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PubMed2004

DNA methylation in prostate cancer.

Prostate cancer is the most common malignancy and the second leading cause of cancer death among men in the United States. There are three well-established risk factors for prostate cancer: age, race and family history. The molecular bases for these risk factors are unclear; however, they may be influenced by epigenetic events. Epigenetic events covalently modify chromatin and alter gene expression. Methylation of cytosine residues within CpG islands on gene promoters is a primary epigenetic event that acts to suppress gene expression. In tumorigenesis, the normal functioning of the epigenetic-regulatory system is disrupted leading to inappropriate CpG island hypermethylation and aberrant expression of a battery of genes involved in critical cellular processes. Cancer-dependent epigenetic regulation of genes involved in DNA damage repair, hormone response, cell cycle control and tumor-cell adhesion/metastasis can contribute significantly to tumor initiation, progression and metastasis and, thereby, increase prostate cancer susceptibility and risk. In this review, we will discuss current research on genes that are hypermethylated in human prostate cancer. We will also discuss the potential involvement of DNA methylation in age-related, race-related and hereditary prostate cancer, and the potential use of hypermethylated genes as biomarkers to detect prostate cancer and assess its risk.

Age Factors↗

PubMed1991

Prostate cancer.

Prostate cancer is the most common malignancy in men and the second leading cause of cancer deaths. Although the mortality rate for prostate cancer has remained unchanged for 50 years, new advances have changed classic concepts in the diagnosis and management of patients with this disease. Our understanding of the anatomy and natural history of patients with prostate cancer has been enhanced. The ability to diagnose early stage prostate tumors has been improved by the introduction of prostate-specific antigen and transrectal ultrasound. Clinical staging of patients with prostate cancer has been refined, which has decreased adverse effects of inappropriate treatment. Modifications in the technique of radical prostatectomy have minimized the morbidity associated with this procedure, making it a more attractive therapeutic option. DNA ploidy analysis holds promise as a predictor of response to hormonal therapy. New agents are available to reduce adverse effects of hormonal therapy. In addition, traditional ideas about the timing of hormonal therapy and the use of total androgen blockade are being challenged. These changes may presage an improved quality of life and improve survival for patients with prostate cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Molecular changes in prostatic cancer.

Prostate cancer is one of the most commonly diagnosed and potentially devastating cancers in men, throughout the world. However, the clinical manifestation of this disease varies greatly, from indolent tumours, requiring little or no treatment, to those aggressive cancers which require radical therapies. Prostate cancer, like all other cancers, develops and progresses as a consequence of an accumulation of genetic changes. While several putative genes have been isolated for the development of breast, ovarian and colon cancer, the aetiology and pathogenesis of prostate cancer remains poorly understood. In this review, we discuss important genetic markers in early, metastatic and hormone refractory prostate cancer which may, in the future, be used as markers for diagnosis and prognosis, as well as targets for therapeutic intervention.

Biomarkers, Tumor↗

PubMed2005

Chromosomal instability in peripheral blood lymphocytes and risk of prostate cancer.

Prostate cancer is an extremely complex disease, and it is likely that chromosomal instability is involved in the genetic mechanism of tumorigenesis. Several chromosomes have been labeled as "players" in the development of prostate cancer, among them chromosome 1 and X chromosome have been reported to harbor prostate cancer susceptibility loci. However, there is little information regarding the background levels of chromosome instability in these patients. In this pilot study, we examined spontaneous chromosome instability in short-term lymphocyte cultures from 126 study subjects, 61 prostate cancer patients, and 65 healthy controls. We evaluated chromosomal instability using a fluorescence in situ hybridization assay using two probes targeting specific regions on X chromosome and chromosome 1. Our results showed a significantly higher mean level of spontaneous breaks involving the X chromosome in patients compared with controls (mean +/- SE, 2.41 +/- 0.26 and 0.62 +/- 0.08, respectively; P < 0.001). Similarly, chromosome 1 spontaneous breaks were significantly higher among cases compared with controls (mean +/- SE, 1.95 +/- 0.24 and 1.09 +/- 0.16, respectively; P < 0.001). Using the median number of breaks in the controls as the cutoff value, we observed an odds ratio (95% confidence interval) of 15.53 (5.74 - 42.03; P < 0.001) for spontaneous X chromosome breaks and 3.71 (1.60 - 8.63; P < 0.001) for chromosome 1 breaks and risk of development of prostate cancer. In conclusion, our preliminary results show that spontaneous chromosome instability could be a risk factor for prostate cancer.

Aged↗

PubMed2003

Glycogen synthase kinase-3beta suppression eliminates tumor necrosis factor-related apoptosis-inducing ligand resistance in prostate cancer.

Prostate cancer is a major health threat for American men. Therefore, the development of effective therapeutic options is an urgent issue for prostate cancer treatment. In this study, we evaluated the effect of glycogen synthase kinase-3beta (GSK-3beta) suppression on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human prostate cancer cell lines. In the presence of lithium chloride (LiCl) or SB216763, the GSK-3beta inhibitors, TRAIL-induced cell death was dramatically enhanced, and the enhanced cell death was an augmented apoptotic response evidenced by increased Annexin V labeling and caspase-3 activation. GSK-3beta gene silencing mediated by a small interference RNA (siRNA) duplex also sensitized the cells to TRAIL, confirming the specificity of GSK-3beta suppression. Importantly, TRAIL stimulation increased GSK-3beta tyrosine phosphorylation at Y216, suggesting that GSK-3beta is activated by TRAIL. Furthermore, TRAIL sensitization was associated with increased proteolytic procession of caspase-8 and its downstream target BID, and z-IETD-FMK, the inhibitor specific to active caspase-8 totally blocked LiCl-induced TRAIL sensitization. Finally, Trichodion, a potent nuclear factor-kappaB (NF-kappaB) inhibitor, could not affect LiCl-induced TRAIL sensitization, although GSK-3beta inhibitors significantly blocked TRAIL-reduced NF-kappaB activity in prostate cancer cells. These results indicate that GSK-3beta suppression sensitizes prostate cancer cells to TRAIL-induced apoptosis that is dependent on caspase-8 activities but independent of NF-kappaB activation, and suggest that a mechanism involving GSK-3beta activation may be responsible for TRAIL resistance in prostate cancer cells.

Apoptosis↗

PubMed2002

G protein-coupled receptors provide survival signals in prostate cancer.

Prostate cancer is the leading cause for noncutaneous cancer-related deaths among men in the United States. The disease is biologically characterized as being either androgen dependent or androgen independent. Whereas androgen-dependent prostate cancer can be successfully treated with androgen ablative therapy, to date no cure exists for androgen-independent disease. Mechanisms involved in the progression of prostate cancer to androgen independence are not known. Here we present evidence that in addition to growth factor receptor tyrosine kinases, G protein- coupled receptors can mediate survival signals in prostate cancer cells. The G protein- coupled receptors exert their effects by activating multiple intracellular signal transduction networks that promote prostate cancer cell survival, including the activation of c-Jun N-terminal kinase, protein kinase B (Akt) and nuclear factor-kB. Prostate-expressed G protein- coupled receptors and their downstream effectors may prove to be effective targets in the treatment of advanced prostate cancer.

Cell Survival↗

PubMed2005

Role of mammalian lignans in the prevention and treatment of prostate cancer.

Prostate cancer is poised to become the most prevalent male cancer in the Western world. In Japan and China, incidence rates are almost 10-fold less those reported in the United States and the European Union. Epidemiological data suggest that environmental factors such as diet can significantly influence the incidence and mortality of prostate cancer. The differences in lifestyle between East and West are one of the major risk factors for developing prostate cancer. Traditional Japanese and Chinese diets are rich in foods containing phytoestrogenic compounds, whereas the Western diet is a poor source of these phytochemicals. The lignan phytoestrogens are the most widely occurring of these compounds. In vitro and in vivo reports in the literature indicate that lignans have the capacity to affect the pathogenesis of prostate cancer. However, their precise mechanism of action in prostate carcinogenesis remains unclear. This article outlines the possible role of lignans in prostate cancer by reviewing the current in vitro and in vivo evidence for their anticancer activities. The intriguing concept that lignans may play a role in the prevention and treatment of prostate cancer over the lifetime of an individual is discussed.

Animals↗

PubMed2003

Treatments for improving survival of patients with prostate cancer.

Prostate cancer is a heterogeneous disease characterised by a long natural history relative to other solid tumours. With the diagnosis of prostate cancer being made earlier, the emphasis of treatment has shifted from palliation of symptoms to altering disease-related morbidity and mortality and thus improving overall survival. Treatment of prostate cancer increasingly involves an approach that combines local therapies directed at the primary tumour together with systemic therapies to potentiate their effect and to control subclinical metastatic disease. Patients with localised tumours who are at high risk of relapsing with radiation therapy alone are surviving longer because of the addition of adjuvant hormonal therapy. Although a survival benefit in similar patients undergoing prostatectomy has not yet been established, preliminary results indicate that adjuvant hormonal therapy delays relapse. Chemotherapy is an effective palliative modality for patients with hormone- refractory metastatic disease, and recently completed phase III trials will determine if chemotherapy can prolong survival for this group. The role of chemotherapy in patients with locally advanced tumours is also being investigated in randomised clinical trials. Because bone is the dominant site of metastases for most patients with prostate cancer, the development of therapies that can slow tumour growth specifically within bone is a logical strategy. Bisphosphonates and bone-targeted radionuclides are two such approaches that have shown encouraging results even in the most advanced stages of the disease. Although one can now reasonably hypothesise that survival has improved because of recent therapeutic advances, it remains to be conclusively established that cytotoxic or other systemic therapy can extend survival of patients with prostate cancer. Only the results of ongoing randomised trials can definitely establish that more patients with locally advanced and metastatic prostate cancer are living longer.

Antineoplastic Agents, Hormonal↗

PubMed2002

Gene expression alterations in human prostate cancer.

Prostate cancer is a disease with a great degree of variation in biological aggressiveness and clinical prognosis. Although more than 30% of the older-aged male population develops prostate cancer, defined by histologic examination, a large number of these cases does not reach the stage displaying clinical symptoms. Among those patients with clinical prostate cancer, only a fraction of cases demonstrate life-threatening biological aggressiveness. Parallel to the clinical complexity of this disease, abnormalities in the prostate cancer genome have been reported in 21 of 23 pairs of human chromosomes, but none can be accountable for the dominant event in the development of prostate cancer. In order to understand the genetic nature of this disease, a comprehensive analysis of its gene expression patterns is needed. This article will review several recent publications in the area of gene expression analysis using microarray technology. I will discuss some of our findings in the area of gene expression alteration in benign prostate tissue adjacent to prostate cancer. The implication of these studies in potential clinical application will be explored.

Gene Expression Profiling↗

PubMedDate not supplied

Imaging of prostate cancer.

Prostate cancer diagnosis and treatment is fast emerging as a major health care issue in the United States. However, there are great uncertainties about the value of specific tests and therapies. Imaging modalities play a major role in the current management of patients with prostate cancer and this role is likely to expand in the future. Transrectal ultrasound is used to identify nonpalpable lesions, direct systematic biopsies, determine gland volume and stage prostate cancers. For staging skeletal metastases, the bone scan is acknowledged as the best method, however controversy surrounds its routine use in patients with low prostate specific antigen (PSA) values. Computed tomography (CT) and transrectal ultrasound have limited value in detecting extracapsular disease but CT can be used in conjunction with percutaneous biopsy to identify nodal metastases. The role of Endorectal coil MRI is currently evolving in the wake of a disappointing multi-institutional trial but MRI still holds the most promise for accurately detecting local extent of prostate cancer. New radiolabeled techniques with monoclonal antibodies and peptide imaging are also having early but promising results. The role of imaging in prostate cancer is continuing to evolve as technology and knowledge about prostate cancer biology improves and health care economics force a more judicious use of imaging resources.

Biopsy↗

PubMed2002

5alpha-reductase 2 polymorphisms as risk factors in prostate cancer.

Prostate cancer is a significant cause of death in Western countries and is under the strong influence of androgens. The steroid 5alpha-reductase 2 catalyzes the metabolism of testosterone into the more potent androgen dihydrotestosterone in the prostate gland. The enzyme is a target in pharmacological treatment of benign prostatic hyperplasia using specific inhibitors such as finasteride. Makridakis et al. have characterized the V89L and A49T polymorphisms in recombinant expression systems. The L allelic variant has a lower Vmax/Km ratio than the V variant. In the A49T polymorphism, the T variant has an increased Vmax/Km ratio. We performed a population-based case-control study of the impact of the SRD5A2 V89L and A49T polymorphisms on the risk of prostate cancer. We also studied the relation between the genotypes and age at diagnosis, tumor, node, metastasis stage, differentiation grade, prostate specific antigen and heredity. The study included 175 prostate cancer patients and 159 healthy controls that were matched for age. There was an association with SRD5A2 V89L LL genotype and metastases at the time of diagnosis, OR 5.67 (95% CI 1.44-22.30) when adjusted for age, differentiation grade, T-stage and prostate specific antigen. Heterozygous prostate cancer cases that carried the SRD5A2 A49T AT genotype were significantly younger than cases that carried the AA genotype, (mean age 66 years vs 71, P = 0.038). The SRD5A2 V89L and A49T polymorphisms were, however, not associated with altered prostate cancer risk. Further studies of the V89L polymorphism may lead to better understanding of the etiology of prostate cancer metastases.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2006

PSA-based vaccines for the treatment of prostate cancer.

Prostate cancer is the second leading cause of cancer-related death among men in the USA. Vaccine strategies represent a novel therapeutic approach. One potential target for a prostate cancer vaccine is prostate-specific antigen, owing to its restricted expression in prostate cancer and normal prostatic epithelial cells. A number of prostate-specific antigen-specific epitopes have been identified that can activate cytotoxic T lymphocytes and, in turn, result in the killing of tumor targets by the peptide-specific cytotoxic T lymphocytes. Strategies employed in clinical trials consist of dendritic cell vaccines, recombinant protein and recombinant DNA vaccines, as well as viral vector delivery of vaccines. New approaches incorporating a combination of a vaccine with traditional treatments for prostate cancer are also being investigated.

Cancer Vaccines↗

PubMed2005

The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer.

Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-dC). Of the 271 genes that were induced by 5-aza-dC treatment, 25 also displayed reduced expression in primary prostate tumors compared with normal prostate tissue, and the decreased expression of only one gene, aldehyde dehydrogenase 1 family, member A2 (ALDH1a2), was also associated with shorter recurrence-free survival. ALDH1a2 encodes an enzyme responsible for synthesis of retinoic acid (RA), a compound with prodifferentiation properties. By immunohistochemistry, we observed that ALDH1a2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1a2 promoter region was significantly hypermethylated in primary prostate tumors compared with normal prostate specimens (P = 0.01). Finally, transfection-mediated reexpression of wild-type ALDH1a2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 resulted in decreased colony growth (P < 0.0001), comparable with treatment with either 5-aza-dC or RA. Taken together, our findings implicate ALDH1a2 as a candidate tumor suppressor gene in prostate cancer and further support a role of retinoids in the prevention or treatment of prostate cancer.

Aldehyde Dehydrogenase↗

PubMed2003

Genetic factors underlying prostate cancer.

Prostate cancer is one of the leading causes of cancer-related death in the USA. In the past decade, tremendous progress has been made in the identification and understanding of the genetic factors related to prostate cancer development. Unlike many other types of cancers, only a small fraction of prostate cancer cases are aggressive and life-threatening. The factors related to prostate cancer development and progression appear complex and diverse. This review summarises some of the important findings in the areas of genome and gene expression abnormalities in prostate cancer, and aims to provide a comprehensive view of new developments in these areas.

Chromosome Aberrations↗

PubMed2003

Evaluation of vitamin D analogs as therapeutic agents for prostate cancer.

Prostate cancer cells contain specific receptors (VDR) for la,25-dihydroxyvitamin D (1alpha,25(OH)2D), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1alph,25(OH)2D for prostate cancer therapy. However, because 1alpha,25(OH)2D can cause hypercalcemia, analogs of 1alpha,25(OH)2D that are less calcemic but which exhibit potent antiproliferative activity would be attractive as therapeutic agents. We studied four vitamin D compounds: 25-hydroxyvitaminD3 [25(OH)D3], which is converted to 1alpha,25(OH)2D3 in prostate cells, and three analogs of 1alpha,25(OH)2D3: EB1089, 19-nor-1alpha,25(OH)2D2 and hexafluoro-1alpha,25(OH)2D3 (F6-1alpha,25(OH)2D3). 19-nor-1alpha,25(OH)2D2 has been shown to be less calcemic than 1alpha,25(OH)2D3 in clinical trials. F6-1alpha,25(OH)2D3 has been shown to be 100-fold more active than 1alpha,25(OH)2D3 and to be longer-lasting in inhibiting keratinocyte proliferation in vitro. EB1089 has been shown to be less calcemic than 1alpha,25(OH)2D3 in rats implanted with Leydig cell tumors. For 25(OH)D3, 19-nor-1alpha,25(OH)2D2 and F6-1alpha,25(OH)2D3, we studied the in vitro effects and compared their activity to 1alpha,25(OH)2D3 on cellular proliferation by 3H-thymidine incorporation assay. In addition, we studied transactivation of the VDR in the presence of 25(OH)D3 and 19-nor-1alpha,25(OH)2D2 in prostate cells. For EB1089, we compared its inhibition of prostate cancer metastasis to that induced by 1alpha,25(OH)2D3 in vivo in the rat Dunning MAT LyLu prostate cancer model. We found that 1alpha,25(OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar dose-dependent inhibition in 3H-thymidine incorporation into DNA in prostate cells and behaved similarly in the CAT reporter gene transactivation assay in PC-3/VDR cells. F6-1alpha,25(OH)2D3 is 10- to 50-fold more active than 1alpha,25(OH)2D3 in 3H-thymidine incorporation into DNA in the primary cultured prostate cells. Likewise, 25(OH)D3 had comparable antiproliferative activity to la,25(OH)2D3. In the rat model, tumor volumes and the number of metastases in the lungs were significantly reduced by both 1alpha,25(OH)2D3 (10.4 +/- 2.81 tumor foci) and EB1089 (7.7+/-1.29 tumor foci) compared to controls (22.7 +/- 1.98 tumor foci). Although serum calcium levels were significantly elevated in both 1alph,25(OH)2D3- and EB1089-treated rats, EB1089 was significantly less calcemic than 1alpha,25(OH)2D3 (12.59+/-0.21 mg/dl versus 14.47+/-.46 mg/dL; 1 microg/kg; p < 0.001). In conclusion, our data indicate that 25(OH)D3 and the three 1alpha,25(OH)2D analogs represent two different solutions to the problem of hypercalcemia associated with vitamin D-based prostate cancer therapies: 25(OH)D3 requires the presence of 25-hydroxyvitaminD-1alpha-hydroxylase, whereas 19-nor-1alpha,25(OH)2D2, F6-1alpha,25(OH)2D3 and EB1089 do not. These compounds may be good candidates for human clinical trials in prostate cancer.

Animals↗

PubMed2006

[Treatment possibilities for patients with advanced prostate cancer].

Prostate cancer is the second leading cause of cancer-related death in Switzerland as well as in other western countries. For patients with advanced disease, ablation of androgens is regarded as optimal first-line treatment. But this treatment is palliative with a median duration of response of about 18 months and hormone refractory prostate cancer remains a challenge. Last year, two large randomised trials demonstrated for the first time a survival benefit with docetaxel based therapy. Additionally, because of better understanding of the biology of hormone refractory prostate cancer a number of new systemic therapies are emerging. To evaluate their usefulness and to make progress in the therapy of this disease, it is essential to enrol prostate cancer patients in clinical trials. Another important issue are bone metastases because they are a significant cause of pain and morbidity in prostate cancer patients. Palliation of pain can be achieved with different means like radiation therapy, radioisotopes, hormonal therapy, chemotherapy, and bisphosphonates. For the optimal treatment of patients with symptomatic advanced prostate cancer a multidisciplinary approach is mandatory.

Antineoplastic Agents↗

PubMed2006

TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer.

Prostate cancer is a common and clinically heterogeneous disease with marked variability in progression. The recent identification of gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4 (17q21), suggests a mechanism for overexpression of the ETS genes in the majority of prostate cancers. In the current study using fluorescence in situ hybridization (FISH), we identified the TMPRSS2:ERG rearrangements in 49.2% of 118 primary prostate cancers and 41.2% of 18 hormone-naive lymph node metastases. The FISH assay detected intronic deletions between ERG and TMPRSS2 resulting in TMPRSS2:ERG fusion in 60.3% (35 of 58) of the primary TMPRSS2:ERG prostate cancers and 42.9% (3 of 7) of the TMPRSS2:ERG hormone-naive lymph node metastases. A significant association was observed between TMPRSS2:ERG rearranged tumors through deletions and higher tumor stage and the presence of metastatic disease involving pelvic lymph nodes. Using 100K oligonucleotide single nucleotide polymorphism arrays, a homogeneous deletion site between ERG and TMPRSS2 on chromosome 21q22.2-3 was identified with two distinct subclasses distinguished by the start point of the deletion at either 38.765 or 38.911 Mb. This study confirms that TMPRSS2:ERG is fused in approximately half of the prostate cancers through deletion of genomic DNA between ERG and TMPRSS2. The deletion as cause of TMPRSS2:ERG fusion is associated with clinical features for prostate cancer progression compared with tumors that lack the TMPRSS2:ERG rearrangement.

5' Untranslated Regions↗

PubMed2006

Urinary markers for prostate cancer.

Prostate cancer is the commonest solid-organ malignancy to affect men in Europe and the USA; it is estimated that one in six men will develop this cancer in their lifetime. Current screening relies on a digital rectal examination with a serum prostate-specific antigen test. Novel urinary diagnostic tests are potentially interesting screening tools for this disease. We examined published reports assessing the use of urinary markers for the diagnosis of prostate cancer. Using a PubMed-based search we identified studies of urinary markers for prostate cancer published from 1985 to February 2006 using the search terms 'urine', 'marker' and 'prostate cancer'. Studies to date have used small cohorts and relied on prostatic biopsies to provide histology. The sensitivity and specificity of markers are wide ranging but with only a few studies published on each putative marker it is difficult to assess their potential impact. Using urinary biomarkers for prostate cancer is a relatively novel diagnostic approach; they are appealing as a screening test because they are not invasive. Further work is needed to identify and validate 'signature markers' indicative of prostatic malignancy. The newer proteomic platforms are promising biomarker discovery tools that might uncover the next generation of urinary biomarkers.

Biomarkers, Tumor↗