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Key Points Prostate cancer is the most common form of non-skin cancer in men in developed countries. The cause(s) of prostate cancer have not yet been clarified. Although heritable factors are implicated, immigration studies indicate that environmental exposures are also important. Chronic infection and inflammation cause cancer in several organs including the stomach, liver and large intestine. Data from histopathological, molecular histopathological, epidemiological and genetic epidemiological studies show that chronic inflammation might also be important in prostate carcinogenesis. The source of intraprostatic inflammation is often unknown, but might be caused by infection (for example, with sexually transmitted agents), cell injury (owing to exposure to chemical and physical trauma from urine reflux and prostatic calculi formation), hormonal variations and/or exposures, or dietary factors such as charred meats. The resultant epithelial cellular injury might cause a loss of tolerance to normal prostatic antigens, resulting in a self-perpetuating autoimmune reaction. Exposures to infectious agents and dietary carcinogens are postulated to directly injure the prostate epithelium, resulting in the histological lesions known as proliferative inflammatory atrophy (PIA), or proliferative atrophy. These lesions are postulated to be a manifestation of the 'field effect' caused by environmental exposures. Despite a strong genetic component to prostate cancer risk, no highly penetrant hereditary prostate cancer genes have been uncovered to date. Although complex, genetic variation in inflammatory genes is associated with prostate cancer risk. Several challenges remain regarding the inflammation hypothesis in prostate cancer, including the determination of the cause(s) of chronic inflammation in the prostate, an understanding of the cellular and molecular biology of the immune response in the prostate, whether inflammatory cells are truly causative in the process, and the determination of the target cell types within the proposed precursor lesions of prostate cancer. The refinement and application of new epidemiological approaches, including high-throughput genetic epidemiology, improved rodent models of prostate inflammation and cancer, and advances in the application of molecular techniques to histopathological studies should provide insights into the cause of prostate inflammation and its relevance to prostate carcinogenesis. Recent evidence indicates that both endogenous and environmental factors induce prostate inflammatory lesions that are proposed to increase the risk of cancer development. This Review explores different approaches aimed at clarifying whether inflammation drives prostate cancer and could be used to develop new prevention strategies. About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease.

[...]as further epidemiologic evidence for an association between trichomonosis and prostate cancer risk, African Americans, who have the highest incidence of trichomonosis [1], also have the highest risks of prostate cancer diagnosis and death [2]. [...]an accumulating body of evidence suggests that trichomonosis contributes to prostate carcinogenesis, a particularly more aggressive or fatal disease. [...]we hypothesize and present preliminary data and published reports that T. vaginalis adherence or binding of specific trichomonad adhesin proteins to normal prostate epithelial cells (PECs) triggers a cell-signaling cascade through known proto-oncogenes, PIM1, c-MYC, and HMGA1, that may ultimately lead to prostate carcinogenesis [9]-[12].

Purpose To begin to explore the possible roles of childhood diet and growth in prostate cancer (PCa) development, we investigated these exposures in relation to two known/suspected PCa risk factors, earlier pubertal timing and greater attained height, in the Longitudinal Studies of Child Health and Development. Methods We used biannual/annual height, weight, and dietary history data to investigate childhood diet, body mass index (BMI), birth length, and childhood height in relation to PCa risk factors (age at peak height velocity (APHV), height at age 13, and adult height) for 64 Caucasian American boys. Results In adjusted models, childhood fat and animal protein intake was positively associated with height at age 13 and adult height ( P  < 0.05). A childhood diet high in fat and animal protein and low in vegetable protein was also associated with earlier APHV ( P  < 0.05), whereas no associations were observed for childhood energy intake or BMI. Birth length and childhood height were positively associated with height at age 13 and adult height, and childhood height was inversely associated with APHV ( P  < 0.05). Conclusion Our findings suggest that both childhood diet and growth potential/growth contribute to earlier pubertal timing and taller attained height in males, supporting roles of these factors in PCa development.

The MYC onco-protein is a transcription factor that regulates cell proliferation, metabolism, protein synthesis, mitochondrial function and stem cell renewal. A region on chromosome 8q24 encompassing the MYC locus is amplified in prostate cancer, but this occurs mostly in advanced disease suggesting that MYC alterations occur late in prostate cancer. In contrast, MYC mRNA is elevated in most prostate cancers, even those of relatively low stage and grade (eg Gleason score 6) suggesting that MYC plays a role in initiation. However, since MYC protein levels are tightly regulated, elevated MYC mRNA does not necessarily imply elevated MYC protein. Thus, it is critical to determine whether MYC protein is elevated in human prostate cancer, and if so, at what stage of the disease this elevation occurs. Prior studies of MYC protein localization have been hampered by lack of suitable antibodies and controls. We utilized a new anti-MYC antibody coupled with genetically defined control experiments to localize MYC protein within human tissue microarrays consisting of normal, atrophy, PIN, primary adenocarcinoma, and metastatic adenocarcinoma. Nuclear overexpression of MYC protein occurred frequently in luminal cells of PIN, as well as in most primary carcinomas and metastatic disease. MYC protein did not correlate with gain of 8q24, suggesting alternative mechanisms for MYC overexpression. These results provide evidence that upregulation of nuclear MYC protein expression is a highly prevalent and early change in prostate cancer and suggest that increased nuclear MYC may be a critical oncogenic event driving human prostate cancer initiation and progression.

Prostate cancer research has been predominantly focused on adult exposures and risk factors. However, because the prostate develops during gestation and early life, exposure to external factors, such as obesity, during development could affect the prostate cancer progression in adults. Our previous work demonstrated that exposure to a high fat/high sugar (HF/HS) diet during gestation and until weaning stimulated prostate hyperplasia and altered the Pten/Akt pathway in adult mice fed a normal diet after weaning. Here, we asked whether maternal exposure to HF/HS would worsen prostate phenotypes in mice lacking Pten, a widely accepted driver of prostate cancer. We found that, at six weeks of age, both Chow (control)-and HF/HS-exposed Pten knockout mice showed evidence of murine PIN that included ducts with central comedo necrosis but that the HF/HS exposure did not influence murine PIN progression. The Pten knockout mice exposed to HF/HS in utero had significantly more mitotic cells than Pten knockouts exposed to Chow diet. In the Pten null background, the maternal HF/HS diet enhanced proliferation but did not have an additive effect on Akt activation. We observed neuroendocrine differentiation in Pten knockout mice, a phenotype that had not been previously described in this model.

Background To examine one-year trajectories of urinary and sexual outcomes, and correlates of these trajectories, among prostate cancer patients treated by radical prostatectomy (RP). Methods Study participants were recruited from 2011 to 2014 at two US institutions. Self-reported urinary and sexual outcomes were measured at baseline before surgery, and 5 weeks, 6 months and 12 months after surgery, using the modified Expanded Prostate Cancer Index Composite-50 (EPIC-50). Changes in EPIC-50 scores from baseline were categorized as improved (beyond baseline), maintained, or impaired (below baseline), using previously-reported minimum clinically important differences. Results Of the 426 eligible participants who completed the baseline survey, 395 provided data on at least one EPIC-50 sub-scale at 5 weeks and 12 months, and were analyzed. Although all mean EPIC-50 scores declined markedly 5 weeks after surgery and then recovered to near (incontinence-related outcomes) or below (sexual outcomes) baseline levels by 12 months post-surgery, some men experienced improvement beyond their baseline levels on each sub-scale (3.3–51% depending on the sub-scale). Having benign prostatic hyperplasia (BPH) at baseline (prostate size ≥ 40 g; an International Prostate Symptom Index Score ≥ 8; or using BPH medications) was associated with post-surgical improvements in voiding dysfunction-related bother at 5 weeks (OR = 3.9, 95% CI: 2.1–7.2) and 12 months (OR = 3.3, 95% CI: 2.0–5.7); and in sexual bother at 5 weeks (OR = 5.7, 95% CI:1.7–19.3) and 12 months (OR = 3.0, 95% CI: 1.2–7.1). Conclusions Our findings provide additional support for considering baseline BPH symptoms when selecting the best therapy for early-stage prostate cancer.

Since the early 1950s when sexually transmitted infections (STIs) were first proposed as a possible risk factor for prostate cancer, numerous epidemiologic studies have been conducted. Initially, these studies were primarily small case-control studies with retrospective, self-reported assessments of a narrow range of STIs, typically either any STIs, or gonorrhea and syphilis. However, as new STIs have been discovered/recognized, new and better tests to detect histories of STIs have been developed, and new resources for prostate cancer research have been created, epidemiologic studies have expanded to include a wide range of STIs, and have moved towards more rigorous, prospective study designs and serological assessment of STI histories. The results of these studies are reviewed and discussed, as well as possible new avenues of research, such as infection and infections not typically considered to be sexually transmitted.

Although we understand various aspects of prostate cancer biology, few reliable risk factors are known. This Opinion article rationalizes why exposures early in life may be key for prostate cancer risk, summarizes our current limited understanding of early-life exposures and provides visions for the future. Although the contribution of lifestyle and environment (non-genetic factors) to prostate carcinogenesis is indicated by international variation in prostate cancer occurrence and migration studies, no conclusive modifiable risk factors have yet been identified. One possible reason for this may be the dearth of epidemiological research on exposures experienced early in life, when the immature prostate may be more susceptible to carcinogenic exposures. In this Opinion article, we summarize the rationale for studying early-life exposures, describe the small body of early-life research and its associated challenges, and point to solutions for future research.

BackgroundAlthough adolescent diet has been proposed to contribute to prostate cancer (PCa) development, no studies have investigated the relation between adolescent dietary patterns and PCa risk or mortality.MethodsUsing data from 164,079 men in the NIH-AARP Diet and Health Study, we performed factor analysis to identify dietary patterns at ages 12–13 years and then used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of total (n = 17,861), non-advanced (n = 15,499), advanced (n = 2362), and fatal PCa (n = 832).ResultsAlthough not entirely consistent across analyses, a higher adolescent plant-based pattern (characterised by vegetables, fruits, and dark bread) score was associated with slightly reduced risks of total (fully adjusted HRQ5vs.Q1 = 0.93, 95% CI: 0.89–0.98, p trend=0.003) and non-advanced PCa (HR = 0.91, 95% CI: 0.87–0.96, p trend<0.001), whereas no associations were observed for advanced or fatal PCa, or for Western modern (characterised by sweets, processed meat, beef, cheese, and pizza) or Western traditional (characterised gravy, eggs, potatoes and white bread) patterns.ConclusionWe found evidence to support a modest, protective role for a plant-based dietary pattern during adolescence on PCa risk. If confirmed in future studies, our findings may help to inform the development of new, primary prevention strategies for PCa.

This Review describes the key insights into urologic chronic pelvic pain syndrome (UCPPS) from the first phase of Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network studies and highlights their implications for understanding the pathophysiological basis and clinical management of UCPPS.