Showing papers by "Peter S. Nelson published in 2006"
TL;DR: The concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia is supported.
Abstract: The greatest risk factor for developing carcinoma of the prostate is advanced age Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia
428 citations
TL;DR: Preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgens levels but appears to have little effect on prostate tissue androgen levels and cellular functions.
Abstract: ContextProstate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men.ObjectiveTo determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004.InterventionParticipants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months.Main Outcome MeasuresThe primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression.ResultsOf the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor.ConclusionsThese preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study.Trial Registrationclinicaltrials.gov Identifier: NCT00161304
378 citations
TL;DR: In identifying a profile of 86 genes that distinguish high- from low-grade carcinomas, this work has generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.
Abstract: Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17β4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high- from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.
282 citations
TL;DR: Despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20-30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected, highlighting the importance of assessing tissue hormone levels.
Abstract: Context: The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences. Objective: The objective of the study was to determine the effect of serum androgen manipulation on intraprostatic androgens in normal men. Design: Thirteen male volunteers ages 35–55 yr (prostate-specific antigen < 2.0 ng/ml; normal transrectal ultrasound) were randomly assigned to: 1) a long-acting GnRH-antagonist, acyline, every 2 wk; 2) acyline plus testosterone (T) gel (10 mg/d); or 3) placebo for 28 d. Serum hormones were assessed weekly. Prostate biopsies were obtained on d 28. Extracted androgens were measured by RIA, and immunohistochemistry for androgen-regulated proteins was performed. Results: The mean decrease in serum T was 94%, whereas prostatic T and dihydrotestosterone lev...
219 citations
TL;DR: It is concluded that the lack of a discernible phenotype in Tmprss2 −/− mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine Proteins 2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.
Abstract: Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2-/- mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2-/- mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2-/- mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2-/- mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.
204 citations
TL;DR: New evidence is presented that IGF‐IR signaling may modulate AR compartmentation and thus alter AR activity in prostate cancer cells and reveal the mechanisms of potential therapeutic effects of these antibodies on AI prostate cancers.
Abstract: The insulin-like growth factor type I receptor (IGF-IR) has been suggested to play an important role in prostate cancer progression and possibly in the progression to androgen-independent (AI) disease. The term AI may not be entirely correct, in that recent data suggest that expression of androgen receptor (AR) and androgen-regulated genes is the primary association with prostate cancer progression after hormone ablation. Therefore, signaling through other growth factors has been thought to play a role in AR-mediated prostate cancer progression to AI disease in the absence of androgen ligand. However, existing data on how IGF-IR signaling interacts with AR activation in prostate cancer are conflicting. In this Prospect article, we review some of the published data on the mechanisms of IGF-IR/AR interaction and present new evidence that IGF-IR signaling may modulate AR compartmentation and thus alter AR activity in prostate cancer cells. Inhibition of IGF-IR signaling can result in cytoplasmic AR retention and a significant change in androgen-regulated gene expression. Translocation of AR from the cytoplasm to the nucleus may be associated with IGF-induced dephosphorylation. Since fully humanized antibodies targeting the IGF-IR are now in clinical trials, the current review is intended to reveal the mechanisms of potential therapeutic effects of these antibodies on AI prostate cancers.
171 citations
TL;DR: It is suggested that T and/or its metabolites may help maintain the physiological balance of autoimmunity and protective immunity by preserving the number of regulatory T cells and the activation of CD8+ T cells.
Abstract: The higher prevalence of autoimmune disease among women compared with men suggests that steroids impact immune regulation. To investigate how sex steroids modulate cellular immune function, we cond...
142 citations
TL;DR: There is a correlation between an increased gradient of osteopontin expression throughout the stages of murine prostate cancer, beginning from the preneoplastic lesions to distant metastases that suggests a proliferative and invasive advantages to those prostate tumor cells overexpressing osteobontin.
Abstract: Osteopontin is a secreted glycosylated phosphoprotein known to be involved in numerous physiologic functions and associated with the late stages of various cancers. We used preneoplastic and neoplastic mouse models of prostate cancer to determine the onset of elevated expression of osteopontin in the development of this disease. Osteopontin alterations occurred early in the disease with dysregulated expression observed in lesions of low-grade prostatic intraepithelial neoplasia (PIN). Over time, osteopontin expressing dysplastic cells seemed to increase in number in high-grade PIN and increased further in adenocarcinoma, and in metastasis, almost all of the cancer cells immunohistochemically stained positive for osteopontin overexpression. We examined the biological properties of human prostate cancer cell lines LNCaP and PC-3, in which osteopontin overexpression was achieved via lentiviral gene transduction. Evidence was obtained that osteopontin could contribute to a proliferative advantage in both cell types, although more significantly in LNCaP than PC-3. Osteopontin also influenced their in vitro invasive ability, and again, most strikingly in the weakly oncogenic LNCaP. Furthermore, excess osteopontin induced the LNCaP cells to acquire a strong intravasation potential in vivo in the chicken embryo chorioallantoic membrane assay for blood vessel penetration. These results establish a correlation between an increased gradient of osteopontin expression throughout the stages of murine prostate cancer, beginning from the preneoplastic lesions to distant metastases that suggests a proliferative and invasive advantages to those prostate tumor cells overexpressing osteopontin. Together, these findings support a strategy designed to target osteopontin in the context of prostate cancer therapy.
118 citations
TL;DR: Molecular analyses of surgical samples should recognize that transcript alterations occur rapidly, and these results are important when designing and analyzing molecular correlates of clinical studies.
Abstract: Purpose Measurements of tissue gene expression are increasingly used for disease stratification, clinical trial eligibility, and assessment of neoadjuvant therapy response. However, the method of tissue acquisition alone could significantly influence the expression of specific transcripts or proteins. This study examines whether there are transcript alterations associated with surgical resection of the prostate gland by radical retropubic prostatectomy. Materials and Methods Twelve patients with clinically localized prostate cancer underwent immediate in situ prostate biopsy after induction of anesthesia for radical prostatectomy. Ex vivo prostate biopsies were performed immediately after surgical removal. Prostate epithelium was acquired by laser-capture microdissection, and transcript abundance levels were quantitated by cDNA microarray hybridization and confirmed by quantitative polymerase chain reaction. Data were analyzed by paired, two-sample t test using Statistical Analysis of Microarray algorithm...
111 citations
TL;DR: The utility of the LNCaP human PCa progression model as a tool to investigate the phenotypic changes required for the progression to AI and metastasis is demonstrated.
64 citations
TL;DR: The results indicate that although DNA sequence fixes boundaries for gene expression variability, there remain considerable latitudes of expression within these genome-defined limits that have the potential to influence phenotypes.
Abstract: Qualitative and quantitative variability in gene expression represents the substrate for external conditions to exert selective pressures for natural selection. Current technologies allow for some forms of genetic variation, such as DNA mutations and polymorphisms, to be determined accurately on a comprehensive scale. Other components of variability, such as stochastic events in cellular transcriptional and translational processes, are less well characterized. Although potentially important, the relative contributions of genomic versus epigenetic and stochastic factors to variation in gene expression have not been quantified in mammalian species. In this study we compared microarray-based measures of hepatic transcript abundance levels within and between five different strains of Mus musculus. Within each strain 23% to 44% of all genes exhibited statistically significant differences in expression between genetically identical individuals (positive false discovery rate of 10%). Genes functionally associated with cell growth, cytokine activity, amine metabolism, and ubiquitination were enriched in this group. Genetic divergence between individuals of different strains also contributed to transcript abundance level differences, but to a lesser extent than intra-strain variation, with approximately 3% of all genes exhibiting inter-strain expression differences. These results indicate that although DNA sequence fixes boundaries for gene expression variability, there remain considerable latitudes of expression within these genome-defined limits that have the potential to influence phenotypes. The extent of normal or expected natural variability in gene expression may provide an additional level of phenotypic opportunity for natural selection.
TL;DR: Fifteen human tissue kallikrein genes have been identified as a cluster on chromosome 19 and noncoding RNAs such as PCA3/DD3 and PCGEM1 has been identified in prostate cancer cells.
Abstract: BACKGROUND
Fifteen human tissue kallikrein (KLK) genes have been identified as a cluster on chromosome 19. KLK expression is associated with various human diseases including cancers. Noncoding RNAs such as PCA3/DD3 and PCGEM1 have been identified in prostate cancer cells.
METHODS
Using massively parallel signature sequencing (MPSS) technology, RT-PCR, and 5′ rapid amplification of cDNA ends (RACE), we identified and cloned a novel gene that maps to the KLK locus.
RESULTS
We have characterized this gene, named as KLK31P by the HUGO Gene Nomenclature Committee, as an unprocessed KLK pseudogene. It contains five exons, two of which are KLK-derived while the rest are “exonized” interspersed repeats. KLK31P is expressed abundantly in prostate tissues and is androgen regulated. KLK31P is expressed at lower levels in localized and metastatic prostate cancer cells than in normal prostate cells.
CONCLUSIONS
KLK31P is a novel androgen regulated and transcribed pseudogene of kallikreins that may play a role in prostate carcinogenesis or maintenance. Prostate 66: 936–944, 2006. © 2006 Wiley-Liss, Inc.
TL;DR: The data show that estrogens have powerful inhibitory effects on CaP in vivo in androgen-depleted environments and suggest novel mechanisms of estrogen-mediated antitumor activity, indicating that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.
01 Jan 2006
TL;DR: This review describes approaches that use cell type-specific analysis methods to identify cancer-associated features with the potential of distinguishing individuals with cancer of the prostate.
Abstract: Cancers of the prostate contribute substantial morbidity and mortality to the male population. The correlation of prostate cancer incidence with aging suggests that the disease burden associated with prostate carcinoma will increase dramatically over the next several decades. Despite the large number of fatalities directly linked to prostate cancer, most men harboring the disease will die of other causes. This fact poses substantial dilemmas for screening programs designed to diagnose cancers at an early stage, as the optimal approach also would provide guidance as to which cancers could or should be observed, versus those malignancies that require curative therapy, and whether localized treatments are sufficient or if additional systemic interventions are indicated. To address these issues, substantial resources have been focused on the identification of biomarkers capable of specifically and sensitively diagnosing prostate cancers and providing prognostic information. However, the discovery and use of biomarkers must contend with the complexity and heterogeneity of body fluids and tissues. This review describes approaches that use cell type-specific analysis methods to identify cancer-associated features with the potential of distinguishing individuals with cancer of the prostate.
TL;DR: Current data indicate that testosterone replacement therapy is being increasingly administered to aging men without apparent harm, and the responsible physician must be aware of the potential effects of testosterone on the prostate, especially as a promoter of carcinoma.
Abstract: Purpose of reviewIn aging men testosterone supplementation, or replacement therapy, is rapidly increasing. Herein we review classic and recent literature regarding the main safety issue: potential adverse effects on the prostate gland. Recent findingsThe advent of transdermal testosterone administration and increasing awareness of the ‘andropause’ syndrome have led to a dramatic upsurge in testosterone replacement therapy over the past decade. Prostatic hyperplasia and carcinoma are common in men who are candidates for treatment. Known or suspected carcinoma is an absolute contraindication to testosterone replacement therapy, but much prostate disease is undiagnosed. Data from testosterone replacement therapy trials and endogenous hormone studies appear to show only a theoretical safety concern, but a recent paper from the Baltimore Longitudinal Aging Study implicates free testosterone levels as a risk factor. Screening for prostate disease by symptoms, gland palpation, and prostate specific antigen testing are recommended before starting testosterone replacement therapy and at 3, 6, and 12-month intervals thereafter. SummaryCurrent data indicate that testosterone replacement therapy is being increasingly administered to aging men without apparent harm. A definitive safety trial, however, has not yet been performed. Pending that study, the responsible physician must be aware of the potential effects of testosterone on the prostate, especially as a promoter of carcinoma, and be knowledgeable about prostatic symptoms, digital rectal exam, and serum prostate specific antigen levels.