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NCI CANCERLIT® Search: Prostate Cancer, Hereditary - October 2001
National Cancer Institute®
Last Modified: November 21, 2001
Table of Contents
1
UI - 21262941
AU - Rhee HW; Zhau HE; Pathak S; Multani AS; Pennanen S; Visakorpi T; Chung
TI -
LW
Permanent phenotypic and genotypic changes of prostate cancer cells
cultured in a three-dimensional rotating-wall vessel.
SO - In Vitro Cell Dev Biol Anim 2001 Mar;37(3):127-40
AD - Department of Urology, University of Virginia Health Sciences Center,
Charlottesville 22908, USA.
A three-dimensional (3D) integrated rotating-wall vessel cell-culture
system was used to evaluate the interaction between a human prostate
cancer cell line, LNCaP, and microcarrier beads alone, or microcarrier
beads previously seeded with either prostate or bone stromal cells. Upon
coculture of LNCaP cells with microcarrier beads either in the presence
or in the absence of prostate or bone stromal cells, 3D prostate
organoids were formed with the expected hormonal responsiveness to
androgen, increased cell growth, and prostate-specific antigen
production. In this communication, we define permanent phenotypic and
genotypic changes of LNCaP cells upon coculture with microcarrier beads
alone, or with microcarrier beads previously seeded with either prostate
or bone stromal cells. Most notably, we observed selective genetic
changes, i.e., chromosomal losses or gains, as evaluated by both
conventional cytogenetic and comparative genomic hybridization, in LNCaP
sublines derived from the prostate organoids. Moreover, the derivative
LNCaP cells appear to have altered growth profiles, and exhibit
permanent and stable changes in response to androgen, estrogen, and
growth factors. The derivative LNCaP sublines showed increased
anchorage-independent growth rate, and enhanced tumorigenicity and
metastatic potential when inoculated orthotopically in castrated athymic
mice. Our results support the hypothesis that further nonrandom genetic
and phenotypic changes in prostate cancer epithelial cells can occur
through an event that resembles "adaptive mutation" such as has been
described in bacteria subjected to nutritional starvation. The
occurrence of such permanent changes may be highly contact dependent,
and appears to be driven by specific microenvironmental factors
surrounding the tumor cell epithelium grown as 3D prostate organoids.
2
UI - 21385143
AU - Kasahara K; Taguchi T; Yamasaki I; Karashima T; Kamada M; Yuri K; Shuin
TI -
T
Fluorescence in situ hybridization to assess transitional changes of
aneuploidy for chromosomes 7, 8, 10, 12, 16, X and Y in metastatic
prostate cancer following anti-androgen therapy.
SO - Int J Oncol 2001 Sep;19(3):543-9
AD - Department of Urology, Kochi Medical School, Nankoku, Kochi 783-8505,
Japan.
There have been few detailed studies conducted on the cell population in
relation to cytogenetic changes between the pre- and post-treatment
periods in patients with prostate cancer. We investigated numerical
chromosome changes associated with anti-androgen therapy, using
fluorescence in situ hybridization (FISH). FISH using
chromosome-specific centromeric probes was used to assess transitional
changes in the frequency of aneuploidy for chromosomes 7, 8, 10, 12, 16,
X, and Y in prostate cancer during the pre- and post-treatment periods.
Gains of chromosomes 7, 8 and 12 were notable in the pre-treatment
samples (8 out of 9 cases in chromosome 7; 8 out of 9 cases in
chromosome 8; 7 out of 9 cases in chromosome 12), while a notable
reduction in the number of cells with extra copies of these chromosomes
was observed in post-treatment specimens. Other chromosomes did not show
noticeable change in their FISH signals at each phase of clinical
treatment in all 9 cases. Changes in cell number with high ploidies of
chromosome 7, 8 and 12 reflect the clinical effects of anti-androgen
therapy at the early phase, which might explain the androgen dependency
of metastatic prostate cancer cells.
3
UI - 21417714
AU - Gupta S; Hastak K; Ahmad N; Lewin JS; Mukhtar H
TI -
Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of
green tea polyphenols.
SO - Proc Natl Acad Sci U S A 2001 Aug 28;98(18):10350-5
AD - Department of Dermatology, Case Western Reserve University & The
Research Institute of University Hospitals of Cleveland, Cleveland, OH
44106, USA.
Development of effective chemopreventive agents against prostate cancer
(CaP) for humans requires conclusive evidence of their efficacy in
animal models that closely emulates human disease. The autochthonous
transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which
spontaneously develops metastatic CaP, is one such model that mimics
progressive forms of human disease. Employing male TRAMP mice, we show
that oral infusion of a polyphenolic fraction isolated from green tea
(GTP) at a human achievable dose (equivalent to six cups of green tea
per day) significantly inhibits CaP development and increases survival
in these mice. In two separate experiments, the cumulative incidence of
palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of
20). In these mice, 95% (19 of 20), 65% (13 of 20), 40% (8 of 20), and
25% (5 of 20) of the animals exhibited distant site metastases to lymph
nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol)
provided as the sole source of drinking fluid to TRAMP mice from 8 to 32
weeks of age resulted in (i) significant delay in primary tumor
incidence and tumor burden as assessed sequentially by MRI, (ii)
significant decrease in prostate (64%) and genitourinary (GU) (72%)
weight, (iii) significant inhibition in serum insulin-like growth
factor-I and restoration of insulin-like growth factor binding protein-3
levels, and (iv) marked reduction in the protein expression of
proliferating cell nuclear antigen (PCNA) in the prostate compared with
water-fed TRAMP mice. The striking observation of this study was that
GTP infusion resulted in almost complete inhibition of distant site
metastases. Furthermore, GTP consumption caused significant apoptosis of
CaP cells, which possibly resulted in reduced dissemination of cancer
cells, thereby causing inhibition of prostate cancer development,
progression, and metastasis of CaP to distant organ sites.
4
UI - 21418977
AU - Vogel W; Maier C; Paiss T
TI -
Prostate cancer and the problem of genotype phenotype correlation.
SO - Cytogenet Cell Genet 2001;93(3-4):162-7
AD - Department of Human Genetics, University of Ulm, Ulm, Germany.
walther.vogel@medizin.uni-ulm.de
5
UI - 21427668
AU - Burchardt M; Burchardt T; Shabsigh A; Ghafar M; Chen MW; Anastasiadis A;
TI -
de la Taille A; Kiss A; Buttyan R
Reduction of wild type p53 function confers a hormone resistant
phenotype on LNCaP prostate cancer cells.
SO - Prostate 2001 Sep 15;48(4):225-30
AD - The Department of Urology, The College of Physicians and Surgeons of
Columbia University, New York, USA.
BACKGROUND: The protein encoded by the p53 gene is required for some
forms of apoptosis and loss or mutations in this gene are found with
increased frequency in advanced and hormone resistant human prostate
cancers. In order to better appreciate whether reduction of wildtype p53
function in prostate cancer cells might contribute to the development of
therapeutic-resistance by these cells, we created stable variants of the
androgen-responsive, wild type p53-expressing human prostate cancer cell
line, LNCaP, by transfection with expression vectors designed to reduce
expression or function of wildtype p53 in them. These cells were then
tested for their ability to form tumors in castrated male nude mice.
METHODS: A conditional eukaryotic expression vector (under tetracycline
regulation) expressing antisense p53 cDNA was constructed and either
directly transfected into LNCaP cells or tranduced into these cells
using recombinant retroviruses containing the vector. Stably
transfected/transduced cells (LNCaP/Asp53) were evaluated by Western
blot analysis for the ability of doxycycline to reduce p53 protein
expression and for their ability to form tumors in castrated male nude
mice treated or untreated with doxycycline. Additionally, we derived an
LNCaP subline (LNCaP/DD) stably expressing a dominant-negative form of
p53 and tested these cells for their ability to form tumors in castrated
male nude mice. RESULTS: LNCaP/Asp53 cells showed reduced expression of
p53 protein when cultured in a medium containing doxycycline and tested
sublines were able to efficiently form tumors in castrated male nude
mice only when the mice were treated with doxycycline. LNCaP/DD cells
were readily able to form tumors in castrated male nude mice whereas
parental LNCaP cells or control-transfected LNCaP cells were not.
CONCLUSION: Loss of wildtype p53 function can contribute to the
phenotype of hormone resistance of prostate cancer cells. Copyright 2001
Wiley-Liss, Inc.
6
UI - 21427669
AU - Olsson P; Bera TK; Essand M; Kumar V; Duray P; Vincent J; Lee B; Pastan
TI -
I
GDEP, a new gene differentially expressed in normal prostate and
prostate cancer.
SO - Prostate 2001 Sep 15;48(4):231-41
AD - Laboratory of Molecular Biology, Division of Basic Sciences, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland
20892-4255, USA.
BACKGROUND: The database of human expressed sequence tags (dbEST) is a
potential source for the identification of tissue specific genes. The
database contains sequences that originate from cDNA libraries from
different tissues cell types and tumors. METHODS: Computer based
analysis identified a cluster of sequence homologous ESTs, containing
ESTs derived only from human prostate cDNA libraries. The tissue
specificity was examined by multiple tissue RNA dot blots and RT-PCR.
The new RNA transcript was characterized using northern blot analysis,
RACE-PCR, and a ribonuclease protection assay. RESULTS: We have
identified a gene differentially expressed in prostate using EST
database analysis and experimental studies. We name the gene GDEP for
gene differentially expressed in prostate. The major GDEP transcript is
about 520 bp long. GDEP RNA was detected in nine prostate tissue
samples, four normal and five cancer. Expression in prostate epithelial
cells was established by in situ hybridization. Weak expression was
detected in the prostate cancer cell line LNCaP. In vitro
transcription/translation indicate that the RNA encodes a small 34 amino
acid protein. The major transcript consists of two exons with one large
intron (> 15 kb). The GDEP gene was mapped to chromosome 4q21.1 by
radiation hybrid mapping. CONCLUSIONS: Our data proves that tissue
specific genes can be identified by EST database mining. The prostate
specificity of GDEP expression indicates that GDEP may be useful in the
diagnosis or treatment of prostate cancer. Published 2001 Wiley-Liss,
Inc.
7
UI - 21427671
AU - Kibel AS; Christopher M; Faith DA; Bova GS; Goodfellow PJ; Isaacs WB
TI -
Methylation and mutational analysis of p27(kip1) in prostate carcinoma.
SO - Prostate 2001 Sep 15;48(4):248-53
AD - Department of Surgery, Washington University School of Medicine, St.
Louis, Missouri 63105, USA. kibela@msnotes.wustl.edu
BACKGROUND: We have previously identified 12p12-13 as a region of
frequent genetic loss in prostate carcinoma. A candidate tumor
suppressor gene at this locus is the cyclin dependent kinase inhibitor
p27(kip1), which has been implicated as a marker of aggressive prostate
carcinoma. Herein, we examine metastatic prostate tumors, xenografts,
and cell lines for gene inactivation via mutational inactivation or
promoter hypermethylation. METHODS: Mutation analysis was performed on
metastatic prostate tumors of 18 patients, eight prostate carcinoma cell
lines, and 18 xenografts by PCR amplification of the entire open reading
frame of p27(kip1). PCR products were sequenced directly using internal
primers. Methylation analysis was performed on four cell lines and nine
xenografts using direct sequencing of cloned PCR products of bisulfite
treated DNA. Presence of a CpG was consistent with methylation of that
cytosine in the original sample. RESULTS: With the exception of the
previously reported homozygous deletion, no additional mutations were
identified. Methylated CpG residues were identified in three xenografts
(LuCAP23, LuCAP35, and PC82) and the methylated residues clustered at
six sites; the cytosines 69, 149, 191, 286, 349, and 487 base pairs 5'
of the ATG start codon. However, no sample demonstrated promotor
methylation in all sequenced clones and the number of methylated base
pairs ranged from seven to three, not the level usually associated with
gene silencing. CONCLUSIONS: Mutational inactivation of p27(kip1) is a
rare event in metastatic prostate carcinoma. While CpG methylation does
occur, it is an infrequent event and does not appear to be the mechanism
of p27(kip1) down regulation in prostate carcinoma. Copyright 2001
Wiley-Liss, Inc.
8
UI - 21427675
AU - Bonkhoff H; Fixemer T; Hunsicker I; Remberger K
TI -
Progesterone receptor expression in human prostate cancer: correlation
with tumor progression.
SO - Prostate 2001 Sep 15;48(4):285-91
AD - Institute of Pathology, University of the Saarland, Homburg/Saar,
Germany. pahbon@med-rz.uni-sb.de
BACKGROUND: The recent discovery of the classical estrogen receptor
alpha (ERalpha) in metastatic and recurrent prostatic adenocarcinoma
suggests that estrogens are implicated in prostate cancer progression.
METHODS: To get more insight into estrogen signaling in prostate cancer
tissue, the current study has examined the immunoprofile of the
estrogen-inducible progesterone receptor (PR), and evaluated its
relation to ERalpha gene expression. RESULTS: In primary tumors, the PR
was detectable in 36% of primary Gleason grade 3 (5 of 14 cases), 33% of
primary Gleason grade 4 (5 of 15 cases), and in 58% of primary Gleason
grade 5 tumors (7 of 12 cases). None of the 41 primary tumors
investigated revealed significant PR expression in more than 50% of
tumor cells. Conversely, moderate to strong receptor expression was
observed in 60% of metastatic lesions (9 of 15 cases), and in 54% of
androgen-insensitive tumors (38 of 71 cases). Irrespective of grades and
stages, the presence of the PR was invariably associated with high
steady state levels of ERalpha mRNA, whereas the ERalpha protein was
undetectable by immunohistochemistry (IHC) in a significant number of
cases (58 of 97 cases). CONCLUSIONS: The progressive emergence of the PR
during tumor progression obviously reflects the ability of metastatic
and androgen-insensitive tumors to use estrogens through a
ERalpha-mediated pathway. The present data provide a theoretical
background for studying the efficiency of antiestrogens and
antigestagens in the medical treatment of advanced prostate cancer.
Copyright 2001 Wiley-Liss, Inc.
9
UI - 21427676
AU - Peters MA; Janer M; Kolb S; Jarvik GP; Ostrander EA; Stanford JL
TI -
Germline mutations in the p73 gene do not predispose to familial
prostate-brain cancer.
SO - Prostate 2001 Sep 15;48(4):292-6
AD - Division of Clinical Research and Human Biology, Fred Hutchinson Cancer
Research Center, Seattle, Washington 98109-1024, USA. mpeters@fhcrc.org
BACKGROUND: Analysis of high-risk prostate cancer (PC) families with at
least one confirmed case of primary brain cancer (BC) has identified a
region of genetic linkage on chromosome 1p36 termed CAPB. The p36 region
of chromosome one has been reported to have frequent loss of
heterozygosity (LOH) in brain and central nervous system (CNS) tumors
and epidemiological studies have shown an increased relative risk of BC
and tumors of the CNS in PC families. In 1997 a reported tumor
suppressor with high homology to p53, termed p73, was mapped to the p36
region of chromosome one. Here, we examine the p73 gene as a potential
candidate for CAPB. METHODS: Ninety-four members from the 12
prostate-brain cancer families in which linkage was originally found
were examined. The complete coding region and intron-exon boundaries of
the p73 gene were analyzed for germline mutations by Single Stranded
Conformational Polymorphism analysis (SSCP) and direct DNA sequencing.
RESULTS: Silent nucleotide substitutions only were detected within the
coding regions of the gene in affected individuals. Nucleotide changes
were detected in introns 1, 6, 8, 9, and 10, but all were located >or=16
base pairs from the splice site, and are thus unlikely to be deleterious
mutations. CONCLUSIONS: Germline mutations in the p73 gene are unlikely
to be critical for inherited susceptibility to PC in this specified
subset of families. Copyright 2001 Wiley-Liss, Inc.
10
UI - 21427678
AU - Wu GJ; Varma VA; Wu MW; Wang SW; Qu P; Yang H; Petros JA; Lim SD; Amin
TI -
MB
Expression of a human cell adhesion molecule, MUC18, in prostate cancer
cell lines and tissues.
SO - Prostate 2001 Sep 15;48(4):305-15
AD - Department of Microbiology & Immunology, Emory University School of
Medicine, Atlanta, Georgia 30322, USA. wu@microbio.emory.edu
BACKGROUND: Over expression of huMUC18, a cell adhesion molecule in the
immunoglobulin gene superfamily, causes a non-metastatic human melanoma
cell line to become metastatic in a nude mouse system. To determine if
MUC18 expression correlates with the malignant progression of prostate
cancer, we investigated differential expression of human MUC18 (huMUC18)
in normal prostate epithelial cells, prostate cancer cell lines, and
prostatic normal and cancer tissues. METHODS: RT-PCR and Western blot
analyses were used to analyze the expression of MUC18 mRNA and protein
in four human prostate cancer cell lines, cultured primary normal
prostate epithelial cells, normal prostate and malignant prostate
tissues. Immunohistochemistry was used to determine the expression of
MUC18 antigen in prostatic tissues at different stages of malignancy.
RESULTS: Human MUC18 mRNA and protein was expressed in three different
prostate cancer cell lines (TSU-PR1, DU145, and PC-3), but not in one
prostate cancer cell line (LNCaP.FGC). HuMUC18 protein was also
expressed at high levels in extracts prepared from tissue sample
sections containing high grade prostatic intraepithelial neoplasia
(PIN), but weakly expressed in extracts prepared from either cultured
primary normal prostatic epithelial cells or the normal prostate gland.
Immunohistochemical analysis showed that huMUC18 was expressed at higher
levels in the epithelial cells of high-grade PIN and prostatic
carcinomas and in cells of a lymph node metastasis compared to that in
normal or benign hyperplastic epithelium (BPH). CONCLUSIONS: We
therefore conclude that MUC18 is expressed at higher levels in
pre-malignant and malignant prostatic epithelium, including metastasis.
We suggest that over-expression of MUC18 may be a new marker of human
prostate cancer and also implicates its possible role in development and
progression of prostate cancer. Copyright 2001 Wiley-Liss, Inc.
11
UI - 21439123
AU - Ghadersohi A; Sood AK
TI -
Prostate epithelium-derived Ets transcription factor mRNA is
overexpressed in human breast tumors and is a candidate breast tumor
marker and a breast tumor antigen.
SO - Clin Cancer Res 2001 Sep;7(9):2731-8
AD - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New
York 14263, USA.
PURPOSE: There is a need to identify novel breast tumor-associated
molecules with a potential as diagnostic/prognostic markers of breast
cancer as well as targets of vaccine and drug discovery against this
cancer. EXPERIMENTAL DESIGN: We used a combination of digital
differential display and reverse transcription-PCR (RT-PCR) methods to
identify breast tumor-associated cDNAs. RESULTS: It was found that
prostate epithelium-derived Ets transcription factor (PDEF) and five
other cDNAs occur at high frequency in the cDNA libraries from normal
human breast tissue and human breast tumors. In contrast, these cDNAs
are either undetectable or present at low frequencies in the cDNA
libraries from other normal human tissues. RT-PCR expression analysis of
PDEF showed it to be overexpressed in 14 of 20 primary human breast
tumors and in one metastases tested. Also, consistent with the digital
differential display data, RT-PCR analysis of PDEF expression showed
highly restricted expression in normal human tissues. Furthermore, we
show that PDEF transcript levels are 192-fold higher in the peripheral
blood of a breast cancer patient in comparison with two normal
individuals and another breast cancer patient. In contrast to PDEF,
RT-PCR analysis of the expression of the other three cDNAs, including
MYL5, Hs.44017, and Hs.215937, showed that these cDNAs are expressed in
several normal human tissues. CONCLUSIONS: These results suggest that
PDEF is a breast tumor-associated cDNA and should be further evaluated
for its potential as a breast tumor marker and a breast tumor antigen.
12
UI - 21439124
AU - Goode EL; Stanford JL; Peters MA; Janer M; Gibbs M; Kolb S; Badzioch MD;
TI -
Hood L; Ostrander EA; Jarvik GP
Clinical characteristics of prostate cancer in an analysis of linkage to
four putative susceptibility loci.
SO - Clin Cancer Res 2001 Sep;7(9):2739-49
AD - Department of Epidemiology, School of Public Health and Community
Medicine, University of Washington, Seattle, 98195-7236, USA.
PURPOSE: Hereditary prostate cancer is an etiologically heterogeneous
disease with six susceptibility loci mapped to date. We aimed to
describe a collection of high-risk prostate cancer families and assess
linkage to multiple markers at four loci: HPC1 (1q24-25), PCaP
(1q42.2-43), HPCX (Xq27-28), and CAPB (1p36). EXPERIMENTAL DESIGN:
Medical record data on 505 affected men in 149 multiply-affected
prostate cancer families were reviewed, and correlations of clinical
traits within each family were calculated. Logarithm of odds (LOD) score
and nonparametric (NPL) linkage analyses were performed; white families
were stratified by age of diagnosis, grade and stage of disease, and
evidence of linkage to the other loci to increase genetic homogeneity.
RESULTS: Age at diagnosis was the most correlated clinical trait within
families. A maximum NPL score of 2.61 (P = 0.007) appeared to confirm
HPC1 linkage for families that had a prevalence of high-grade or
advanced-stage prostate cancer and which were not likely to be linked to
PCaP, HPCX, or CAPB. Because the NPL scores improved when families more
likely to be linked to the other loci were excluded, HPC1 may act
independently of the other loci. The relationship of HPC1 and aggressive
disease was strongest in families with median age at diagnosis > or =65
years (NPL, 3.48; P = 0.0008). CONCLUSIONS: The current results suggest
that HPC1 linkage may be most common among families with more severe
prostate cancer. Stratification by clinical characteristics may be a
useful tool in prostate cancer linkage analyses and may increase our
understanding of hereditary prostate cancer.
13
UI - 21439150
AU - Hobisch A; Ramoner R; Fuchs D; Godoy-Tundidor S; Bartsch G; Klocker H;
TI -
Culig Z
Prostate cancer cells (LNCaP) generated after long-term interleukin 6
(IL-6) treatment express IL-6 and acquire an IL-6 partially resistant
phenotype.
SO - Clin Cancer Res 2001 Sep;7(9):2941-8
AD - Department of Urology, University of Innsbruck, Innsbruck A-6020,
Austria.
PURPOSE: The levels of interleukin-6 (IL-6) are frequently elevated in
sera from patients with advanced prostate carcinoma. Our main objective
was to investigate changes in responsiveness to IL-6 and/or androgen
that occur in LNCaP cells after long-term treatment with IL-6. This in
vitro model could be of clinical relevance because of its similarity
with late-stage prostate carcinoma. EXPERIMENTAL DESIGN: LNCaP human
prostate cancer cells were treated with IL-6 at a concentration of 5
ng/ml. After 20 passages, the new subline LNCaP-IL-6+ has been
established. Passages 20-40 are referred to as low passages (LP) and
passages 41-73 as high passages (HP). LNCaP cells passaged at the same
time in the absence of IL-6 were used as controls (LNCaP-IL-6-). Cells
were counted after treatment with either IL-6 or the synthetic androgen
methyltrienolone (R1881), and cell cycle analysis was performed. Binding
of IL-6 or R1881 was assessed by radioligand binding assays. Reporter
gene activity was measured by chloramphenicol acetyltransferase assay.
Prostate-specific antigen in LNCaP-IL-6+ supernatants was measured by an
enzyme immunoassay. Expression of IL-6 mRNA and protein was assessed by
reverse transcription-PCR and ELISA, respectively. RESULTS: The basal
proliferation rate in HP LNCaP-IL-6+ cells was higher than that in
LNCaP-IL-6- cells. IL-6 inhibited proliferation of LNCaP-IL-6- cells but
not that of either LP or HP of LNCaP-IL-6+ cells. This inability to
elicit a growth-inhibitory response was associated with lack of effect
on cell cycle distribution in the LNCaP-IL-6+ subline. In parallel, IL-6
binding decreased gradually during long-term IL-6 treatment and, in HP,
reached only 33% of the levels measured in controls. Binding of
radiolabeled androgen increased 2-fold in HP LNCaP-IL-6+ cells. Reporter
gene assays revealed that R1881, at nanomolar concentrations, was a more
potent androgen receptor activator in LNCaP-IL-6+ than in LNCaP-IL-6-
cells. However, androgen- and IL-6-induced prostate-specific antigen
secretion decreased in long-term IL-6-treated cells. IL-6 cDNA fragments
were detected by reverse transcription-PCR in HP LNCaP-IL-6+ cells but
not in controls or LP. IL-6 protein was first detected in passage 36 of
LNCaP-IL-6+ cells, and it increased in HP. CONCLUSIONS: Long-term
treatment of LNCaP human prostate cancer cells with IL-6 leads to
abolishment of inhibitory growth response. In contrast to control cells,
the LNCaP-IL-6+ subline expresses IL-6 mRNA and protein.
14
UI - 21455238
AU - Latil AG; Azzouzi R; Cancel GS; Guillaume EC; Cochan-Priollet B; Berthon
TI -
PL; Cussenot O
Prostate carcinoma risk and allelic variants of genes involved in
androgen biosynthesis and metabolism pathways.
SO - Cancer 2001 Sep 1;92(5):1130-7
AD - Center for Research into Prostate Pathologies, Evry, France.
a.latil@cerepp.org
BACKGROUND: Ethnicity, when it is used to mean shared genetic
inheritance within a group, has become one of the most important factors
in determining prostate carcinoma risk. Genetic polymorphisms were
hypothesized to be the probable explanation for differences in risk
among ethnic groups. The authors evaluated the association between
polymorphisms in genes involved in the androgen biosynthesis and
metabolism pathway and the risk of prostate carcinoma. METHODS: Two
hundred twenty-six patients with the pathologic diagnosis of sporadic
prostate tumor and 156 healthy matched (age, ethnic group) male controls
from a large epidemiologic cohort were genotyped for previously
described polymorphisms in the androgen receptor (AR), 5alpha-reductase
type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The
different polymorphisms in prostate carcinoma patients also were
analyzed according to age of onset, preoperative prostate-specific
antigen level, tumor stage, and tumor grade. RESULTS: The distribution
of the tetranucleotide simple tandem repeat polymorphism (STRP) in
intron 4 of CYP19 was significantly different in control and cancer
patients (P = 0.012). The 171 allele and the 187 allele were associated
with prostate carcinoma risk (P = 0.05 and P = 0.045, respectively).
Conversely, no association was observed between prostate carcinoma risk
and the other polymorphisms studied as follow: the CAG repeat in exon 1
of AR, the (TA)n dinucleotide repeat polymorphism in the 3' untranslated
region, and the A49T or V89L substitutions in SDR5A2, the single base
pair (bp) (a T to C transition) polymorphism that creates an additional
Sp1-type (CCACC box) promoter site in CYP17. In prostate carcinoma
patients, CAG repeats of AR, and TA repeats of SDR5A2 are associated
with age of onset (P = 0.05 and P < 0.001, respectively). CONCLUSIONS:
The association between the 171-bp allele of CYP19 and prostate
carcinoma risk suggests that aromatase could be used as a new indicator
for prostate carcinoma prevention in men of White French ethnogeographic
origin. Conversely, it is possible that an individual carries both a
high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2)
resulting in no overall difference in risk observed across the
population. For these reasons, the development of a polygenic model,
incorporating multiple loci from the individual genes may maximize the
chance of identifying individuals with high-risk genotypes. Copyright
2001 American Cancer Society.
15
UI - 21423022
AU - Ranganathan S; McCauley RA; Dexter DW; Hudes GR
TI -
Modulation of endogenous beta-tubulin isotype expression as a result of
human beta(III)cDNA transfection into prostate carcinoma cells.
SO - Br J Cancer 2001 Sep 1;85(5):735-40
AD - Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia,
PA 19111, USA.
Increases of individual beta tubulin isotypes in antimicrotubule drug
resistant cell lines have been reported by several laboratories. We have
previously described elevations in beta(III)and beta(IVa)isotypes in
estramustine and paclitaxel resistant human prostate carcinoma cells. To
investigate further the function of beta tubulin isotypes in
antimicrotubule drug response, human prostate carcinoma cells that
normally have very low to undetectable levels of beta(III)were stably
transfected with beta(III)cDNA in pZeoSV system. An 18 bp haemagglutinin
(HA) epitope tag was added at the 3' end prior to cloning into the
vector. Cells were transfected with pZeoSV or pZeoSV-beta(III)plasmids
and selected in the presence of Zeocin. Immunofluorescent staining of
the transfectant cells have shown significant expression and
incorporation of HA-tagged beta(III)tubulin into cellular microtubules.
Quantitation of Western blots revealed the HA-tagged beta(III)levels to
be approximately 7-fold higher than the vector control cells. RT-PCR
analysis confirmed the increase at the transcript level and also
revealed a collateral increase of beta(II)and beta(IVb)transcripts. Cell
viability assays indicated that sensitivity of beta(III)transfected
cells to various antimicrotubule agents was similar to vector
transfected cells: IC50 values for estramustine, paclitaxel, colchicine
and vinblastine were 4 microM, 4 nM, 22 nM and 2 nM, respectively for
both cell lines. Thus, overexpression of beta(III)isotype in human
prostate carcinoma cells by stable transfection failed to confer
antimicrotubule drug resistance to these cells. Counterregulatory
increases of endogenous beta(II)and beta(IVb)tubulin isotypes in these
beta(III)transfected cells may be a compensatory mechanism used by the
cells to overcome the effects of elevated beta(III)levels on the
cellular microtubules. These results highlight the difficulty in
isolating the contribution of single tubulin isotypes in drug response
studies. Copyright 2001 Cancer Research Campaign.
16
UI - 21262974
AU - Kanazawa M; Ogata Y; Aoyagi K; Stearns ME; Shirouzu K
TI -
Significance of cysteine rich transcription factor (CRTF) in the
synthesis of tissue inhibitor of metalloproteinases 1 (TIMP-1) in
gastrointestinal cancers.
SO - J Exp Clin Cancer Res 2001 Mar;20(1):145-51
AD - Dept. of Surgery, Kurume University School of Medicine, Fukuoka, Japan.
We previously reported that a novel promoter enhancer element "human
tissue inhibitors of metalloproteinases 1 (TIMP-1) enhancer" (HTE) and a
novel transacting protein "cysteine rich transcription factor" (CRTF)
induced TIMP-1 synthesis in prostate cancer cells 2xN.I.PC-3. In the
present study, to clarify the significance of CRTF in gastrointestinal
cancers we measured the binding activity of CRTF to HTE using an
electrophoretic mobility shift assay (EMSA), and the TIMP-1
concentration by ELISA after various stimulation of six cancer cell
lines (KE-3, TE-9, MKN-28, MKN-45, KM12SM, SW620). In three cell lines
(KE-3, MKN-45, SW620), both the binding activity of CRTF and TIMP-1
concentration significantly increased after IL-10 stimulation. Fetal
bovine serum (FBS) did not affect the binding activity of CRTF, whereas
FBS induced TIMP-1 synthesis in all cell lines. In KE-3 esophageal
cancer cells and SW620 colon cancer cells, both the binding activity of
CRTF and TIMP-1 concentration increased in the presence of a conditioned
medium (CM) of fibroblasts which was isolated from human colon cancer
tissues, but did not increase in MKN-45 cells. Moreover, in the
fibroblasts, both the binding activity of CRTF and the TIMP-1
concentration increased in the presence of CM from KM12SM, SW620, and
TE-9 cancer cell lines. These results suggested that IL-I0, and unknown
factors in addition to IL-10, induced TIMP-1 synthesis via an increase
in the binding activity of CRTF in gastrointestinal cancers, and that
interaction between cancer cells and fibroblasts may play an important
role in TIMP-1 synthesis through a signal transduction pathway
consisting of CRTF phosphorylation and HTE activation.
17
UI - 21291363
AU - Strom SS; Spitz MR; Yamamura Y; Babaian RJ; Scardino PT; Wei Q
TI -
Reduced expression of hMSH2 and hMLH1 and risk of prostate cancer: a
case-control study.
SO - Prostate 2001 Jun 1;47(4):269-75
AD - Department of Epidemiology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas 77030, USA.
BACKGROUND: Although prostate cancer is the most common incident cancer
in men, not much is known about its etiology. We tested the hypothesis
that expression levels of hMSH2 and hMLH1 in unaffected (normal) tissue
play a role in the etiology of prostate cancer. METHODS: Total RNA was
extracted from peripheral blood lymphocytes of subjects ascertained by a
case-control study (70 patients and 97 age- and ethnicity-matched
controls). A multiplex reverse transcription-polymerase chain reaction
assay was used to simultaneously evaluate the relative expression of
hMSH2 and hMLH1, using beta-actin as the internal control. RESULTS: The
relative gene expression levels of hMSH2 and hMLH1 were significantly
lower in cases than in controls (P < 0.05 for both genes). When compared
with the highest tertile of the controls, low expression levels (the
middle and lowest tertiles) of hMLH1 were associated with significantly
increased risk of prostate cancer in a dose-response relationship (ORs =
2.68, and 4.31; 95% confidence interval = 1.00-7.23 and 1.64-11.30,
respectively) after adjustment for age, ethnicity, smoking status, and
family history of prostate cancer. CONCLUSIONS: These results suggest
that reduced expression of hMLH1 in peripheral lymphocytes may be a risk
factor for prostate cancer. However, it cannot be ruled out that the
reduced expression we observed may be caused by the disease status. Our
findings and the factors that may affect the expression of hMLH1 need
further confirmation in larger prospective studies. Copyright 2001
Wiley-Liss, Inc.
18
UI - 21291364
AU - Tieva A; Stattin P; Wikstrom P; Bergh A; Damber JE
TI -
Gonadotropin-releasing hormone receptor expression in the human
prostate.
SO - Prostate 2001 Jun 1;47(4):276-84
AD - Institute of Surgical and Perioperative Sciences, Urology & Andrology,
Umea University, Umea, Sweden.
BACKGROUND: Inhibitory effects of gonadotropin-releasing hormone (GnRH)
analogs on prostate cancer cell proliferation, both in vivo and in
vitro, indicate the presence of specific binding sites for GnRH on
prostate cancer cells. To investigate this issue further, we examined
the expression of GnRH receptor (GnRH-R) mRNA and protein in human
prostate biopsies as well as in other extrapituitary tissues. METHODS:
The relative quantity of GnRH-R mRNA was determined by reverse
transcriptase-polymerase chain reaction (RT-PCR) and
immunohistochemistry (IHC) in human prostate biopsies. Extrapituitary
GnRH-R levels were determined by a semiquantitative PCR reaction.
RESULTS: Using PCR, a relatively high expression level of GnRH-R mRNA
was found in prostate tumor tissue followed by normal prostate, thymus,
and kidney expression levels. The levels showed by heart, brain,
placenta, lung, liver, skeletal muscle, pancreas, colon, ovary, small
intestine, spleen, and testis were low but detectable, whereas
peripheral blood leukocyte showed no demonstrable product. GnRH-R
immunoreactivity was localized in both luminal and basal epithelial
cells in benign and malignant prostate tissue, and GnRH-R were also
observed in intraprostatic lymphocytes. The relative GnRH-R mRNA levels
in prostate biopsies from 16 patients showed a wide range of individual
differences, but these differences were not related to histological
grade. Castration therapy did not significantly influence GnRH-R mRNA
expression in normal and malignant prostate tissue. CONCLUSIONS: These
results suggest that epithelial cells and infiltrating lymphocytes are
targets for GnRH action in the human prostate. Comparative data show
relatively high GnRH-R expression in human prostate tissue compared to
other human tissues. Copyright 2001 Wiley-Liss, Inc.
19
UI - 21369698
AU - Goodarzi G; Mashimo T; Watabe M; Cuthbert AP; Newbold RF; Pai SK; Hirota
TI -
S; Hosobe S; Miura K; Bandyopadhyay S; Gross SC; Balaji KC; Watabe K
Identification of tumor metastasis suppressor region on the short arm of
human chromosome 20.
SO - Genes Chromosomes Cancer 2001 Sep;32(1):33-42
AD - Department of Medical Microbiology and Immunology, Southern Illinois
University School of Medicine, Springfield, Illinois 62702, USA.
Acquisition of metastatic ability by prostate cancer cells is the
hallmark of their lethal trait and outcome. However, the genetic
alterations underlying the clinical progression and pathogenesis of
prostate cancer are not well understood. Several studies involving loss
of heterozygosity (LOH) and comparative genomic hybridization analysis
have identified distinctively altered regions on various human
chromosomes, and genomic imbalance of chromosome 20 was implicated in
progression and recurrence of prostate tumors. To examine the role of
chromosome 20 in prostate neoplasms, we introduced this chromosome into
highly metastatic rat prostate cancer cells using the microcell-mediated
chromosome transfer technique. Introduction of the chromosome resulted
in significant suppression of the metastatic ability of the hybrid
cells, by as much as 98%, without any interference with the in vivo
growth rate or tumorigenicity of primary tumor in SCID mice. Our STS-PCR
analysis on 10 hybrid clones indicates that the suppressor activity of
chromosome 20 is located in the p11.23-12 region. Further examination of
the hybrid clones by experimental metastasis assay and histologic
analysis as well as Matrigel invasion assay suggests the involvement of
the suppressor region at an early stage of invasion and extravasation.
We also investigated the status of the chromosome 20 suppressor region
in pathology specimens from human prostate cancer patients and detected
the frequent loss of this region in high-grade tumors. These results
suggest the presence of a putative suppressor gene on human chromosome
20 that is functionally involved in development of prostate cancer
metastases. Copyright 2001 Wiley-Liss, Inc.
20
UI - 21427142
AU - Andriani F; Nan B; Yu J; Li X; Weigel NL; McPhaul MJ; Kasper S; Kagawa
TI -
S; Fang B; Matusik RJ; Denner L; Marcelli M
Use of the probasin promoter ARR2PB to express Bax in androgen
receptor-positive prostate cancer cells.
SO - J Natl Cancer Inst 2001 Sep 5;93(17):1314-24
AD - Department of Medicine, Baylor College of Medicine, and VA Medical
Center, Houston, TX 77030, USA.
BACKGROUND: Adenovirus-mediated overexpression of the apoptosis-inducing
protein Bax can induce apoptosis in prostate cancer cell lines.
Constitutive overexpression of Bax could result in unwanted apoptosis in
every site of accidental Bax accumulation in vivo. Therefore, we
developed an adenoviral construct (Av-ARR2PB-Bax) in which the probasin
promoter, modified to contain two androgen response elements, drives Bax
expression. This promoter would be expected to limit expression of Bax
to cells expressing the androgen receptor. METHODS: A variety of
androgen receptor (AR)-positive and -negative cell lines of prostatic or
nonprostatic origin were infected with Av-ARR2PB-Bax or a control virus,
Av-ARR2PB-CAT, in which the same promoter drives expression of the
chloramphenicol acetyl transferase-reporter gene. Bax expression and
apoptosis in vitro were assessed by western blot analysis. Tumor size
and apoptosis in vivo were assessed after four weekly injections of
Av-ARR2PB-Bax or Av-ARR2PB-CAT into subcutaneous LNCaP xenografts
growing in uncastrated male mice. All statistical tests were two-sided.
RESULTS: Bax was overexpressed in an androgen-dependent way in
AR-positive cell lines of prostatic origin but not in AR-positive cells
of nonprostatic origin or in AR-negative cell lines of either prostatic
or nonprostatic origin. The androgen dihydrotestosterone activated
apoptosis in LNCaP cells infected with Av-ARR2PB-Bax but not in those
infected with Av-ARR2PB-CAT. Av-ARR2PB-Bax-injected LNCaP xenograft
tumors decreased in tumor size from 34.1 mm3 (95% confidence interval
[CI] = 25.1 mm3 to 43.1 mm3) to 24.6 mm3 (95% CI = -2.5 mm3 to 51.7
mm3), but the difference was not statistically significant (P =.5).
Tumors injected with Av-ARR2PB-CAT increased in size, from 28.9 mm3 (95%
CI = 12.7 mm3 to 45.1 mm3) to 206 mm3 (95% CI = 122 mm3 to 290 mm3) (P
=.002) and contained statistically significant more apoptotic cells
(23.3% [95% CI = 21.1% to 25.6%] versus 9.5% [95% CI = 8.0% to 11.1])
(P<.001). CONCLUSIONS: Av-ARR2PB-Bax induces androgen-dependent
therapeutic apoptosis in vitro and in vivo by activating apoptosis in
AR-positive cells derived specifically from prostatic epithelium and
does not affect nonprostatic cells.
21
UI - 21441842
AU - So MJ; Cheville JC; Katzmann JA; Riehle DL; Lohse CM; Pankratz VS; Sebo
TI -
TJ
Factors that influence the measurement of prostate cancer DNA ploidy and
proliferation in paraffin embedded tissue evaluated by flow cytometry.
SO - Mod Pathol 2001 Sep;14(9):906-12
AD - Swarthmore College, Swarthmore, Pennsylvania, USA.
DNA ploidy and proliferation have been shown in several studies to be
prognostic markers for prostate cancer. Flow cytometry (FCM) is often
used in the determination of ploidy and proliferation. However, FCM
cannot readily distinguish among benign epithelium, stromal and
inflammatory cells, high grade prostatic intraepithelial neoplasia
(HGPIN), and cancer cells. In this study, we evaluated H&E histologic
features of 322 radical prostatectomy formalin-fixed, paraffin-embedded
tissue blocks used for determining DNA ploidy, percent S-phase (%S), and
%S + %G2M by FCM. The microscopic findings included Gleason score,
extent of cancer and HGPIN in the tissue block, and presence of a needle
track. The amount of cancer in the block was expressed as a percentage
of the total tissue surface area in quartiles: < or =25%, 26-50%,
51-75%, and > or =76%. The extent of HGPIN was recorded in rough 5%
intervals. Needle track effect was defined as a combination of
fibrohistiocytic reaction, fibrin clot, granuloma formation, and chronic
inflammation. The associations between these histologic features and DNA
ploidy and proliferation (%S and %S + %G2M) were assessed. In
multivariate analyses, Gleason score, the amount of tumor in the tissue
block, and the extent of HGPIN were significantly associated with
ploidy. Gleason score was the only parameter significantly associated
with the proliferation measure of %S. If we included %G2M as part of the
proliferative fraction of the histogram, however, both Gleason score and
the amount of tumor in the block were significantly associated with this
measure of proliferation. The presence of a needle track was not
significantly associated with DNA ploidy, %S, or %S + %G2M. In summary,
prostate cancer DNA ploidy and proliferation results assessed by FCM in
paraffin-embedded tissue blocks were associated with the Gleason score,
amount of cancer in the tissue block, and extent of HGPIN. However, the
presence of a needle track was not associated with the FCM results.
22
UI - 21443291
AU - Warren P; Li L; Song W; Holle E; Wei Y; Wagner T; Yu X
TI -
In vitro targeted killing of prostate tumor cells by a synthetic
amoebapore helix 3 peptide modified with two gamma-linked glutamate
residues at the COOH terminus.
SO - Cancer Res 2001 Sep 15;61(18):6783-7
AD - Oncology Research Institute of the Greenville Hospital System,
Greenville, South Carolina 29605, USA.
Prostate-specific membrane antigen (PSMA) is a trans-membrane protein
specifically expressed in LNCaP cells, malignant human prostate tissues,
and the surrounding neovasculature. PSMA is a unique exopeptidase with
reactivity toward poly-gamma-glutamated folates. It can sequentially
remove the poly-gamma-glutamyl termini. To target prostate tumor cells,
a novel procytolytic peptide was designed with a backbone consisting of
an amoebapore H3 domain modified by two gamma-linked glutamate residues
at the epsilon-amino group of the COOH-terminal lysine residue. The
strategy behind the design of this prolytic peptide was to inactivate
the lytic amoebapore H3 peptide by replacing its functionally important
COOH-terminal positive charge with negatively charged groups, which in
turn might be selectively removed by the PSMA exopeptidase. This peptide
exhibited little cytolytic activity toward PSMA-negative cells, such as
PC-3 cells. On the other hand, this peptide exhibited strong cytolytic
activity toward PSMA-positive LNCaP cells in a concentration-dependent
manner. The carboxypeptidase inhibitor 4,4'-phosphonicobis
(butane-1,3-dicarboxylic acid) can inhibit this activity. Moreover, this
peptide also exhibited cytolytic activity toward PSMA cDNA-transfected
PC-3 cells.
23
UI - 21443293
AU - Xie X; Zhao X; Liu Y; Zhang J; Matusik RJ; Slawin KM; Spencer DM
TI -
Adenovirus-mediated tissue-targeted expression of a caspase-9-based
artificial death switch for the treatment of prostate cancer.
SO - Cancer Res 2001 Sep 15;61(18):6795-804
AD - Department of Immunology, Baylor College of Medicine, Houston, Texas
77030, USA.
Clinical experience with suicide gene therapy for prostate cancer using
first-generation approaches has provided a basis for developing improved
strategies. Given the low proliferation rate exhibited by prostate
cancer, one improvement would be to develop suicide genes that
effectively kill both dividing and nondividing cells. A second
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