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PubMed1999

[Epidemiology of prostatic cancer].

Prostate cancer is the most common type of cancer in Norway, with more than 2,400 new cases each year. Hormones, diet, and chemical and genetic factors are implicated in the aetiology. It is not clear whether alcohol and tobacco increase the risk of prostate cancer. Median age at diagnosis is 74-75 years. The incidence has increased steadily with a doubling of the number of cases over 20-25 year periods. Prostate cancer mortality in Norway is the highest among the Nordic countries and among the highest in the world. Five-year relative survival for all cases combined is 60%. Approximately 55-60% of the patients dies from the disease. The incidence is lower in the three northernmost counties. Elsewhere in the country the incidence varies between counties according to variations in diagnostic practice. Serological analysis of Prostate Specific Antigen after 1990 has lead to an increase in the number of new cases, mainly because of earlier diagnosis. Prostate cancer is often a slowly growing tumour which is clinically asymptomatic for many years. Latent carcinoma is found at autopsy in 30-35% of men above 50 years of age. Today, prevention of prostate cancer is not feasible, though specific advice about life style and diet might decrease the risk.

Adult↗

PubMed2000

[Diet probably plays an important role in the development of prostatic cancer].

Prostate cancer is the most common malignant disease in Sweden and the most common cause of cancer-related death among Swedish men. There is, however, a wide geographical variation in the age-standardized incidence and mortality rates. The highest incidence is found in north-western Europe and the US and the lowest in the Asian countries. The reasons for these discrepancies are thought to be related to environmental factors such as variations in dietary pattern. High intake of calories, high Body Mass Index, and consumption of animal fat are all associated with an increased risk of prostate cancer, while high intake of soy and other phytoestrogens, selenium, vitamin A and high serum levels of vitamin D are associated with low risk. As well, gonadal hormones and growth factors are believed to be involved in the complex etiology of prostate cancer. Genetic factors play an important role in the development of prostate cancer, and a hereditary form of the disease, accounting for approximately 5-10% of cases, has been identified. In order to develop effective preventive strategies to reduce prostate cancer mortality and morbidity, it is necessary to expand our knowledge about the etiology of this common disease.

Age Factors↗

PubMed2005

[Nutrition and physical activity in prevention of prostate cancer].

Prostate cancer is one of the most common cancers among Polish men. The precise causes of prostate cancer remain unclear. Apart from age, ethnic origin and genetic factors, also diet and physical activity level seem to be important. This paper presents actual opinions on the role of nutrition and physical activity in the primary prevention of prostate cancer. According to scientific investigation lifestyle modification may be a promising strategy in prostate cancer prevention. However, the present evidence for elaborating clear recommendations is still insufficient.

Humans↗

PubMed2002

Androgen receptor as a target in androgen-independent prostate cancer.

Prostate cancer is dependent on androgen stimulation mediated by the androgen receptor (AR), a member of the steroid hormone receptor family of ligand-dependent nuclear receptors. Most patients respond to standard androgen ablation therapies, but virtually all patients eventually relapse with disease that has been termed hormone-refractory or androgen-independent disease. Efforts to use AR antagonists, such as flutamide or bicalutamide, to enhance responses to primary androgen ablation therapy or to treat androgen-independent prostate cancer have been disappointing, which has diminished enthusiasm for more aggressive or alternative methods to block AR function. However, many lines of evidence indicate that AR function contributes to tumor cell survival after androgen ablation and to growth of androgen-independent prostate cancer. This article outlines a number of mechanisms that may contribute to AR activity in androgen-independent prostate cancer, including AR amplification, AR mutation, altered expression of AR coactivator and corepressor proteins, and activation of other pathways that can enhance AR function. Understanding the mechanisms responsible for AR function in androgen-independent prostate cancer should allow the more rational development of antagonists that can enhance the efficacy of androgen ablation therapies.

Androgen Antagonists↗

PubMed2005

The changing face of prostate cancer.

Prostate cancer remains the most common noncutaneous human malignancy, and the second most lethal tumor among men. However, the natural history of the disease is often prolonged, and the survival benefits of local therapy for men with low-risk tumors may not be realized for a decade or more, as is increasingly well demonstrated in long-term observational cohorts in both the United States and Europe. A significant proportion of men with prostate cancer may be overdiagnosed, in the sense that diagnosis may not improve their lifespan or quality of life. However, the extent to which overdiagnosis represents a true problem relates to the consistency with which diagnosis leads invariably to active treatment. Prostate cancer is diagnosed at progressively earlier stages and with lower risk features; despite these trends, patients are less likely now than a decade ago to undergo a trial of active surveillance. Rates of brachytherapy and hormonal therapy use, in particular, have risen markedly. Important progress has been made in recent years in prostate cancer risk assessment. These advances, in combination with biomarkers in later stages of development, should be expected in the coming years to yield further improvements in clinicians' ability to diagnose prostate cancer early, and guide appropriately selected patients toward increasingly tailored treatment.

Humans↗

PubMed1994

Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer.

Prostate cancer can be detected at an early, potentially curable stage by screening based on digital rectal examination and serum prostate specific antigen (PSA). The value of screening appears doubtful, based on high 10-year survival rates in selected cases of early prostate cancer, but this follow-up time may be insufficient. By linking the information on 21172 men who took part in a screening examination in Finland, 1968-73, with data from the Finnish Cancer Registry, 44 cases of prostate cancer diagnosed up to 1980 were identified. Serum samples from cancer cases and from 74 controls matched for age and time of sampling were assayed for PSA and its complex with alpha 1-antichymotrypsin (PSA-ACT). With a cut-off for PSA of 2.5 micrograms/L giving 92% specificity, 95% of the cancers developing within the first 5 years, and 52% developing in 6-10 years tested positive. As a potential screening test with a 5-year interval for men under 65, the sensitivity would be 92% and specificity 97%. The ratio of PSA-ACT to total PSA was lower in controls than in patients with cancer. Using this ratio, we could eliminate half of the false-positive results in the range 2.5-25 micrograms/L without loss of sensitivity. Cancer was typically diagnosed 5-10 years after PSA exceeded 2.5 micrograms/L, and the median survival after diagnosis was 3.6 years. 10-year survival after drawing the sample was 71% in cancer cases with a PSA concentration less than 4 micrograms/L and 48% in those with higher concentrations. The corresponding figures at 15 years were 53% and 27%, and at 20 years 43% and 18%, respectively. These results suggest it is advisable to confine screening for prostate cancer to men with a life expectancy of clearly more than 10 years--ie, younger men, who have the greatest chance to benefit from early detection.

Age Distribution↗

PubMed2003

Hsp90 as a therapeutic target in prostate cancer.

Prostate cancers are hormone-dependent malignancies that respond to drugs that reduce circulating testosterone levels or prevent binding of this ligand to the androgen receptor (AR). While effective, these approaches are not curative and, in almost all cases, progression to a castration-resistant state is eventually observed. The mechanisms underlying the development of hormone resistance are poorly defined but several molecular changes are commonly associated with this process. Since a common element of these resistance mechanisms is restoration of AR signaling, agents that target AR expression represent an attractive treatment option for prostate cancer patients with disease progression following castration. Prior to ligand binding, AR exists in a complex with heat shock protein 90 (Hsp90) and other co-chaperones. The AR-Hsp90 interaction maintains AR in a high-affinity ligand-binding conformation, which is necessary for efficient response to hormone. 17-Allyamino-17-demethoxygeldanamycin (17-AAG) is an inhibitor of the Hsp90 chaperone protein. Inhibition of Hsp90 function causes the proteasomal degradation of proteins that require this chaperone for maturation or stability. Hsp90 clients include several proteins of potential importance in mediating prostate cancer progression, including wild-type and mutated AR, HER2, and Akt. In murine models of prostate cancer, 17-AAG causes the degradation of these client proteins at nontoxic doses and inhibits the growth of hormone-naive and castration-resistant tumors. These data suggest that inhibitors of Hsp90 may represent a novel strategy for the treatment of patients with prostate cancer and clinical trials to test this hypothesis are currently ongoing.

Androgen Antagonists↗

PubMed2005

Genetic alterations in prostate cancer.

Prostate cancer is the most common nondermatologic malignancy in men. Prostate cancer is characterized by clinical and biologic heterogeneity that has complicated molecular and epidemiologic studies. Like other epithelial malignancies, prostate tumors exhibit complex karyotypic abnormalities and harbor many specific genetic alterations. Although recent work has begun to elucidate many of the specific mutations associated with prostate cancer, we still lack a clear understanding of the complement of genetic changes that suffice to program the malignant state. Here, we review our current understanding of the genetic changes found in prostate cancer and explore the connections between specific genetic alterations and malignant phenotypes including cell growth, survival, invasion, and metastasis.

Cell Transformation, Neoplastic↗

PubMedDate not supplied

Three-dimensional modeling of biopsy protocols for localized prostate cancer.

Prostate cancer is the most common malignant tumor in American men, yet only a small percentage of men will develop clinically significant disease. Needle core biopsies are used to confirm the presence of cancer prior to surgery. While needle core biopsies have shown some ability to predict tumor volume and grade in prostatectomy specimens, for the individual patient they are neither sensitive nor specific enough to guide therapy. In this paper, we describe a system for simulating needle biopsies on three-dimensional models of cancerous prostates reconstructed from serial sections. First we segment the serial sections, delineating tumors and landmarks. Next, we register the sections using a color-merging scheme, and reconstruct the three-dimensional model using modified-shape-based interpolation. The resulting volume can be rendered, and simulated needle core biopsies can be taken from the reconstructed model. We use our system to simulate two different biopsy protocols on a reconstructed prostate specimen.

Biopsy, Needle↗

PubMed2001

Markers of bone turnover in prostate cancer.

Prostate cancer is the most common malignancy in elderly men and is often associated with bone metastases. Although bone metastases are osteosclerotic, histological and biochemical studies clearly indicate an increase of both bone formation and bone resorption, providing the rational for using bisphosphonate as a palliative treatment in these patients. The recent development of specific and sensitive biochemical markers, reflecting the overall rate of bone formation and bone resorption, has improved the non-invasive assessment of bone turnover abnormalities in patients with prostate cancer. The immunoassays for bone-specific alkaline phosphatase and type I collagen propeptides are currently the most sensitive markers to assess bone, formation. The best indices of bone resorption are the immunoassay for the pyridinoline cross-links and the related peptides that can be measured in urine and more recently in serum. A better knowledge of the biochemistry, especially of the age-related post-translational modifications of type I collagen in the abnormal bone matrix, associated with bone metastases from prostate cancer may lead to markers of increased sensitivity. A recent example is the demonstration that the isomerization and racemization of the aspartic acid residue in C-telopeptides of type I collagen is impaired in patients with prostate cancer and bone metastases, a pattern than can be detected with specific conformational antibodies. The most sensitive markers of bone formation and bone resorption are markedly increased in patients with bone metastases compared with patients with cancer but without metastases, the levels correlating with the extent of the bone involvement. However, their sensitivity remains limited, suggesting that the currently available biochemical markers cannot be used as a surrogate for bone scintigraphy in the diagnosis of bone involvement. A few studies have suggested that the measurement of bone markers may be useful in the assessment of response to anti-endocrine therapy, although available data indicate a lower sensitivity than with prostates specific antigen. Additional longitudinal studies are required to assess the potential use of bone markers, especially to identify patients who relapse during the course of the treatment and, more specifically 3 those that result from the progression in bone metastases.Clearly, the established use of bone markers is for monitoring effects of bisphosphonate treatment. Several studies have shown a rapid decrease of bone resorption markers in patients with prostate cancer and bone metastases, the magnitude of the decrease correlating with the efficacy of the treatment in reducing bone pain. Thus, bone markers are likely to become a useful and objective tool to monitor bisphosphonate treatment and individual the therapy scheme.

Biomarkers↗

PubMed2002

Radical prostatectomy versus watchful waiting in early prostate cancer.

Prostate cancer continues to be a significant factor in morbidity and mortality. Due to high prevalence (most common cancer in U.S. males) and mortality (second most common cause of cancer deaths in males), prostate cancer is one of the most crucial health problems in men. The discussion of managing early prostate cancer is not only common, but also complicated. Treatment decisions involve scant survival data and quality of life issues such as impotence and urinary incontinence. Watchful waiting has also had to fight the paradigm of surgery curing cancer.

Decision Making↗

PubMed2004

Molecular aspects of diagnostic nucleolar and nuclear envelope changes in prostate cancer.

Prostate cancer is still diagnosed by pathologists based on subjective assessment of altered cell and tissue structure. The cellular-level structural changes diagnostic of some forms of cancer are known to be induced by cancer genes, but the relation between specific cellular-level structural features and cancer genes has not been explored in the prostate. Two important cell structural changes in prostate cancer-nucleolar enlargement and nuclear envelope (NE) irregularity-are discussed from the perspective that they should also relate to the function of the genes active in prostate cancer. Enlargement of the nucleolus is the key diagnostic feature of high-grade prostatic intraepithelial neoplasia (PIN), an early stage that appears to be the precursor to the majority of invasive prostate cancers. Nucleolar enlargement classically is associated with increased ribosome production, and production of new ribosomes appears essential for cell-cycle progression. Several cancer genes implicated in PIN are known (in other cell types) to augment ribosome production, including c-Myc, p27, retinoblastoma, p53, and growth factors that impact on ERK signaling. However, critical review of the available information suggests that increased ribosome production per se may be insufficient to explain nucleolar enlargement in PIN, and other newer functions of nucleoli may therefore need to be invoked. NE irregularity develops later in the clonal evolution of some prostate cancers, and it has adverse prognostic significance. Nuclear irregularity has recently been shown to develop dynamically during interphase following oncogene expression, without a requirement for post-mitotic NE reassembly. NE irregularity characteristic of some aggressive prostate cancers could reflect cytoskeletal forces exerted on the NE during active cell locomotion. NE irregularity could also promote chromosomal instability because it leads to chromosomal asymmetry in metaphase. Finally, NE irregularity could impact replication competence, transcriptional programming and nuclear pore function.

Biological Evolution↗

PubMed2001

The molecular pathogenesis of prostate cancer: Implications for prostate cancer prevention.

Prostate cancer has become 1 of the most commonly diagnosed cancers in the United States and 1 of the leading causes of cancer death in North America and Western Europe. Survey studies of prostate tissues obtained at autopsy indicate that the development of life-threatening prostate cancer in the US likely occurs over decades. Insights from epidemiologic studies implicate environmental factors, principally dietary components, as major risk factors for prostate cancer development. An accumulating body of basic research data suggests that normal and neoplastic prostate cells may be subjected to a relentless barrage of genome-damaging stresses, and that dietary components and male sex steroids might modulate the level of genome threatening insults. Finally, over the past 5 years, analyses of somatic genome alterations in prostatic carcinoma cells have revealed that somatic inactivation of GSTP1, encoding the carcinogen-detoxification enzyme glutathione S-transferase pi, may serve as an initiating genome lesion for prostatic carcinogenesis. These diverse observations can be integrated into a transcendent mechanistic hypothesis for the pathogenesis of prostate cancer: normal prostate cells acquiring somatic GSTP1 defects may suffer chronic genome damage, influenced by dietary practices, that promote neoplastic transformation, while prostatic carcinoma cells, which characteristically contain defective GSTP1 alleles, remain susceptible to further genome-damaging stresses that promote malignant cancer progression. This hypothesized critical role for GSTP1 inactivation in the earliest steps of prostatic carcinogenesis provides several attractive opportunities for prostate cancer prevention strategies, including (1) restoration of GSTP1 function, (2) compensation for inadequate GSTP1 activity (via use of therapeutic inducers of other glutathione S-transferases (GST), and (3) abrogation or attenuation of genome-damaging stresses.

Atrophy↗

PubMed2005

Regulation of androgen receptor signaling in prostate cancer.

Prostate cancer is a significant cause of morbidity and mortality worldwide. Normal prostate tissue is regulated by androgens, which activate the androgen receptor, a nuclear receptor transcription factor. Most prostate tumors retain androgen dependence, therefore, current therapies for advanced prostate cancer either reduce androgen levels or prevent binding to the androgen receptor. Despite this regimen, prostate cancer invariably progresses to a fatal, androgen-refractory state. Although these relapsed tumors are androgen independent, they are still dependent on the androgen receptor for their growth and survival. The focus of this review will be to highlight our current understanding of the mechanisms of androgen receptor activation in androgen-refractory prostate cancer. How these mechanisms of androgen receptor activation could be targeted in this advanced stage of the disease is also discussed.

Androgens↗

PubMed2004

Management of patients with hormone refractory prostate cancer.

Prostate cancer is the second most common cancer in men in the UK, and the incidence of prostate cancer has increased dramatically over the past two decades. Although most men are diagnosed at early stage, more than 50% develop locally advanced or metastatic disease. Androgen ablation with luteinising hormone-releasing hormone (LHRH) agonists alone, or in combination with anti-androgens, is the standard treatment for men with metastatic prostate cancer. Unfortunately, almost all men develop progressive disease after a variable time period, despite the maximal androgen blockade. The management of hormone refractory prostate cancer (HRPC) is challenging, as there is no uniformly accepted strategy. Various treatment options, including second-line hormone therapy, are discussed. Chemotherapy is being increasingly used and, importantly, docetaxel and estramustine may play an important role in the near future. The role of radiotherapy, strontium-89, bisphosphonates, novel agents and future therapies are also outlined.

Antineoplastic Agents↗

PubMed2000

Expression of the multidrug resistance gene in human prostate cancer.

Prostate cancer has become the most common cancer in males and the second most common cause of male cancer death in England and Wales. Death rates have doubled over the last 20 years. Prostate cancer is characterized by a high initial response rate to hormonal therapy. Drug-resistance is a significant cause of relapse in cancer. The multidrug resistance genes (MDR) encode resistance to a diverse family of cytotoxic chemotherapy agents. There are four known MDR genes, two of which are present in humans. MDR1 encodes for P-glycoprotein, a 170-kDa transmembrane calcium-dependent efflux pump. We examined P-glycoprotein expression by immunocytochemistry in 96 patients with prostate cancer and 20 patients with benign prostatic hypertrophy. A direct correlate was found between tumor grade, stage, and prostate specific antigen levels, indicating the possible significance of this protein in recurrent prostate cancer.

Journal Article↗

PubMed2005

Hedgehog signaling in prostate cancer.

Prostate cancer is the most common malignancy and the second leading cancer-related cause of death in men in the USA. Despite enormous efforts in understanding the molecular basis of prostate cancer, very little progress has been made in prevention and treatment of this often lethal cancer. Recent studies have demonstrated that hedgehog signaling is frequently activated in advanced or metastatic prostate cancers. With small molecule inhibitors available to analyze the hedgehog signaling pathway, a novel rationale for prostate cancer therapy can be devised.

Animals↗

PubMed2003

Intensity-modulated radiation therapy for prostate cancer.

Prostate cancer is among the most common solid malignancies. A number of treatment alternatives exist for localized prostate cancer, including observation, prostatectomy, brachytherapy, and external-beam radiation therapy (EBRT). External-beam radiation therapy has changed dramatically during the past several years. Older techniques paved the way for 3-dimensional conformal radiation therapy (CRT), which in turn facilitated the introduction of intensity-modulated radiation therapy (IMRT). The prostate has served as a model disease site for the implementation of IMRT. As indicated by a growing body of experience, IMRT for prostate cancer represents a major technologic and clinical advance for radiation therapy. In this article, a review is provided of the evolution of EBRT leading to IMRT, the unique features making the prostate an ideal disease site for employing IMRT, the details of the clinical implementation of prostate IMRT and supporting technologic advancements, and the currently reported clinical outcomes of IMRT in prostate cancer. In addition, future directions of prostate IMRT, both technologic and clinical, are discussed.

Dose-Response Relationship, Radiation↗