National Cancer Institute®
Last Modified: February 1, 2002
UI - 11734337
AU - Wang Q; Holmes DI; Powell SM; Lu QL; Waxman J
TI - Analysis of stromal-epithelial interactions in prostate cancer identifies PTPCAAX2 as a potential oncogene.
SO - Cancer Lett 2002 Jan 10;175(1):63-9
AD - Department of Cancer Cell Biology, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, W12 ONN, London, UK.
A PCR-based subtractive hybridisation technique was used to identify genes involved in stromal-epithelial interactions in prostate cancer. Eight genes were identified as being differentially expressed in benign prostatic fibroblast cells after stimulation with tumourigenic LNCaP conditioned media. One of these genes, protein tyrosine phosphatase CAAX2 (PTPCAAX2; also described as PTP4A and OV-1), has recently been shown to be oncogenic in hamster pancreatic epithelial cells. We show that PTPCAAX2 expression is up-regulated 4-fold in benign prostatic fibroblast cells 24 h after stimulation with LNCaP conditioned media and up-regulated 9-fold in prostatic tumour fibroblast cells. PTPCAAX2 overexpression was also detected in both androgen-dependent and androgen-independent prostate cancer cell lines and prostate tumour tissue, as determined by RT-PCR analysis and in situ hybridisation. These observations of PTPCAAX2 overexpression in prostate tumour cells and tissue suggest that PTPCAAX2 may potentially function as an oncogene in prostate cancer.
UI - 11788727
AU - Collis SJ; Sangar VK; Tighe A; Roberts SA; Clarke NW; Hendry JH;
TI - Margison GP Development of a novel rapid assay to assess the fidelity of DNA double-strand-break repair in human tumour cells.
SO - Nucleic Acids Res 2002 Jan 15;30(2):E1
AD - CRC Experimental Radiation Oncology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
Cellular survival following ionising radiation-mediated damage is primarily a function of the ability to successfully detect and repair DNA double-strand breaks (DSBs). Previous studies have demonstrated that radiosensitivity, determined as a reduction in colony forming ability in vitro, may be related to the incorrect repair (misrepair) of DSBs. The novel rapid dual fluorescence (RDF) assay is a plasmid-based reporter system that rapidly assesses the correct rejoining of a restriction-enzyme produced DSBs within transfected cells. We have utilised this novel assay to determine the fidelity of DSB repair in the prostate tumour cell line LNCaP, the bladder tumour cell line MGH-U1 and a radiosensitive subclone S40b. The two bladder cell lines have been shown in previous studies to differ in their ability to correctly repair plasmids containing a single DSB. Using the RDF assay we found that a substantial portion of LNCaP cells [80.4 +/- 5.3(standard error)%] failed to reconstitute reporter gene expression; however, there was little difference in this measure of DSB repair fidelity between the two bladder cell lines (48.3 +/- 3.5% for MGH-U1; 39.9 +/- 8.2% for S40b). The RDF assay has potential to be developed to study the relationship between DSB repair fidelity and radiosensitivity as well as the mechanisms associated with this type of repair defect.
UI - 11525289
AU - Thurman SA; Ramakrishna NR; DeWeese TL
TI - Radiation therapy for the treatment of locally advanced and metastatic prostate cancer.
SO - Hematol Oncol Clin North Am 2001 Jun;15(3):423-43
AD - Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Radiation therapy for locally advanced PCa continues to evolve. A current treatment recommendation for nonmetastatic, high-risk disease includes AS combined with RT. The precise duration and sequencing of AS has not been established but most frequently includes treatment in the neoadjuvant, concomitant and, occasionally, adjuvant periods. As technology allows higher doses without significant increases in morbidity and as clinical data provide proof of a radiation dose response, RT doses continue to escalate. The goal of therapy for metastatic disease continues to focus on the relief of pain and the improvement in quality of life. Multiple studies document the significant role RT plays in achieving these goals. Focal RT and systemic radioisotopes have become the mainstay of management in this patient group and the development of newer isotopes that cause less marrow toxicity will improve the therapeutic ratio and provide an opportunity for their use with systemic chemotherapy. As molecular and genomic technologies advance, directed targeting of critical cellular radiation-response pathways hold the promise of improved radiation response and individualized, tailored therapy.
UI - 11525293
AU - Ferrer FA; Rodriguez R
TI - Prostate cancer gene therapy.
SO - Hematol Oncol Clin North Am 2001 Jun;15(3):497-508
AD - The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland 21287-2101, USA.
Cancer-specific gene therapy is still in its infancy. Although the first gene therapy trials were initiated in the late 1980s, it was only more recently that the first successful treatment of a genetic disease was reported.3 The current problems with low efficiency of gene transfer coupled with the immunologic difficulties with certain vectors indicate that more effort needs to be directed at the basic science of gene transfer. Ultimately, successful cancer-specific gene therapy will require combinations of the lessons learned from the ex vivo and in vivo paradigms. The next generation of gene therapy trials likely will focus on combination therapy with conventional chemotherapeutic agents, differentiating agents, or radiation therapy. The obstacles to the development of gene-based human therapeutics (i.e., molecular medicine) are formidable, but the benefits are so great that eventually the technical issues of gene transfer methodology will be worked out, and ultimately this will become the standard of care, not only for inborn errors of metabolism, but also for cancer.
UI - 11525296
AU - Reese DM
TI - New agents for prostate cancer.
SO - Hematol Oncol Clin North Am 2001 Jun;15(3):547-57
AD - Department of Medicine, UCSF Comprehensive Cancer Center, University of California San Francisco, USA. email@example.com
Given the poor results with currently available therapies, it is imperative that new treatments be developed for patients with advanced prostate cancer. The next generation of therapies will include many novel biologic agents targeted at molecular defects in the cancer cell. Investigating the efficacy and safety of these compounds and evaluating their utility in combination with traditional therapies such as chemotherapy or radiotherapy are major goals of prostate cancer clinical research for the next decade.
UI - 11780394
AU - Yin L; Fu S; Wang X; Nanakorn T; Won J; Deisseroth A
TI - Sensitization of prostate cancer cell lines to 5-fluorocytosine induced by adenoviral vector carrying a CD transcription unit.
SO - Chin Med J (Engl) 2001 Sep;114(9):972-5
AD - Department of Pathophysiology, Shanghai Medical University, Shanghai 200032, China. firstname.lastname@example.org
OBJECTIVE: To investigate the efficiency of the cytosine deaminase adenoviral/5-fluorocytosine system on prostate cancer cell lines. METHODS: We used cell culture, infectivity and sensitivity tests, to observe bystander effect by animal tests. RESULTS: Established prostate cancer cell lines are eventually infectible by adenoviral vector. The ratio of vector/cell at which infection occurs depends on the specific cell line. The peak of expression of the transferred cytosine deaminase gene occurred in cells at different time, but persisted beyond 11 days. These prostate cell lines are sensitized to 5-fluorocytosine by infection with adenoviral vector carrying the cytosine deaminase gene. Only 5% of the LNCap and 10% of the RM-1 cells were infected and produced 100% cell death. In the animal test, there was significant inhibition of tumor growth at a ratio of 400 vector particles/cell with the systematic treatment of 5-fluorocytosine. CONCLUSIONS: Adenoviral vector carrying a cytosine deaminase transcription unit can sensitize prostate cancer cell lines to 5-fluorocytosine. The system can significantly inhibit the growth of prostatic tumors in mice.
UI - 11807954
AU - Hursting SD; Shen JC; Sun XY; Wang TT; Phang JM; Perkins SN
TI - Modulation of cyclophilin gene expression by N-4-(hydroxyphenyl)retinamide: association with reactive oxygen species generation and apoptosis.
SO - Mol Carcinog 2002 Jan;33(1):16-24
AD - Laboratory of Biosystems and Cancer, National Cancer Institute at Frederick, Frederick, Maryland, USA.
To explore the mechanisms underlying the pro-apoptotic effects of the synthetic retinoid N-4-(hydroxyphenyl)retinamide (4-HPR) on LNCaP human prostate cancer cells, we used the differential display-polymerase chain reaction (DD-PCR) technique to identify 4-HPR-responsive genes. RNA extracted from LNCaP cells that had been treated for 24 h with 4-HPR at a dose (2.5 microM) optimal for apoptosis induction was used for DD-PCR analysis using random primers. A differentially expressed 115 bp fragment was cloned and sequenced and then identified in GenBank as having a high degree of homology with several members of the cyclophilin gene family. Northern blot analyses using specific probes for cyclophilin A, cyclophilin D, and the cloned 115-bp fragment were performed on RNA extracted from LNCaP cells and MCF-7 human breast cancer cells treated with 4-HPR, N-acetylcysteine (NAC, an anti-oxidant), 4-HPR plus NAC, cyclosporin A, R-1881 (a synthetic androgen), dehydroepiandrosterone, all-trans retinoic acid, or prednisone. 4-HPR downregulated the transcript detected by the 115-bp fragment. Expression patterns detected by the 115-bp fragment and cyclophilin D probes were identical in response to each treatment; none of these treatments affected cyclophilin A expression. Furthermore, expression of mRNA transcripts detected by the 115-bp fragment and cyclophilin D probes correlated with the generation of reactive oxygen species (ROS), as detected by measurement of 2,7-dichlorofluorescein oxidation. Therefore, members of the cyclophilin gene family, such as cyclophilin D (a component of the mitochondrial permeability transition pore previously linked with oxidative stress and apoptosis), may play a role in the ROS-mediated apoptotic effects of 4-HPR. Published 2002 Wiley-Liss, Inc.
UI - 11501969
AU - Sampson ER; Yeh SY; Chang HC; Tsai MY; Wang X; Ting HJ; Chang C
TI - Identification and characterization of androgen receptor associated coregulators in prostate cancer cells.
SO - J Biol Regul Homeost Agents 2001 Apr-Jun;15(2):123-9
AD - Department of Pathology, and The Cancer Center, University of Rochester, NY, USA.
The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily that mediates the effects of androgens on target tissues. Over the last decade, it has become apparent that NRs require accessory factors for optimal activation of target gene expression. Numerous NR coregulators have been identified, with diverse structures and potential mechanisms of coregulation, creating an increasingly complicated picture of NR action. Due to the expanding complexity of the coregulator field, this review will focus on the AR ligand-binding domain (LBD) and N-terminal interacting proteins identified by our lab. The LBD-interacting proteins ARA70, ARA55 and ARA54 were first characterized and ARA70 was found to have a relatively higher specificity for the AR in human prostate cancer DU145 cells. Characterization of the functional relationship between the AR and these coregulators indicated that ARA70 and ARA55 could enhance the androgenic effects of 17beta-estradiol (E2) and hydroxyflutamide (HF), an antiandrogen commonly used in the treatment of prostate cancer. ARA160, an AR N-terminal interacting protein also known as TATA element modulatory factor (TMF), was subsequently shown to cooperate with ARA70 in enhancing AR activity. Another AR N-terminal interacting protein, ARA24, interacted with the poly-Q tract, a region within the N-terminus of the AR linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy). More recently, our lab has identified ARA267, a SET domain containing protein, and supervillin, an F-actin binding protein, as AR coregulators. Collectively, the data from these studies indicate that these coregulators are necessary for optimal AR transactivation. Interruption of the interaction between AR and these proteins may serve as a new therapeutic target in the treatment of prostate cancer.
UI - 11510986
AU - Culp LA; Holleran JL; Miller CJ
TI - Tracking prostate carcinoma micrometastasis to multiple organs using histochemical marker genes and novel cell systems.
SO - Histol Histopathol 2001 Jul;16(3):945-53
AD - Department of Molecular Biology and Microbiology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. email@example.com
Studies of human prostate carcinoma (PCA) have been hampered by only a few cell systems from already-metastatic human disease. We have developed a novel cell system by using tissue cultured CWR22R cells from a xenograft of a primary tumor from a human patient. These cells were transfected with the bacterial lacZ gene to maximize their detection during progression and metastasis in nude mice. LZ-CWR22R cells are extremely stable for lacZ expression over 25 passages and metastasize to lung, liver, and bone from the subcutis - major sites of metastasis of the human disease. A matrigel vehicle facilitated development of primary tumors and micrometastases in all organs. While some micrometastases developed into overt metastases, others remained as micrometastases for long periods of time, possibly providing a model of latency of metastatic disease. An experimental metastasis model (tail vein injection) also generated micrometastases in lung, liver, and bone with differing kinetics of formation and stability. Serial sections of many individual lung micrometastases within one hour of injection indicated considerable heterogeneity in cellular composition (from 1 to 19 cells/site) while liver sites at later times were comprised of only 1 or 2 cells (the size of bone sites were comparable to those of liver). By combining use of these histochemically-tagged PCA cell systems with high resolution molecular analyses (laser-capture microdissection), it will now be possible to analyze gene expression patterns characteristic of micrometastases developing in several different organs.
UI - 11519827
AU - Krupski T; Harding MA; Herce ME; Gulding KM; Stoler MH; Theodorescu D
TI - The role of vascular endothelial growth factor in the tissue specific in vivo growth of prostate cancer cells.
SO - Growth Factors 2001;18(4):287-302
AD - Department of Molecular Physiology and Biological Physics, University of Virginia, Health Sciences Center, Charlottesville, USA.
Despite the fact that cancer cells can be found in many vascular beds, continued growth of the metastatic tumor focus exhibits a significant degree of 'organ tropism', with only certain organs exhibiting the ravages of metastatic disease. Since a limiting factor to the growth of metastases beyond 2 mm in diameter, may be a lack of angiogenesis, we sought to determine whether tumor overexpression of vascular endothelial growth factor (VEGF), a potent angiogenic factor related to prostate cancer metastasis, is causally related to organ specific tumor growth in a prostate cancer xenograft model. LnCaP-C4-2 is a subline of the human prostate cancer cell line LnCaP which unlike its parent, has a predilection for growth in bone, a common site for human prostate cancer metastasis. LnCaP-C4-2, is tumorigenic when injected intrafemorally in mice but requires co-injection of stromal components (Matrigel) to be tumorigenic in the subcutaneous site. Because of this site-specific tumorigenicity profile and relatively low VEGF mRNA and protein expression, this line was transfected with a full length cDNA encoding the 165 isoform of VEGF. Cells either overexpressing or not expressing the transfected gene were selected for study in vivo and in vitro. Overexpression of VEGF did not seem to affect in vitro cell growth. Such overexpression did affect tumorigenicity and in vivo tumor growth rates when cells were inoculated in the subcutaneus site. Interestingly, the dependency of subcutaneous tumorigenicity on Matrigel co-inoculation was still observed in cells overexpressing VEGF. In contrast to the impact that VEGF overexpression has on subcutaneous tumorigenicity, no such effect was observed when cells were inoculated in orthotopic/prostate (primary) or intrafemoral (metastatic) sites. In view of the importance of tumor-stromal interactions in growth of xenografts, we sought to determine if the host strain is important to the observed tumorigenicity effects of VEGF overexpression. No differences in subcutaneous tumorigenicity as a function of either Matrigel use or VEGF expression levels were observed when SCID/bg and RAG/pfp mouse strains were compared. In conclusion, our data indicate that the biological impact of prostate tumor VEGF overexpression is organ/site specific, leading to the speculation that it may play a part in the observed organ tropism of metastatic spread. In addition, these results highlight the importance of the tumor microenvironment in determining the biological impact of transfected and overexpressed genes in the study of tumor biology.
UI - 11719283
AU - Gregory CW; He B; Wilson EM
TI - The putative androgen receptor-A form results from in vitro proteolysis.
SO - J Mol Endocrinol 2001 Dec;27(3):309-19
AD - Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Activation domains in the 114 kDa androgen receptor (AR) NH(2)- and carboxyl-terminal regions are thought to contribute to different extents to AR-mediated transactivation. We investigated using anti-peptide antibodies whether smaller AR forms that migrate like the previously described 87 kDa AR-A occur in vivo resulting in constitutive or increased gene activation. Immunoblots of prostate cancer and fibroblast cell culture extracts revealed 114 and 84 kDa AR forms. Antibody mapping indicated the 84 kDa AR lacked the ligand-binding domain and comigrated with the constitutively active AR fragment AR1-660. AR expressed in COS cells was 114 and 92 kDa. Migration of the 92 kDa AR was slightly slower than that of a 90 kDa expressed fragment that was designed to initiate at the second methionine (residue 189) and lacked the NH(2)-terminal FxxLF interaction sequence. The 92 kDa AR did not result from alternative initiation since it was observed when the second methionine was changed to alanine. Optimization of extraction conditions indicated that both 84 and 92 kDa forms resulted from in vitro proteolytic cleavage and that cleavage by caspase-3 could account for the 92 kDa form. The results suggest that AR forms with gel mobility similar to that of the previously described 87 kDa AR-A result from in vitro proteolytic cleavage of NH(2)- or carboxyl-terminal regions during cell extraction and storage and that smaller forms with increased transcriptional activity do not occur in vivo.
UI - 11693894
AU - Stern DF
TI - HER-2 testing in prostate carcinoma.
SO - Cancer J 2001 Sep-Oct;7(5):372-4
AD - Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
UI - 11693898
AU - Liu HL; Gandour-Edwards R; Lara PN Jr; de Vere White R; LaSalle JM
TI - Detection of low level HER-2/neu gene amplification in prostate cancer by fluorescence in situ hybridization.
SO - Cancer J 2001 Sep-Oct;7(5):395-403
AD - Department of Internal Medicine, University of California, San Francisco, USA.
PURPOSE: Although expression of the HER-2/neu oncogene has been correlated with tumor progression in prostate cancer, the biologic significance of detecting HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) or evidence for protein overexpression by immunohistochemistry (IHC) remains unclear. In this study, we directly compared HER-2/neu FISH and IHC to determine which may be more predictive of the response to trastuzumab. PATIENTS AND METHODS: Forty patients with prostate cancer were analyzed for gene amplification by FISH performed with HER-2/neu and chromosome 17 (CEP 17) DNA probes (Vysis). Protein expression was examined by immunofluorescence and by IHC using the DAKO HercepTest antibody protocol and a monoclonal antibody to Her-2/neu on archival paraffin sections. The patients included 30 men with primary tumors that were treated with radical prostatectomy. Of these, 15 demonstrated subsequent disease progression within 3 years. Five patients with prostatic intraepithelial neoplasia were tested, as were five with metastatic disease whose samples were obtained before androgen ablation therapy. RESULTS: None of the 30 primary prostate cancer specimens showed overexpression for HER-2/neu by immunofluorescence or by IHC with the DAKO protocol. One sample showed 3+ membrane expression with the monoclonal antibody. In contrast, low copy number gene amplifications (3-8 HER-2/neu signals/nucleus) were detected in 16 of 30 samples (53%) by FISH. Most amplified cells were diploid for CEP 17, demonstrating that amplification was not due to total cell aneuploidy. FISH and IHC determined that prostatic intraepithelial neoplasia samples were normal. Four of five (80%) metastatic samples were amplified for HER-2/neu by FISH. Nearly 70% of metastatic cancer cells among all five specimens demonstrated aneuploidy. A single lymph node metastasis showed 3+ membrane staining by IHC (DAKO). CONCLUSIONS: In contrast to breast cancer, FISH detects HER-2/neu amplification in a substantial proportion of prostate cancers that do not overexpress HER-2/neuby IHC. Although the biologic significance of this finding is uncertain, it has implications for the direction of current and planned clinical trials of trastuzumab in advanced prostate cancer, including determination of patient eligibility.
UI - 11785977
AU - Zhou Y; Toth M; Hamman MS; Monahan SJ; Lodge PA; Boynton AL; Salgaller
TI - ML Serological cloning of PARIS-1: a new TBC domain-containing, immunogenic tumor antigen from a prostate cancer cell line.
SO - Biochem Biophys Res Commun 2002 Jan 18;290(2):830-8
AD - Department of Molecular Medicine, Northwest Hospital, Suite 101, Bothell, Washington 98021, USA. firstname.lastname@example.org
Identifying immunogenic tumor antigens plays a critical role in developing efficient diagnostic and therapeutic strategies for treatment of cancer. Using a recently developed technology, serological identification of antigens by recombinant expression cloning (SEREX), we identified a total of 8 genes whose expression elicited antibody responses in prostate cancer patients. Of the 8 genes, 5 represented known genes in the GenBank database, 2 were previously uncharacterized genes, and 1 showed sequence homology to a mouse gene. The sequence feature and the expression of one of the novel genes, prostate antigen recognized and identified by SEREX (PARIS-1), are determined in this study. The PARIS-1 cDNA is 3257 bp in length and contains a complete open reading frame of 2751 bp encoding for a primary translation product of 917 amino acids. Using Northern blot hybridization assay, we detected a single species of approximately 3.3 kb PARIS-1 mRNA that is differentially expressed in prostate normal and cancer cells. Western blot analysis confirmed the expression of the PARIS-1 protein in these cells. Structure analysis revealed that PARIS-1 protein contains a TBC domain that is conserved in the family of cell cycle-regulatory and Rab GTPase-activating proteins (Rab-GAP). Thus, the PARIS-1 protein may play a role in regulation of cell differentiation and growth or represent a new member of the Rab-GAP family.
UI - 11782371
AU - Fan S; Ma YX; Wang C; Yuan RQ; Meng Q; Wang JA; Erdos M; Goldberg ID;
TI - Webb P; Kushner PJ; Pestell RG; Rosen EM p300 Modulates the BRCA1 inhibition of estrogen receptor activity.
SO - Cancer Res 2002 Jan 1;62(1):141-51
AD - Department of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
We previously reported that expression of the breast cancer susceptibility gene BRCA1 strongly inhibits the transcriptional activity of the estrogen receptor (ER-alpha) in human breast and prostate cancer cell lines but only weakly inhibits ER-alpha activity in cervical cancer cells (S. Fan et al., Science (Wash. DC), 284: 1354-1356, 1999). We now report that the ability of BRCA1 to repress ER-alpha activity correlates with its ability to induce down-regulation of the cellular levels of the transcriptional coactivator p300 in breast and prostate, but not in cervical cancer cells. On the other hand, BRCA1 failed to alter the expression of the CREB binding protein (CBP), the structural and functional homologue of p300, in any of these cell types. Ectopic expression of either p300 or CBP "rescued" (i.e., reversed) the BRCA1 inhibition of ER-alpha activity, whereas two other nuclear receptor coactivators, the p300/CBP-associated factor (PCAF) and the glucocorticoid receptor-interacting protein-1 (GRIP1), failed to rescue the ER-alpha activity. The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells. These findings suggest that the cofactors p300 and CBP modulate the ability of the BRCA1 protein to inhibit ER-alpha signaling. They further suggest that the BRCA1 inhibition of ER-alpha activity may be attributable, at least in part, to the down-regulation of p300.
UI - 11782385
AU - Kufer P; Zippelius A; Lutterbuse R; Mecklenburg I; Enzmann T; Montag A;
TI - Weckermann D; Passlick B; Prang N; Reichardt P; Dugas M; Kollermann MW; Pantel K; Riethmuller G Heterogeneous expression of MAGE-A genes in occult disseminated tumor cells: a novel multimarker reverse transcription-polymerase chain reaction for diagnosis of micrometastatic disease.
SO - Cancer Res 2002 Jan 1;62(1):251-61
AD - Institute of Immunology, University of Munich, 80336 Munich, Germany. email@example.com
Systemically disseminated tumor cells have become the subject of intensive research as the presumed seminal precursors of later distant metastasis. We describe here a novel sensitive multimarker nested reverse transcription (RT)-PCR capable of detecting the individual expression of human MAGE-A genes MAGE-1, -2, -3/6, -4, and -12 by rare, disseminated tumor cells in bone marrow and blood of patients with many different types of cancer. We analyzed bone marrow aspirates from 106 patients with breast, lung, colorectal, and prostate cancer and with different sarcomas. Heterogeneous expression of the different MAGE genes was found frequently in all those kinds of malignancies, in sharp contrast to 30 bone marrow and 20 blood samples from healthy donors, which were completely MAGE negative. Expression of at least one MAGE gene in bone marrow was more frequent than cytokeratin-positive tumor cells detected by immunocytochemistry, although the results of both tests overlapped considerably. In 30 patients with clinically localized prostate cancer, analysis by the multimarker MAGE RT-PCR of bilateral bone marrow aspirates from the right and left iliac crest revealed a positivity rate of 60%, which was twice as high as that obtained with either an established prostate-specific antigen RT-PCR or by cytokeratin-based immunocytochemistry. Analysis of primary prostate cancer revealed MAGE expression patterns considerably concordant with those found in the corresponding bone marrow aspirates. Prostate cancer patients carrying an exceptionally high risk of metastatic relapse, as defined by clinical prognostic factors, were significantly more often MAGE positive than patients with a distinctly lower risk (P = 0.02, Fisher's exact test). More frequent MAGE expression in the peripheral blood of patients with metastatic prostate cancer compared with those with clinically localized disease added further evidence for the prognostic impact of the multimarker MAGE RT-PCR. Moreover, MAGE-positive bone marrow samples from a small group of seven sarcoma patients demonstrated the relevance of our multimarker RT-PCR in nonepithelial tumors. Because MAGE antigens can induce autologous cytolytic T lymphocytes in vivo, the determination of individual MAGE expression patterns in cancer patients may furthermore identify candidate vaccine targets for adjuvant immunotherapy.
UI - 11782357
AU - Filippova GN; Qi CF; Ulmer JE; Moore JM; Ward MD; Hu YJ; Loukinov DI;
TI - Pugacheva EM; Klenova EM; Grundy PE; Feinberg AP; Cleton-Jansen AM; Moerland EW; Cornelisse CJ; Suzuki H; Komiya A; Lindblom A; Dorion-Bonnet F; Neiman PE; Morse HC 3rd; Collins SJ; Lobanenkov VV Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity.
SO - Cancer Res 2002 Jan 1;62(1):48-52
AD - Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
CTCF is a widely expressed 11-zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Because CTCF targets include oncogenes and tumor suppressor genes, we screened over 100 human tumor samples for mutations that might disrupt CTCF activity. We did not observe any CTCF mutations leading to truncations/premature stops. Rather, in breast, prostate, and Wilms' tumors, we observed four different CTCF somatic missense mutations involving amino acids within the ZF domain. Each ZF mutation abrogated CTCF binding to a subset of target sites within the promoters/insulators of certain genes involved in regulating cell proliferation but did not alter binding to the regulatory sequences of other genes. These observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function."
UI - 11802201
AU - Patel S; Turner PR; Stubberfield C; Barry E; Rohlff CR; Stamps A; Tyson
TI - K; Terrett J; Box G; Eccles S; Page MJ Hyaluronidase gene profiling and role of hyal-1 overexpression in an orthotopic model of prostate cancer.
SO - Int J Cancer 2002 Feb 1;97(4):416-24
AD - Oxford GlycoSciences, Abingdon Science Park, Abingdon, Oxfordshire, United Kingdom.
The mRNA levels of hyal-1, hyal-2, LUCA3 and PH20, the 4 hyaluronidases with demonstrated endoglucosaminidase activity, were extensively profiled in normal and tumor tissues and cell lines, using dot blot analysis and quantitative PCR. In normal tissues, hyal-1, hyal-2 and LUCA3 all showed unique patterns of mRNA expression, but were generally of widespread distribution, whereas PH20 mRNA was restricted to testes. In a small set of breast tumor samples, no elevations in hyal-1, hyal-2 or LUCA3 mRNA were seen. Hyaluronidase activity measured by a novel assay or zymography was also not elevated in sera from a number of breast cancer patients, compared to sera from normal volunteers. In ex vivo xenograft tumor cell lines, however, hyal-1 or hyal-2 mRNA levels were frequently elevated, whereas LUCA3 was only infrequently elevated and PH20 not at all. Two cell lines were engineered to overexpress hyal-1: a breast cancer line (CAL51) and a prostate cancer line (PC3M). Although the in vitro properties of the hyal-1 overexpressing cell lines were indistinguishable from the parental cells, the orthotopic growth of hyal-1 expressing PC3M cells in nu/nu mice resulted in significantly increased numbers of metastases, supportive of a role for hyal-1 in extravasation and metastatic tumor formation in this model of prostate cancer. Copyright 2001 Wiley-Liss, Inc.
UI - 11796315
AU - Platz EA; Krithivas K; Kantoff PW; Stampfer MJ; Giovannucci E
TI - ATAAA repeat upstream of glutathione S-transferase P1 and prostate cancer risk.
SO - Urology 2002 Jan;59(1):159-64
AD - Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
OBJECTIVES: Expression of glutathione S-transferase pi (GSTP1), a detoxification enzyme that also binds steroid hormones, is diminished or absent in human prostate tumors possibly because of promoter hypermethylation. Upstream of its promoter is a polymorphic ATAAA repeat of unknown functional significance. We evaluated whether this polymorphism is associated with prostate cancer. METHODS: Incident prostate cancer cases (n = 186) and controls (n = 398) were identified among participants in the Physicians' Health Study. DNA was extracted from peripheral whole blood, and the region encompassing the repeat was amplified using fluorescent-labeled primers. The fragments were run on polyacrylamide gels and sized by Genescan software. Alleles were designated by polymerase chain reaction fragment size. We estimated the relative risk of prostate cancer for the GSTP1 gene ATAAA alleles and genotype from logistic regression models controlling for age and cigarette smoking status. RESULTS: Fifteen GSTP1 ATAAA alleles were observed; C (19 repeats), G (21 repeats), and I (22 repeats) accounted for 80% among the controls. Compared with C, the relative risks for prostate cancer were 1.1 (95% confidence interval 0.7 to 1.7) for G and 0.8 (95% confidence interval 0.6 to 1.2) for I. The relative risks were also not statistically significantly elevated for the less common alleles. Compared with CC, the most common genotype, none of the other genotypes appeared to be associated with an increased risk of prostate cancer. CONCLUSIONS: The results of this study do not support an important role of the ATAAA repeat polymorphism upstream from the GSTP1 promoter in prostate cancer incidence.
UI - 11781655
AU - van der Poel HG; McCadden J; Verhaegh GW; Kruszewski M; Ferrer F;
TI - Schalken JA; Carducci M; Rodriguez R A novel method for the determination of basal gene expression of tissue-specific promoters: an analysis of prostate-specific promoters.
SO - Cancer Gene Ther 2001 Dec;8(12):927-35
AD - Brady Urologic Institute, Johns Hopkins Medical School, Baltimore, Maryland 21287, USA.
Because the toxicity of suicide gene therapeutics is directly related to basal promoter activity, we developed an assay to test for promoter "leakiness" using a diphtheria toxin mutant. Sequences of 15 prostate-specific gene promoter constructs were cloned in an expression plasmid (pBK; Stratagene, La Jolla, CA) backbone driving expression of an attenuated mutant of diphtheria toxin A (tox176). Low expression levels of the DT-tox176 result in significant protein synthesis inhibition reflected by a decreased expression of the luciferase activity of a simultaneously transfected CMV luciferase construct. ID50 (dose of plasmid with 50% luciferase inhibition) was calculated for each promoter construct in different cell lines. Highest transactivational activity (ID50 <75 ng) was found for the CMV promoter in all cell lines, which is in agreement with the dual luciferase assay findings. Unlike the dual luciferase findings, however, the DT-tox176 assay showed protein inhibition of CN65 (PSA promoter/enhancer) and PSE-hK2 (PSA enhancer and basal human kallikrein 2 promoter) in HEK293 and DLD cells indicating "leakiness" of these promoter constructs. Low basal promoter activity in nonprostate cell lines was found for the minimal PSA promoter, hK2, DD3, and OC promoters. The DT-tox176 assay can better predict basal promoter activity compared to less sensitive dual luciferase assay.
UI - 11795433
AU - Nelson WG; De Marzo AM; Deweese TL; Lin X; Brooks JD; Putzi MJ; Nelson
TI - CP; Groopman JD; Kensler TW Preneoplastic prostate lesions: an opportunity for prostate cancer prevention.
SO - Ann N Y Acad Sci 2001 Dec;952():135-44
AD - The Johns Hopkins Comprehensive Cancer Center, Baltimore, Maryland 21231-1000, USA. firstname.lastname@example.org
Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses.
UI - 11795434
AU - Brawley OW; Barnes S; Parnes H
TI - The future of prostate cancer prevention.
SO - Ann N Y Acad Sci 2001 Dec;952():145-52
AD - Office of the Director, National Cancer Institute, Bethesda, Maryland 20852, USA.
The dramatic international variation in prostate cancer mortality rates suggest an environmental influence. This combined with a building understanding of the genetic mechanisms of carcinogenesis encourages a search for ways to prevent it. Androgenic stimulation over a period of time has been suggested a cause of prostate cancer. The corollary to this hypothesis is that lowering androgenic stimulation over time will prevent prostate cancer. Decreasing androgenic stimulation of the prostate with 5-alpha-reductase inhibitors such as finasteride has been shown to decrease prostate size and may prevent prostate cancer. A large, long-term clinical trial is underway using finasteride to determine if it can prevent prostate cancer. Results are expected in 2004. Epidemiologic and laboratory studies also suggest that high selenium and vitamin E intake lowers risk of prostate cancer. Recent serendipitous findings of two randomized clinical trials support the hypothesis that selenium and vitamin administration will decrease prostate cancer risk. A study to assess these compounds is beginning. Other promising, but less developed, interventions in chemoprevention of prostate cancer include vitamin D supplementation and diet modification. All will need to be rigorously evaluated before they can be advocated for prostate cancer prevention.
UI - 11772238
AU - Mitsiades CS; Koutsilieris M
TI - Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer.
SO - Expert Opin Investig Drugs 2001 Jun;10(6):1099-115
AD - Department of Experimental Physiology, Medical School, University of Athens, 75 Micras Asias, Goudi 11527, Athens, Greece.
We review the extensive body of data on the molecular aetiology of hormone refractory disease in metastatic prostate cancer patients. Particular emphasis is placed on the crucial role of the bone micro-environment, especially the intercellular interactions of metastatic prostate cancer cells and osteoblasts in promoting the establishment of hormone refractory disease. Resistance of tumour cells to anticancer therapies is generally viewed as a phenomenon almost exclusively determined by chromosomal defects and/or gene mutations. However, it is now well-documented that the local milieu of the bone metastases can also protect tumour cells from anticancer therapy- induced apoptosis, either independently or synergistically with resistance-related genetic alterations. A key determinant of this protection is the urokinase/plasmin cascade which modulates the local concentration of survival factors, such as insulin-like growth factor (IGF-1). The molecular pathways whereby this major growth and survival factor for prostate cancer cells exerts its anti-apoptotic effect on prostate cancer cells are discussed.
UI - 11572417
AU - Barnholtz-Sloan JS; de Andrade M; Chakraborty R
TI - The impact of population admixture on traditional linkage analysis.
SO - Ethn Dis 2001 Autumn;11(3):519-31
AD - Karmanos Cancer Institute and Wayne State University, Integrated Biostatistics Unit, Detroit, Michigan 48201, USA. email@example.com
INTRODUCTION: Families of admixed ancestry are routinely excluded from traditional (Log of the Odds [LOD] score) linkage analysis or are analyzed as being derived from a homogeneous population using the proband's ethnicity. Using traditional linkage analysis with these families can cause complications due to the mixing of different disease rates and allele frequencies that occurs. The presence of admixture violates the key assumptions of Hardy-Weinberg Equilibrium (HWE) and Linkage Equilibrium (LE) invoked in the current methods of linkage analysis. If one or more of these assumptions are violated, incorrect inference for linkage could result. DESIGN AND METHODS: Through simulation, we investigated the effect of admixture of two populations on the LOD score under various conditions, using prostate cancer as our underlying disease model. Four-generation homogeneous and admixed families were simulated with 27 markers and two linked, bi-allelic disease loci. Two different types of admixture were tested: admixture within a family unit and a mixture of homogeneous families within a data set. All mixing was done at the founder level in three different proportions: 30/70, 50/50 and 70/30. RESULTS AND CONCLUSIONS: We observed that the LOD scores under both models of admixture were closest to the homogeneous family scores of the population having the highest mixing proportion. Random sampling of families or ascertainment of families with disease affection status did not affect this observation, nor did the mode of inheritance (dominant/recessive) or sample size. Thus, the presence of families of mixed population ancestry impacts linkage analysis in terms of the LOD score and the estimate of the recombination fraction.
UI - 11773976
AU - Kawakami K; Husain SR; Bright RK; Puri RK
TI - Gene transfer of interleukin 13 receptor alpha2 chain dramatically enhances the antitumor effect of IL-13 receptor-targeted cytotoxin in human prostate cancer xenografts.
SO - Cancer Gene Ther 2001 Nov;8(11):861-8
AD - Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
IL-13Ralpha2 chain, the primary interleukin-13 (IL-13) binding protein, plays an important role in IL-13 binding and internalization. Based on these findings, in our previous study we transiently transfected four cancer cell lines that do not express IL-13Ralpha2 chain and demonstrated that these cells acquired increased sensitivity to IL-13 receptor-targeted recombinant cytotoxin, IL13-PE38QQR, which is composed of IL-13 and a mutated form of a Pseudomonas exotoxin. Although some prostate cancer cell lines express functional IL-13R, they are not highly sensitive to IL-13 cytotoxin. Here we investigated whether human prostate cancer and normal prostate epithelial cell lines express IL-13Ralpha2 chain and whether they can be sensitized to the cytotoxic effect of IL-13 cytotoxin after transient or stable gene transfer of IL-13Ralpha2 chain. Gene transfer of IL-13Ralpha2 chain improved binding activity of IL-13 and sensitivity to IL-13 cytotoxin in vitro. In vivo experiments demonstrated that gene transfer of IL-13Ralpha2 chain dramatically enhanced the antitumor activity of IL-13 cytotoxin in human prostate cancer xenograft models. These results suggest that IL-13R-targeted cytotoxin therapy of prostate cancer may be dramatically enhanced by gene transfer of IL-13Ralpha2 chain and this strategy, the combination of gene therapy and cytotoxin therapy, may be utilized in the treatment of localized prostate cancer.