP and DU 145 cells. Forced expression of ICER in LNCaP cells caused inhibition of cell growth and thymidine incorporation and halted cells at the G(1) phase of the cell cycle. These ICER-bearing LNCaP cells were rendered unable to grow in soft agar and unable to form tumors in nude mice. These results suggest that deregulation of ICER expression may be related to carcinogenesis of the prostate gland.
UI - 21397949
AU - Segawa N; Nakamura M; Nakamura Y; Mori I; Katsuoka Y; Kakudo K
TI - Phosphorylation of mitogen-activated protein kinase is inhibited by calcitonin in DU145 prostate cancer cells.
SO - Cancer Res 2001 Aug 15;61(16):6060-3
AD - Department of Urology, Osaka Medical College, Takatsuki City, Osaka, Japan. email@example.com
One of the causes of insensitivity to androgen ablation therapy in prostate cancer is thought to be attributable to elevated neuropeptides secreted by neuroendocrine cells in the tumor mass. Calcitonin (CT), one of these neuropeptides, is reported to be associated with the growth of prostate cancer. There is an increase in mitogen-activated protein (MAP) kinase activation as prostate cancer progresses to a more advanced and androgen-independent disease. We examined the effect of CT on signal transduction and the relation between CT and early-response genes in the human androgen-insensitive prostate cancer cell line, DU145. The basal phosphorylation level of extracellular signal-regulated kinase 1/2, which is a key kinase in the mediation of growth factor-induced mitogenesis in prostate cancer cells, was constitutively up-regulated. N-[2-(4-bromocinnamyl) aminoethyl]-5-isoquinoline-sulfonamide (H89), a specific inhibitor of protein kinase A, potentiated the effects of more increased phosphorylation of extracellular signal-regulated kinase 1/2. CT induced the inhibition of this MAP kinase phosphorylation, and this effect was completely abolished by pretreatment with H89. Our findings demonstrate that CT caused the inhibition of constitutive MAP kinase phosphorylation in a protein kinase A-dependent manner in DU145. The transient increase of c-fos expression was detected after CT treatment, whereas expression of c-jun RNA was down-regulated after CT treatment. These results suggest that CT may regulate early-response genes, c-fos and c-jun, via a MAP kinase cascade. In conclusion, these findings suggest that DU145 might be a useful model as a therapeutic approach of neuropeptides in androgen-independent prostatic carcinoma.
UI - 21397977
AU - Nickerson T; Chang F; Lorimer D; Smeekens SP; Sawyers CL; Pollak M
TI - In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR).
SO - Cancer Res 2001 Aug 15;61(16):6276-80
AD - Cancer Prevention Research Unit of the Jewish General Hospital and McGill University, Montreal, Quebec, H3T 1E2 Canada.
Androgen deprivation therapies for metastatic prostate cancer are useful initially, but progression to androgen independence usually results in relapse within 2 years. The molecular mechanisms underlying the clinically important transition from androgen dependence to androgen independence are poorly described. Several lines of investigation have suggested that insulin-like growth factors (IGFs) are involved in the biology of prostate cancer, but little is known about their relevance to progression to androgen independence. We used three in vivo models of androgen-dependent (AD) human prostate cancer to study this issue. Progression to androgen-independent (AI) growth was associated with a 60-fold increase in expression of IGF-I mRNA in LAPC-9 xenografts and a 28-fold increase in IGF-I expression in LNCAP xenografts, relative to the initial AD neoplasms. IGF type I receptor (IGF-IR) mRNA levels were approximately 2.5-fold and approximately 5-fold higher, respectively, in AI LAPC-9 and LNCaP tumors compared with the original AD neoplasms. AI growth of these xenografts was also associated with significant reductions in IGF binding protein-3 expression. LAPC-4 xenografts, which previously have been shown to exhibit molecular pathology related to HER-2/neu expression with progression to AI, showed relatively minor changes in expression of the genes investigated, but we nevertheless found evidence of increased IGF-IR phosphorylation with progression to androgen independence in this model. Taken together with prior observations, our results suggest that deregulation of expression of genes related to any one of several critical receptor tyrosine kinase regulatory systems, including IGF signaling, may confer androgen independence.
UI - 21379841
AU - Sidiropoulos M; Chang A; Jung K; Diamandis EP
TI - Expression and regulation of prostate androgen regulated transcript-1 (PART-1) and identification of differential expression in prostatic cancer.
SO - Br J Cancer 2001 Aug 3;85(3):393-7
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
Prostate androgen regulated transcript 1 (PART-1), is a gene predominantly expressed in the prostate gland and is regulated by androgens in human prostate cancer cell lines. Here, we report additional characteristics of PART-1 tissue expression and hormonal regulation and study its expression profile in human normal and matched prostate cancer tissues. Since PART-1 shows similarity to prostate-specific antigen (PSA) in prostate specificity and regulation, we hypothesized that it may be implicated in prostate carcinogenesis or may be a potential new biomarker. We used reverse transcriptase polymerase chain reaction (RT-PCR) to further characterize PART-1 tissue expression and hormonal regulation in the LNCaP prostate cancer cell line. RT-PCR analysis revealed that PART-1 is expressed not only in the prostate and salivary gland, but also in other tissues, including the thymus and placenta. In addition to androgen stimulation, PART-1 is also up-regulated by progestins, oestrogens and glucocorticoids. We further studied the expression of PART-1 in 27 paired (from the same patient) cancerous and non-cancerous prostatic tissues, with qualitative and quantitative RT-PCR (LightCycler technology), in order to examine whether PART-1 is overexpressed or underexpressed in cancer. Our results indicated that PART-1 is more frequently overexpressed in the cancerous prostatic tissue. We conclude that this gene is overexpressed in prostate cancer and may represent a novel prostate cancer tumour marker. Copyright 2001 Cancer Research Campaign.
UI - 21379850
AU - Hammond LA; Van Krinks CH; Durham J; Tomkins SE; Burnett RD; Jones EL; Chandraratna RA; Brown G
TI - Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells.
SO - Br J Cancer 2001 Aug 3;85(3):453-62
AD - Division of Cancer Studies, University of Birmingham Medical School, Edgbaston, Birmingham, B15 2TT, UK.
Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, K(d) for binding to RARs = 2-5 nM) inhibited colony formation (by 50%) by all three lines at 16-34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12-22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RARbeta, and an antagonist with predominant activity at RARbeta and RARgamma (AGN194431) inhibited colony formation at concentrations (approximately 100 nM) commensurate with a K(d)value of 70 nM at RARgamma. An RARalpha antagonist (AGN194301) was less potent (IC(50) approximately 200 nM), but was more active than specific agonists of RARalpha and of betagamma. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARgamma-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma. Copyright 2001 Cancer Research Campaign.
UI - 21215798
AU - Lee YG; Korenchuk S; Lehr J; Whitney S; Vessela R; Pienta KJ
TI - Establishment and characterization of a new human prostatic cancer cell line: DuCaP.
SO - In Vivo 2001 Mar-Apr;15(2):157-62
AD - Hallym University, College of Medicine, Seoul, Korea.
BACKGROUND: The lack of appropriate, clinically relevant, cell-based model systems has limited prostate cancer research and the development of new therapeutic modalities. Here we report the isolation and characterization of a new adherent prostate cancer cell line, derived from the dura mater of a cancer patient. METHODS: Prostate cancer tissue was harvested at autopsy from a metastatic lesion to the dura mater of a patient with hormone refractory prostate cancer. This tissue was xenografted into SCID mice and later harvested and plated on tissue culture dishes. For characterization, soft agar clonegenic assay, in vivo xenograft growth, in vitro doubling time, karyotype analysis, immunocytochemistry for cytokeratin-18, androgen receptor, and PAP (prostatic acid phosphatase) expression, RT PCR for PAP, PSMA (prostate specific membrane antigen), expression and northern and western blot analysis to determine expression of Rb and p53, were performed. RESULTS: DuCap grows in vitro (passage 55), forms colonies in soft agar, produces tumors in SCID mice (xenograft passage 12), and is androgen sensitive. DNA content was hypertriploid. PSA was detected in mouse serum and media. Cells were AR, PAP and cytokeratin-18 positive by immunocytochemistry. PSMA and PAP were detected by RT-PCR. AR, P53, and Rb were expressed in Northern blot analysis. P53 protein was detected in Western blot analysis but Rb protein was not. CONCLUSIONS: This cell line exhibits many phenotypic characteristics of clinical prostate carcinoma, including expression of PSA, PSMA, PAP and AR.
UI - 21215799
AU - Korenchuk S; Lehr JE; MClean L; Lee YG; Whitney S; Vessella R; Lin DL; Pienta KJ
TI - VCaP, a cell-based model system of human prostate cancer.
SO - In Vivo 2001 Mar-Apr;15(2):163-8
AD - Departments of Surgery and Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Drive-7303 CCGC, Ann Arbor, Michigan 48109-0946, USA.
OBJECTIVES: We report the isolation and characterization of a novel prostate cancer cell line derived from a vertebral metastatic lesion, Vertebral-Cancer of the Prostate (VCaP). METHODS: Prostate cancer tissue was harvested at autopsy from a metastatic lesion to a lumbar vertebral body of a patient with hormone refractory prostate cancer. This tissue was aseptically xenografted into SCID mice and later harvested and plated on tissue culture dishes. For characterization, soft agar clonegenic assay, in vivo xenograft growth, in vitro doubling time, karyotype analysis, immunocytochemistry for cytokeratin-18 expression immunochemistry for PSA (prostate specific antigen), RT PCR for PAP (prostatic acid phosphatase) and northern blot and western blot analysis to determine expression of Rb and p53, were performed. Androgen receptor expression was measured by transient transfection with a luciferase reporter construct. RESULTS: VCaP cells are immortal in vitro and can be passaged serially in vivo. They express large quantities of prostate specific antigen (PSA). This cell line also expresses prostatic acid phosphatase (PAP), cytokeratin-18 and the androgen receptor, and is androgen sensitive in vitro and in vivo. CONCLUSIONS: This cell line was derived from a metastatic tumor to the vertebrae of a prostate cancer patient. It exhibits many of the characteristics of clinical prostate carcinoma, including expression of PSA, PAP, and AR. We believe that VCaP will be a useful addition to the existing models of prostate cancer, and enable more advanced study of the mechanisms of prostate cancer progression and metastasis.
UI - 21302032
AU - Huss WJ; Maddison LA; Greenberg NM
TI - Autochthonous mouse models for prostate cancer: past, present and future.
SO - Semin Cancer Biol 2001 Jun;11(3):245-60
AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Prostate cancer continues to be the second leading cancer related death among men. In order to more fully develop effective prevention and intervention strategies for this prevalent disease, the underlying molecular mechanisms of initiation, progression and metastatic spread must be understood. To this end mouse models have an essential role in prostate cancer research in that they can closely mimic the pathological and biochemical features of the disease. In this review we discuss the history of autochthonous murine models of prostate cancer, the essentials of the idealized mouse model for prostate cancer and speculate on approaches towards this goal. Copyright 2001 Academic Press.
UI - 21371754
AU - Yousef GM; Bharaj BS; Yu H; Poulopoulos J; Diamandis EP
TI - Sequence analysis of the human kallikrein gene locus identifies a unique polymorphic minisatellite element.
SO - Biochem Biophys Res Commun 2001 Aug 3;285(5):1321-9
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Minisatellites are repetitive sequences of DNA that are present throughout the genome. Although the origin and function of these minisatellites is still unknown, they found clinical applications as markers of many diseases, including cancer. Also, they are useful tools for DNA fingerprinting and linkage analysis. Kallikreins are serine proteases that appear to be involved in many diseases including brain disorders and malignancy. We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes. In this study, we examined the kallikrein locus ( approximately 300 Kb) for all known repeat elements. About 50% of this genomic area is occupied by different repeat elements. We also identified unique minisatellite elements that are restricted to chromosome 19q13. Ten clusters of these minisatellites are distributed along the locus on either DNA strand. The clusters are located in the promoters and enhancers of genes, in introns, and in untranslated regions of the mRNA. Analysis of these elements indicates that they are polymorphic, thus they can be useful in linkage analysis and DNA fingerprinting. Our preliminary results indicate also that the distribution of the different alleles of these minisatellites might be associated with malignancy. Copyright 2001 Academic Press.
UI - 21410163
AU - Dhanasekaran SM; Barrette TR; Ghosh D; Shah R; Varambally S; Kurachi K; Pienta KJ; Rubin MA; Chinnaiyan AM
TI - Delineation of prognostic biomarkers in prostate cancer.
SO - Nature 2001 Aug 23;412(6849):822-6
AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Prostate cancer is the most frequently diagnosed cancer in American men. Screening for prostate-specific antigen (PSA) has led to earlier detection of prostate cancer, but elevated serum PSA levels may be present in non-malignant conditions such as benign prostatic hyperlasia (BPH). Characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms may identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer. Using microarrays of complementary DNA, we examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. We assessed two of these genes-hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase-at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome. Thus, the integration of cDNA microarray, high-density tissue microarray, and linked clinical and pathology data is a powerful approach to molecular profiling of human cancer.
UI - 21413531
AU - Chetcuti A; Margan SH; Russell P; Mann S; Millar DS; Clark SJ; Rogers J; Handelsman DJ; Dong Q
TI - Loss of annexin II heavy and light chains in prostate cancer and its precursors.
SO - Cancer Res 2001 Sep 1;61(17):6331-4
AD - Department of Medicine, University of Sydney, NSW 2006, Australia.
Annexin II mRNA coding for a calcium binding protein was found to be absent in prostate cancer by subtractive hybridization and Northern analysis. In contrast to high expression in normal and benign hyperplastic glandular and basal epithelium, Annexin II heavy (p36) and light (p11) chains in 31/31 prostate cancer specimens were lost immunohistochemically. In glands involved by prostate intraepithelial neoplasia, 65% lost both chains in glandular epithelial cells, whereas basal cells were all positively stained. Southern analysis of cancer DNA showed no noticeable deletion in p36 gene. LNCaP cells treated with 5-azacytidine re-expressed p36, suggesting methylation could be responsible for the silencing.
UI - 21413533
AU - van Bokhoven A; Varella-Garcia M; Korch C; Miller GJ
TI - TSU-Pr1 and JCA-1 cells are derivatives of T24 bladder carcinoma cells and are not of prostatic origin.
SO - Cancer Res 2001 Sep 1;61(17):6340-4
AD - Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. firstname.lastname@example.org
We have shown previously that the putative prostate carcinoma cell lines TSU-Pr1 and JCA-1 share a common origin. The observation that these cell lines have p53 and Ha-ras mutations identical to those in bladder carcinoma cell line T24 prompted us to investigate their possible interrelations. We used cytogenetics and DNA profiling to compare the genetic backgrounds of the three cell lines. At least 12 structural chromosomal abnormalities are shared between T24, TSU-Pr1, and JCA-1 cells. DNA profiles were identical for all three cell lines. These results clearly indicate that the cell lines TSU-Pr1 and JCA-1 are not of prostatic origin but are derivatives of the bladder carcinoma cell line T24. TSU-Pr1 and, to a lesser extent, JCA-1 are frequently used as models in prostate cancer research, and numerous publications have appeared based on these lines. Several other T24 cross-contaminants have been identified in the past, and some of these, such as ECV304, continue to be used under the wrong identity. Our findings highlight the insidious problem that can occur when information regarding cross-contamination does not reach individual researchers and/or the importance of the problem is not fully acknowledged.
UI - 21413557
AU - Wang L; McDonnell SK; Elkins DA; Slager SL; Christensen E; Marks AF; Cunningham JM; Peterson BJ; Jacobsen SJ; Cerhan JR; Blute ML; Schaid DJ; Thibodeau SN
TI - Role of HPC2/ELAC2 in hereditary prostate cancer.
SO - Cancer Res 2001 Sep 1;61(17):6494-9
AD - Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
The HPC2/ELAC2 gene on chromosome 17p was recently identified as a candidate gene for hereditary prostate cancer (HPC). To confirm these findings, we screened 300 prostate cancer patients (2 affected members/family) from 150 families with HPC for potential germ-line mutations using conformation-sensitive gel electrophoresis, followed by direct sequence analysis. The minimum criteria for our families with HPC was the presence of 3 affected men with prostate cancer. A total of 23 variants were identified, including 13 intronic and 10 exonic changes. Of the 10 exonic changes, 1 truncating mutation was identified, a Glu216Stop nonsense mutation. This nonsense variant was found in 2 of 3 affected men in a single family. The remaining nine alterations included five missense, three silent, and one variant in the 3' untranslated region. To additionally test for potential associations of polymorphic variants and increased risk for disease, we genotyped two common polymorphisms, Ser217Leu and Ala541Thr, in 446 prostate cancer patients from 164 families with HPC and 502 population-based controls. The frequency of the Leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the Thr541 variant (5.4% among patients versus 5.2% among controls). In contrast to previous reports, we found no association of the joint effects of Leu271 and Thr541 (odds ratio, 1.04; 95% confidence interval, 0.57-1.89). Overall, our results did not reveal any association between these two common polymorphisms and the risk for HPC. The finding of a nonsense mutation in the HPC2/ELAC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, our data also suggest that germ-line mutations of the HPC2/ELAC2 are rare in HPC and that the variants Leu217 and Thr541 do not appear to influence the risk for HPC. Cumulatively, these results suggest that alterations within the HPC2/ELAC2 gene play a limited role in genetic susceptibility to HPC.
UI - 21417672
AU - Jeronimo C; Nomoto S; Caballero OL; Usadel H; Henrique R; Varzim G; Oliveira J; Lopes C; Fliss MS; Sidransky D
TI - Mitochondrial mutations in early stage prostate cancer and bodily fluids.
SO - Oncogene 2001 Aug 23;20(37):5195-8
AD - Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2195, USA.
We recently demonstrated the existence of specific patterns of somatic mitochondrial DNA (mtDNA) mutations in several cancers. Here we sought to identify the presence of mtDNA mutations in prostate cancer and their paired PIN lesions. The D-loop region, 16S rRNA, and the NADH subunits of complex I were sequenced to identify mtDNA mutations in 16 matched PIN lesions and primary prostate cancers. Twenty mtDNA mutations were detected in the tumor tissue of three patients. Identical mutations were also identified in the PIN lesion from one patient. This patient with multiple point mutations also harbored a high frequency of microsatellite instability (MSI-H) in nuclear mononucleotide repeat markers. Remarkably, identical mutations were also detected in all (3/3) matched urine and plasma samples obtained from these patients. Although mitochondrial mutations are less common in prostate adenocarcinoma, they occur early in cancer progression and they can be detected in bodily fluids of early stage disease patients. The identification of MtDNA mutations may complement other early detection approaches for prostate cancer.
UI - 21433657
AU - Beilin J; Harewood L; Frydenberg M; Mameghan H; Martyres RF; Farish SJ; Yue C; Deam DR; Byron KA; Zajac JD
TI - A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects.
SO - Cancer 2001 Aug 15;92(4):941-9
AD - Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. email@example.com
BACKGROUND: The development of prostate carcinoma is androgen-dependent. The coding sequence of the androgen receptor (AR) gene contains a CAG repeat polymorphism that has been shown to influence AR activity in vitro. Studies of this polymorphism as a prostate carcinoma risk factor have been conflicting. METHODS: A matched case-control design was used in a clinic-based multicenter study of Australian prostate carcinoma subjects. Cancer subjects were matched by age and locality with controls, all of whom had a serum prostate specific antigen (PSA) level of less than 4 mg/L. Conditional logistic regression was used to determine the relative risk of prostate carcinoma dependent on AR gene CAG number. The association of disease characteristics at diagnosis with the polymorphism also was assessed. RESULTS: Five hundred forty-five cases of prostate carcinoma and 456 matched case-control pairs were recruited. Association studies of disease characteristics at diagnosis showed age at diagnosis to be associated with AR CAG number by univariate (P = 0.004) and multivariate (adjusting for PSA, stage, and grade) linear regression (P = 0.018). No association was observed between the polymorphism and disease stage (TNM-based categories; P = 0.277), histologic grade (P = 0.41), or PSA level at diagnosis (P = 0.48). In the pairwise case-control analysis, the odds ratio of prostate carcinoma for a change of 5 CAG repeats gave an odds ratio of 0.9821 (95% confidence interval, 0.84-1.15). CONCLUSIONS: In this Australian study population, the AR CAG repeat polymorphism was not a risk factor for prostate carcinoma, but a shorter repeat sequence was associated with earlier age at diagnosis. Copyright 2001 American Cancer Society.
UI - 21313755
AU - Macoska JA; Xu J; Ziemnicka D; Schwab TS; Rubin MA; Kotula L
TI - Loss of expression of human spectrin src homology domain binding protein 1 is associated with 10p loss in human prostatic adenocarcinoma.
SO - Neoplasia 2001 Mar-Apr;3(2):99-104
AD - Department of Surgery, The University of Michigan School of Medicine, Ann Arbor, MI 48109-0946, USA.
The gene encoding human spectrin Src homology domain binding protein 1, or Hssh3bp1, which is a marker of macropinocytic vesicles and a potential regulator of macropinocytosis, co-localizes to a YAC containing chromosome 10p sequences at loci D10S89 and D10S111 that are frequently deleted in prostate tumors. Expression of Hssh3bp1 was evaluated at the protein level in 17 paired normal and malignant prostate tumor samples using the monoclonal antibody 2G8 to Hssh3bp1. These experiments demonstrated that 4/6 tumors (67%) with 10p deletion failed to express Hssh3bp1 protein compared to 5/11 (46%) tumors with intact 10p. Thus, loss of Hssh3bp1 expression is concordant with allelic loss of adjacent 10p sequences in human prostate tumors. In addition, two prostate tumor cell lines contain an exon skipping mutation in the Hssh3bp1 gene that leads to the abnormal splicing of the mRNA and loss of a portion of Abl tyrosine kinase SH3 domain binding site in the protein. These data are consistent with a role for Hssh3bp1 as a candidate tumor suppressor gene inactivated during prostate tumorigenesis.
UI - 21423217
AU - Luscombe CJ; French ME; Liu S; Saxby MF; Jones PW; Fryer AA; Strange RC
TI - Outcome in prostate cancer associations with skin type and polymorphism in pigmentation-related genes.
SO - Carcinogenesis 2001 Sep;22(9):1343-7
AD - Department of Urology and. Clinical Biochemistry Research Laboratory, School of Postgraduate Medicine, North Staffordshire Hospital, Stoke-on-Trent, Staffordshire, UK.
Epidemiological studies have suggested that UV exerts a protective effect on prostate cancer. Accordingly, we determined, in 210 prostate cancer cases, whether parameters of exposure, skin type and polymorphism in MC1R, VDR and TYR were associated with the outcome parameters, histological grade, clinical stage and presence of bone metastases. We used logistic regression analysis, with correction for age and metastases, stage and grade in the models, to determine if the frequencies of individual factors were different in the patient groups. The development of metastases was not associated with UV exposure parameters. Paradoxically, patients with skin type 1 were at significantly reduced risk [P = 0.027, odds ratio (OR) 0.17, 95% CI 0.03-0.82] of developing metastases compared with cases with skin type 4. MC1R Val92/Val92 and VDR ff were associated with increased risk of metastases (ORs 4.30 and 4.98, respectively). Further, cumulative exposure (P = 0.005, OR 0.85/year) and increasing proportion of outdoor occupation (P = 0.001, OR 0.84/unit) were associated with reduced risk of advanced stage tumours. Skin types, MC1R or VDR genotypes were not significantly associated with advanced stage. None of the exposure parameters, skin types or genotypes were associated with tumour grade. While MC1R Val92/Val92 and VDR ff were only associated with bone metastases, TYR genotypes were associated with each of the outcome parameters. Thus, in logistic regression models that included age, but not advanced stage and high grade histology, TYR A1A2 was significantly associated with reduced risk of metastases (P = 0.033, OR 0.41). Similarly, in models that included age but not the other outcome parameters, associations between TYR A2A2 and high-grade and advanced stage were significant (P = 0.040, OR 0.41) or approached significance (P = 0.052, OR 0.44), respectively. These data indicate for the first time that pigmentation response to UV is associated with outcome in prostate cancer.
UI - 21423225
AU - Zhu W; Zhang JS; Young CY
TI - Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP.
SO - Carcinogenesis 2001 Sep;22(9):1399-403
AD - Department of Biochemistry and Molecular Biology, Mayo Graduate School, Mayo Clinic/Foundation, Rochester, MN 55905, USA.
A number of reports have shown that the polyphenolic flavonoid silymarin (SM) is an effective anticancer agent. Agents with novel mechanisms of blocking androgen receptor (AR) function may be useful for prostate cancer prevention and therapy. Previous studies showed that silibinin (SB), the major active component of SM, could inhibit cell proliferation of a human prostate cancer cell line, LNCaP, by arresting the cell cycle at the G(1) phase without causing cell death. This study further delineates the potential molecular mechanism by which SM and SB exhibit antiproliferative effects on androgen-responsive prostate cancer cells by inhibiting function of the AR. We observed that SM and SB inhibited androgen-stimulated cell proliferation as well as androgen-stimulated secretion of both prostate-specific antigen (PSA) and human glandular kallikrein (hK2). Additionally, for the first time, we show that an immunophilin, FKBP51, is androgen regulated and that this up-regulation is suppressed by SM and SB. We further demonstrate that transactivation activity of the AR was diminished by SM and SB using gene transfer of PSA promoter and hK2 androgen-responsive element constructs. However, expression and steroid-binding ability of total AR were not affected by SM in western blotting and ligand-binding assays. Intriguingly, we found that nuclear AR levels are significantly reduced by SM and SB in the presence of androgens using western blotting assay and immunocytochemical staining. This study provides a new insight into how SM and SB negatively modulate androgen action in prostate cancer cells.