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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The androgen receptor (AR) is involved in the development and progression of prostate cancer. In order to find new compounds that may present novel mechanisms to attenuate the function of AR, we investigated the effect of a natural flavonoid chemical, quercetin, on androgen action in an androgen-responsive LNCaP prostate cancer cell line. Western blot analysis showed that AR protein expression was inhibited by quercetin in a dose-dependent manner. To demonstrate that the repression effects on AR expression can actually reduce its function, we found that quercetin inhibited the secretion of the prostate-specific, androgen-regulated tumor markers, PSA and hK2. The mRNA levels of androgen-regulated genes such as PSA, NKX3.1 as well as ornithine decarboxylase (ODC) were down-regulated by quercetin. Transient transfections further showed that quercetin inhibited AR-mediated PSA expression at the transcription level. Finally, it was demonstrated that quercetin could repress the expression of the AR gene at the transcription level. Our result suggests that quercetin can attenuate the function of AR by repressing its expression and has the potential to become a chemopreventive and/or chemotherapeutic agent for prostate cancer.
Carcinogenesis 2001 Mar
PMID:Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. 1123 80

Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.
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PMID:Executive Summary of the National Cancer Institute Workshop: Highlights and recommendations. 1129 90

The androgen receptor (AR) and cognate ligands regulate vital aspects of prostate cellular growth and function including proliferation, differentiation, apoptosis, lipid metabolism, and secretory action. In addition, the AR pathway also influences pathological processes of the prostate such as benign prostatic hypertrophy and prostate carcinogenesis. The pivotal role of androgens and the AR in prostate biology prompted this study with the objective of identifying molecular mediators of androgen action. Our approach was designed to compare transcriptomes of the LNCaP prostate cancer cell line under conditions of androgen depletion and androgen stimulation by generating and comparing collections of expressed sequence tags (ESTs). A total of 4400 ESTs were produced from LNCaP cDNA libraries and these ESTs assembled into 2486 distinct transcripts. Rigorous statistical analysis of the expression profiles indicated that 17 genes exhibited a high probability (P>0.9) of androgen-regulated expression. Northern analysis confirmed that the expression of KLK3/PSA, FKBP5, KRT18, DKFZP564K247, DDX15, and HSP90 is regulated by androgen exposure. Of these, only KLK3/PSA is known to be androgen-regulated while the other genes represent new members of the androgen-response program in prostate epithelium. LNCaP gene expression profiles defined by two independent experiments using the serial analysis of gene expression (SAGE) method were compared with the EST profiles. Distinctly different expression patterns were produced from each dataset. These results are indicative of the sensitivity of the methods to experimental conditions and demonstrate the power and the statistical limitations of digital expression analyses.
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PMID:Digital expression profiles of the prostate androgen-response program. 1186 60

Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were reported to be associated with prostate cancer risk in families with hereditary prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC who underwent prostate cancer treatment and in 250 control subjects who participated in prostate cancer-screening programs and had normal digital rectal examination and PSA levels (<4 ng/ml). Significantly different allele frequencies between case subjects and control subjects were observed for each of the five variants (P value range.01-.04). Haplotype analyses provided consistent findings, with a significant difference in the haplotype frequencies from a global score test (P=.01). Because the haplotype that is associated with the increased risk for prostate cancer did not harbor any of the known rare mutations, it appears that the observed association of common variants and prostate cancer risk are independent of the effect of the known rare mutations. These results consistently suggest that MSR1 may play an important role in prostate carcinogenesis.
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PMID:Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. 1247 93

The present study was undertaken to develop a panel of human prostate cancer cell sublines that represent a phenotypic continuum of prostate carcinogenesis. We cloned and established more than two dozen LNCaP sublines from parental LNCaP cells by the limiting dilution method, akin to a fluctuation analysis, in vitro. The newly established LNCaP sublines differ in hormone-sensitivity, anchorage-independent growth ability and rate of PSA production. These LNCaP sublines may represent the naturally occurring heterogeneity in human prostate cancer and, therefore, could be useful for studying the effects of anticarcinogenic agents on cell clones that are derived from the same parental cell population.
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PMID:Establishment and characterization of sublines of LNCaP human prostate cancer cells. 1288 43

The failure of prostate cancer treatment is largely due to the development of androgen independence, since the androgen depletion therapy remains the front-line option for this cancer. Previously, we reported that over-expression of the helix-loop-helix protein Id-1 was associated with progression of prostate cancer and ectopic expression of Id-1 induced serum-independent proliferation in prostate cancer cells. In the present study, we investigated if exogenous Id-1 expression in the androgen sensitive LNCaP cells had any effect on androgen-dependent cell growth and studied the molecular mechanisms involved. Using stable Id-1 transfectants, we found that expression of Id-1 was able to reduce androgen-stimulated growth and S phase fraction of the cell cycle in LNCaP cells, indicating that Id-1 may be involved in the development of androgen independence in these cells. The Id-1-induced androgen-independent prostate cancer cell growth was correlated with up-regulation of EGF-R (epidermal growth factor-receptor) and PSA (prostate specific antigen) expression, as confirmed by western blotting analysis and luciferase assays. In contrast, down-regulation of Id-1 in androgen-independent DU145 cells by its antisense oligonucleotides resulted in suppression of EGF-R expression at both transcriptional and protein levels. In addition, the results from immunohistochemistry study showed that Id-1 expression was significantly elevated in hormone refractory prostate cancer tissues when compared with the hormone-dependent tumours. Our results suggest that up-regulation of Id-1 in prostate cancer cells may be one of the mechanisms responsible for developing androgen independence and this process may be regulated through induction of EGF-R expression. Inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of androgen-independent prostate cancer cell growth.
Carcinogenesis 2004 Apr
PMID:Id-1 expression induces androgen-independent prostate cancer cell growth through activation of epidermal growth factor receptor (EGF-R). 1468 27

The prostatic epithelium is functionally organized in stem cell units. This unit consists of a slow turn over stem cell within the basal epithelial layer which can replenish itself and provide progeny which differentiate down either a neuroendocrine or exocrine pathway. The maturation along the exocrine pathway initially involves transit amplifying cells within the basal layer proliferating and subsequently the progeny maturing into intermediate cells. These intermediate cells migrate into the luminal layer where they terminally differentiate into non-proliferative secretory luminal cells which express prostate specific differentiation markers, like PSA. A growing body of experimental evidence has identified the proliferating transit amplifying/intermediate cells as the cells of origin for the common prostatic adenocarcinomas. Using a series of growth characteristics, and mRNA and protein markers, we have validated that primary cultures can be established in serum free defined media from surgically resected human prostates which are composed of essentially pure population of transit amplifying cells. At each serial passage, the subsequent cultures undergo enhanced maturation into intermediate cells and by the 7-10th passage these cells eventually lose their proliferative ability. This study validates that these cells are a useful and relevant system for the determination of molecular events involved in prostatic carcinogenesis.
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PMID:In vitro culturing and characteristics of transit amplifying epithelial cells from human prostate tissue. 1468 91

Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000 prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemal et al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA (>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakr et al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scale clinical trial where all men entered the trial without an elevated PSA (<3 ng/ml) were subsequently biopsied, indicate the prevalence of histologic prostate cancer is much higher than anticipated by PSA screening. Environmental factors, such as diet and lifestyle, have long been recognized contributors to the development of prostate cancer. Recent studies of the molecular alterations in prostate cancer cells have begun to provide clues as to how prostate cancer may arise and progress. For example, while inflammation in the prostate has been suggested previously as a contributor to prostate cancer development [Gardner and Bennett, 1992; Platz, 1998; De Marzo et al., 1999; Nelson et al., 2003], research regarding the genetic and pathological aspects of prostate inflammation has only recently begun to receive attention. Here, we review the subject of inflammation and prostate cancer as part of a "chronic epithelial injury" hypothesis of prostate carcinogenesis, and the somatic genome and phenotypic changes characteristic of prostate cancer cells. We also present the implications of these changes for prostate cancer diagnosis, detection, prevention, and treatment.
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PMID:Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment. 1475 77

The prostatic membrane antigen (PSMA) is a protein that is expressed in the prostatic epithelium. We studied the expression of PSMA in a series of 55 patients with different stages of prostate cancer and we compared the PSMA staining in prostate cancer cells, in high-grade prostatic intraepithelial neoplasia (PIN) and in histologically benign prostatic epithelium for the same specimen. For this purpose archival paraffin-embedded specimens were studied by immunohistochemistry with a monoclonal antibody 7E11-C5.3 against PSMA using the streptavidin-biotin method. The mean percentage of PSMA immunoreactivity was 56.67% in prostate cancer (CaP) cells, and 48.6% in PIN cells, which was significantly higher than benign-appearing prostatic epithelium (5.72%) (for each pair, p<0.001). PSMA expression was greater in CaP with a higher Gleason score (p=0.01), but no relationship was found with serum PSA value. We conclude that PSMA overexpression is detected in high-grade PIN and is associated with a higher Gleason score of prostate cancer. It is a potential marker for studying carcinogenesis and progression of prostate cancer.
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PMID:Expression of prostate specific membrane antigen (PSMA) in prostatic adenocarcinoma and prostatic intraepithelial neoplasia. 1516 32

Tissue kallikreins are members of the S1 family (clan SA) of trypsin-like serine proteases and are present in at least six mammalian orders. In humans, tissue kallikreins (hK) are encoded by 15 structurally similar, steroid hormone-regulated genes (KLK) that colocalize to chromosome 19q13.4, representing the largest cluster of contiguous protease genes in the entire genome. hKs are widely expressed in diverse tissues and implicated in a range of normal physiologic functions from the regulation of blood pressure and electrolyte balance to tissue remodeling, prohormone processing, neural plasticity, and skin desquamation. Several lines of evidence suggest that hKs may be involved in cascade reactions and that cross-talk may exist with proteases of other catalytic classes. The proteolytic activity of hKs is regulated in several ways including zymogen activation, endogenous inhibitors, such as serpins, and via internal (auto)cleavage leading to inactivation. Dysregulated hK expression is associated with multiple diseases, primarily cancer. As a consequence, many kallikreins, in addition to hK3/PSA, have been identified as promising diagnostic and/or prognostic biomarkers for several cancer types, including ovarian, breast, and prostate. Recent data also suggest that hKs may be causally involved in carcinogenesis, particularly in tumor metastasis and invasion, and, thus, may represent attractive drug targets to consider for therapeutic intervention.
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PMID:Human tissue kallikreins: physiologic roles and applications in cancer. 1519 20


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