Prostate Cancer

Skip Regulates TGF-β1-Induced Extracellular Matrix Degrading Proteases Expression in Human PC-3 Prostate Cancer Cells

Victor Villar, Jelena Kocic, and Juan F. Santibanez — Mon, 20 May 2013 15:27:57 +0000

Purpose. To determine whether Ski-interacting protein (SKIP) regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and uPA Inhibitor (PAI-1) in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA) compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment.

HMGB1: A Promising Therapeutic Target for Prostate Cancer

Sun, 12 May 2013 13:48:29 +0000

High mobility group box 1 (HMGB1) was originally discovered as a chromatin-binding protein several decades ago. It is now increasingly evident that HMGB1 plays a major role in several disease conditions such as atherosclerosis, diabetes, arthritis, sepsis, and cancer. It is intriguing how deregulation of HMGB1 can result in a myriad of disease conditions. Interestingly, HMGB1 is involved in cell proliferation, angiogenesis, and metastasis during cancer progression. Furthermore, HMGB1 has been demonstrated to exert intracellular and extracellular functions, activating key oncogenic signaling pathways. This paper focuses on the role of HMGB1 in prostate cancer development and highlights the potential of HMGB1 to serve as a key target for prostate cancer treatment.

Emerging Molecularly Targeted Therapies in Castration Refractory Prostate Cancer

Wed, 08 May 2013 17:47:48 +0000

Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.

Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer

Mon, 29 Apr 2013 15:14:21 +0000

Prostate cancer (PCa) is one of the most common malignancies found in males. The development of PCa involves several mutations in prostate epithelial cells, usually linked to developmental changes, such as enhanced resistance to apoptotic death, constitutive proliferation, and, in some cases, to differentiation into an androgen deprivation-resistant phenotype, leading to the appearance of castration-resistant PCa (CRPCa), which leads to a poor prognosis in patients. In this review, we summarize recent findings concerning the main deregulations into signaling pathways that will lead to the development of PCa and/or CRPCa. Key mutations in some pathway molecules are often linked to a higher prevalence of PCa, by directly affecting the respective cascade and, in some cases, by deregulating a cross-talk node or junction along the pathways. We also discuss the possible environmental and nonenvironmental inducers for these mutations, as well as the potential therapeutic strategies targeting these signaling pathways. A better understanding of how some risk factors induce deregulation of these signaling pathways, as well as how these deregulated pathways affect the development of PCa and CRPCa, will further help in the development of new treatments and prevention strategies for this disease.

Blood Level Omega-3 Fatty Acids as Risk Determinant Molecular Biomarker for Prostate Cancer

Mon, 25 Mar 2013 11:28:13 +0000

Previous researches involving dietary methods have shown conflicting findings. Authors sought to assess the association of prostate cancer risk with blood levels of omega-3 polyunsaturated fatty acids (n-3 PUFA) through a meta-analysis of human epidemiological studies in available online databases (July, 2012). After critical appraisal by two independent reviewers, Newcastle-Ottawa Quality Assessment Scale (NOQAS) was used to grade the studies. Six case control and six nested case control studies were included. Results showed nonsignificant association of overall effect estimates with total or advanced prostate cancer or high-grade tumor. High blood level of alpha-linolenic acid (ALA) had nonsignificant positive association with total prostate cancer risk. High blood level of docosapentaenoic acid (DPA) had significant negative association with total prostate cancer risk. Specific n-3 PUFA in fish oil, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) had positive association with high-grade prostate tumor risk only after adjustment of interstudy variability. There is evidence that high blood level of DPA that is linked with reduced total prostate cancer risk and elevated blood levels of fish oils, EPA, and DHA is associated with high-grade prostate tumor, but careful interpretation is needed due to intricate details involved in prostate carcinogenesis and N-3 PUFA metabolism.

Circulating MicroRNAs as Biomarkers of Prostate Cancer: The State of Play

Nikhil Sapre and Luke A. Selth — Tue, 12 Mar 2013 15:50:26 +0000

MicroRNAs are key regulators of gene expression and play critical roles in both normal physiology and pathology. Recent research has demonstrated that these molecules are present in body fluids, such as serum, plasma, and urine, and can be readily measured using a variety of techniques. More importantly, emerging evidence suggests that circulating or urine miRNAs are useful indicators of disease. Here, we consider the potential utility of such miRNAs as noninvasive biomarkers of prostate cancer, a disease that would benefit substantially from novel diagnostic and prognostic tools. The studies aimed at identifying diagnostic, prognostic, and/or predictive miRNAs for prostate cancer are summarised and reviewed. Finally, practical considerations that will influence the translation of this recent research into clinical implementation are discussed.

Hypofractionated External-Beam Radiotherapy for Prostate Cancer

L. Chinsoo Cho, Robert Timmerman, and Brian Kavanagh — Thu, 07 Mar 2013 16:46:52 +0000

There are radiobiological rationales supporting hypofractionated radiotherapy for prostate cancer. The recent advancements in treatment planning and delivery allow sophisticated radiation treatments to take advantage of the differences in radiobiology of prostate cancer and the surrounding normal tissues. The preliminary results from clinical studies indicate that abbreviated fractionation programs can result in successful treatment of localized prostate cancer without escalation of late toxicity.

Urologic Characteristics and Sexual Behaviors Associated with Prostate Cancer in an African-Caribbean Population in Barbados, West Indies

Anselm J. M. Hennis, Suh-Yuh Wu, Barbara Nemesure, and M. Cristina Leske — Mon, 25 Feb 2013 13:21:31 +0000

Prostate cancer (PC) is the principal malignancy affecting African descent men in the Caribbean and the USA. Disparities in incidence, prevalence, and mortality in these populations are poorly understood. We evaluated the urologic characteristics and sexual behaviors of men with histologically confirmed PC (cases) and age-matched controls in the nationwide Prostate Cancer in a Black Population (PCBP) study conducted in Barbados. Cases were around 1.5 to 3 times more likely to report symptoms of prostatic enlargement, hematuria/hematospermia, and previous prostatitis. Sexually transmitted infections (STIs) were similar among cases (24.5%) and controls (26.7%). First sexual intercourse before the age of 16 was associated with an increased likelihood of both low- (Gleason score < 7; OR 1.63; 95% CI: 1.03–1.66) and high-grade PC (Gleason score ≥ 7; OR 1.82; 1.11–2.99). PC risk decreased with later age of sexual debut (). More lifetime sexual partners was associated with increased odds of high grade PC (). The contribution of sexual behaviors to the development and the outcomes of PC is likely due to multiple mechanisms, and further study will be necessary to elucidate the underlying pathophysiologic mechanisms in this and similar populations.

Analysis of Preoperative Detection for Apex Prostate Cancer by Transrectal Biopsy

Thu, 21 Feb 2013 09:05:03 +0000

Background. The aim of this study was to determine concordance rates for prostatectomy specimens and transrectal needle biopsy samples in various areas of the prostate in order to assess diagnostic accuracy of the transrectal biopsy approach, especially for presurgical detection of cancer in the prostatic apex. Materials and Methods. From 2006 to 2011, 158 patients whose radical prostatectomy specimens had been evaluated were retrospectively enrolled in this study. Concordance rates for histopathology results of prostatectomy specimens and needle biopsy samples were evaluated in 8 prostatic sections (apex, middle, base, and transitional zones bilaterally) from 73 patients diagnosed at this institution, besides factors for detecting apex cancer in total 118 true positive and false negative apex cancers. Results. Prostate cancer was found most frequently (85%) in the apex of all patients. Of 584 histopathology sections, 153 (49%) from all areas were false negatives, as were 45% of apex biopsy samples. No readily available preoperative factors for detecting apex cancer were identified. Conclusions. In Japanese patients, the most frequent location of prostate cancer is in the apex. There is a high false negative rate for transrectal biopsy samples. To improve the detection rate, transperitoneal biopsy or more accurate imaging technology is needed.

Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent

Wed, 13 Feb 2013 08:36:16 +0000

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

Androgen Receptor-Target Genes in African American Prostate Cancer Disparities

Thu, 10 Jan 2013 16:27:46 +0000

The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis-acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging (“transcriptional convergence”) on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs.

The Role of Targeted Focal Therapy in the Management of Low-Risk Prostate Cancer: Update on Current Challenges

Daniel W. Smith, Diliana Stoimenova, Khadijah Eid, and Al Barqawi — Mon, 31 Dec 2012 15:20:33 +0000

Prostate cancer is one of the most prevalent cancers among men in the United States, second only to nonmelanomatous skin cancer. Since prostate-specific antigen (PSA) testing came into widespread use in the late 1980s, there has been a sharp increase in annual prostate cancer incidence. Cancer-specific mortality, though, is relatively low. The majority of these cancers will not progress to mortal disease, yet most men who are diagnosed opt for treatment as opposed to observation or active surveillance (AS). These men are thus burdened with the morbidities associated with aggressive treatments, commonly incontinence and erectile dysfunction, without receiving a mortality benefit. It is therefore necessary to both continue investigating outcomes associated with AS and to develop less invasive techniques for those who desire treatment but without the significant potential for quality-of-life side effects seen with aggressive modalities. The goals of this paper are to discuss the problems of overdiagnosis and overtreatment since the advent of PSA screening as well as the potential for targeted focal therapy (TFT) to bridge the gap between AS and definitive therapies. Furthermore, patient selection criteria for TFT, costs, side effects, and brachytherapy template-guided three-dimensional mapping biopsies (3DMB) for tumor localization will also be explored.

Androgen Deprivation Therapy Toxicity and Management for Men Receiving Radiation Therapy

Matthew E. Johnson and Mark K. Buyyounouski — Sun, 30 Dec 2012 18:01:18 +0000

Androgen deprivation therapy is commonly used in combination with radiotherapy as part of the definitive treatment for men with clinically localized and locally advanced prostate cancer. Androgen deprivation has been associated with a wide range of iatrogenic effects impacting a variety of body systems including metabolic, musculoskeletal, cardiovascular, neurocognitive, and sexual. This review aims to provide the radiation oncology community with the knowledge to monitor and manage androgen deprivation therapy toxicity in an effort to provide the highest level of care for patients and to minimize the iatrogenic effects of androgen deprivation as much as possible.

Paradoxical Roles of Tumour Necrosis Factor-Alpha in Prostate Cancer Biology

Brian W. C. Tse, Kieran F. Scott, and Pamela J. Russell — Thu, 27 Dec 2012 13:34:46 +0000

Tumour necrosis factor (TNF) is a pleiotropic cytokine with dual roles in cancer biology including prostate cancer (PCa). On the one hand, there is evidence that it stimulates tumour angiogenesis, is involved in the initiation of PCa from an androgen-dependent to a castrate resistant state, plays a role in epithelial to mesenchymal plasticity, and may contribute to the aberrant regulation of eicosanoid pathways. On the other hand, TNF has also been reported to inhibit neovascularisation, induce apoptosis of PCa cells, and stimulate antitumour immunity. Much of the confusion surrounding its seemingly paradoxical roles in cancer biology stems from the dependence of its effects on the biological model within which TNF is investigated. This paper will address some of these issues and also discuss the therapeutic implications.

Risk Stratification after Biochemical Failure following Curative Treatment of Locally Advanced Prostate Cancer: Data from the TROG 96.01 Trial

Mon, 24 Dec 2012 11:41:44 +0000

Purpose. Survival following biochemical failure is highly variable. Using a randomized trial dataset, we sought to define a risk stratification scheme in men with locally advanced prostate cancer (LAPC). Methods. The TROG 96.01 trial randomized 802 men with LAPC to radiation ± neoadjuvant androgen suppression therapy (AST) between 1996 and 2000. Ten-year follow-up data was used to develop three-tier post-biochemical failure risk stratification schemes based on cutpoints of time to biochemical failure (TTBF) and PSA doubling time (PSADT). Schemes were evaluated in univariable, competing risk models for prostate cancer-specific mortality. The performance was assessed by c-indices and internally validated by the simple bootstrap method. Performance rankings were compared in sensitivity analyses using multivariable models and variations in PSADT calculation. Results. 485 men developed biochemical failure. c-indices ranged between 0.630 and 0.730. The most discriminatory scheme had a high risk category defined by PSADT < 4 months or TTBF < 1 year and low risk category by PSADT > 9 months or TTBF > 3 years. Conclusion. TTBF and PSADT can be combined to define risk stratification schemes after biochemical failure in men with LAPC treated with short-term AST and radiotherapy. External validation, particularly in long-term AST and radiotherapy datasets, is necessary.

Personalized Management in Low-Risk Prostate Cancer: The Role of Biomarkers

Thu, 13 Dec 2012 15:52:52 +0000

Current criteria to predict low-risk prostate cancer (PCa) are still subject to discussion as a substantial number of PCa patients who progress to a more aggressive disease seem to be missed, using these criteria. The main challenge in PCa diagnosis, therefore, is to distinguish patients with low-risk PCa who will show slow progression of disease from patients at risk for progression to a more aggressive cancer. The current discovered biomarkers could potentially guide in this management and improve detection, staging, and prognosis. This paper provides an overview of the current available serum-, urine-, and tissue-based biomarkers in PCa and evaluates the clinical usefulness of these biomarkers in the detection and management of low-risk PCa.

Vitamin D Levels in Subjects with Prostate Cancer Compared to Age-Matched Controls

Subhashini Yaturu, Sonya Zdunek, and Barbara Youngberg — Wed, 12 Dec 2012 07:52:50 +0000

Prostate cancer (PCa) is the second most common cancer in men worldwide and the second leading cause of cancer deaths in men in the United States. Vitamin D is considered to have anticancer properties, currently thought to work mainly through its nuclear receptor or vitamin D receptor. In this retrospective study, we compared vitamin D levels in subjects with PCa with those of age-matched men without PCa. Study subjects included 479 in each group with a mean age of 73 and a mean creatinine of 1.05 and 1.15. Levels of 25 (OH) vitamin D were and in subjects with and without PCa. Levels of 1,25 (OH) vitamin D were and in subjects with and without PCa. In contrast to other studies, we did not find a significant difference in vitamin D levels. Among prostate cancer patients, vitamin D levels correlated positively with age (, ), and were negatively associated with BMI (, ), glucose (, ), HbA1C (, ), and PTH (; ). The data do not show the causal effect of vitamin D levels on PCa.

Growth and Progression of TRAMP Prostate Tumors in Relationship to Diet and Obesity

Tue, 04 Dec 2012 14:04:36 +0000

To clarify effects of diet and body weight on prostate cancer development, three studies were undertaken using the TRAMP mouse model of this disease. In the first experiment, obesity was induced by injection of gold thioglucose (GTG). Age of prostate tumor detection (~33 wk) and death (~43 wk) was not significantly different among the groups. In the second study, TRAMP-C2 cells were injected into syngeneic C57BL6 mice and tumor progression was evaluated in mice fed either high-fat or low-fat diets. The high fat fed mice had larger tumors than did the low-fat fed mice. In the third study, tumor development was followed in TRAMP mice fed a high fat diet from 6 weeks of age. There were no significant effects of body weight status or diet on tumor development among the groups. When the tumors were examined for the neuroendocrine marker synaptophysin, there was no correlation with either body weight or diet. However, there was a significant correlation of the expression of synaptophysin with earlier age to tumor detection and death. In summary, TRAMP-C2 cells grew faster when the mice were fed a high-fat diet. Further synaptophysin may be a marker of poor prognosis independent of weight and diet.

Recent Trends in Prostate Cancer Incidence by Age, Cancer Stage, and Grade, the United States, 2001–2007

Jun Li, Joseph A. Djenaba, Ashwini Soman, Sun Hee Rim, and Viraj A. Master — Tue, 27 Nov 2012 16:24:05 +0000

Objective. To examine prostate cancer trends by demographic and tumor characteristics because a comprehensive examination of recent prostate cancer incidence rates is lacking. Patients and Methods. We described prostate cancer incidence rates and trends using the 2001–2007 National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program data (representing over 93% of US population). Because of coding changes in cancer grade, we restricted analysis to 2004–2007. We conducted descriptive and trend analyses using SEER*Stat. Results. The overall prostate cancer incidence rate was stable from 2001 to 2007; however, rates significantly increased among men aged 40–49 years (APC = 3.0) and decreased among men aged 70–79 years (APC = 2.3), and 80 years or older (APC = −4.4). About 42% of localized prostate cancers diagnosed from 2004 to 2007 were poorly differentiated. The incidence of poorly differentiated cancer significantly increased among localized (APC = 8.0) and regional stage (APC = 6.1) prostate cancers during 2004–2007. Conclusions. The recent trend in prostate cancer incidence was stable but varied dramatically by age. Given the large proportion of poorly differentiated disease among localized prostate cancers and its increasing trend in more recent years, continued monitoring of prostate cancer incidence and trends by demographic and tumor characteristics is warranted.

Intake of Grains and Dietary Fiber and Prostate Cancer Aggressiveness by Race

Tue, 13 Nov 2012 13:48:19 +0000

Purpose. To examine the associations among intake of refined grains, whole grains and dietary fiber and aggressiveness of prostate cancer in African Americans (AA, ) and European Americans (EA, ) in a population-based, case-only study (The North Carolina-Louisiana Prostate Cancer Project, PCaP). Methods. Prostate cancer aggressiveness was categorized as high, intermediate or low based on Gleason grade, PSA level and clinical stage. Dietary intake was assessed utilizing the NCI Diet History Questionnaire. Logistic regression (comparing high to intermediate/low aggressive cancers) and polytomous regression with adjustment for potential confounders were used to determine odds of high prostate cancer aggressiveness with intake of refined grains, whole grains and dietary fiber from all sources. Results. An inverse association with aggressive prostate cancer was observed in the 2nd and 3rd tertiles of total fiber intake (OR = 0.70; 95% CI, 0.50–0.97 and OR = 0.61; 95% CI, 0.40–0.93, resp.) as compared to the lowest tertile of intake. In the race-stratified analyses, inverse associations were observed in the 3rd tertile of total fiber intake for EA (OR = 0.44; 95% CI, 0.23–0.87) and the 2nd tertile of intake for AA (OR = 0.57; 95% CI, 0.35–0.95). Conclusions. Dietary fiber intake was inversely associated with aggressive prostate cancer among both AA and EA men.

Relationship of Dietary Intake of Omega-3 and Omega-6 Fatty Acids with Risk of Prostate Cancer Development: A Meta-Analysis of Prospective Studies and Review of Literature

Michael E. Chua, Maria Christina D. Sio, Mishell C. Sorongon, and Jun S. Dy — Wed, 24 Oct 2012 10:07:51 +0000

Objective. To determine the relationship between dietary omega-3 fatty acids (n-3 PUFA) and omega-6 fatty acids (n-6 PUFA) with prostate cancer risk from meta-analysis of prospective studies. Design. The literature retrieved from electronic biomedical databases up to June 2011 was critically appraised. General variance-based method was used to pool the effect estimates at 95% confidence interval. Heterogeneity was assessed by Chi2 and quantified by . Results. Eight cohort studies were included for meta-analysis. n-3 PUFA, n-6 PUFA, and their derivatives were not significantly associated with risk of prostate cancer in general. A significant negative association between high dietary intake of alpha-linolenic acid (ALA) and prostate cancer risk (pooled RR: 0.915; 95% CI: 0.849, 0.985; ) was noted. Likewise, a slightly positive association was noted on dietary long-chain n-3 PUFA, composed of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with prostate cancer risk (pooled RR: 1.135; 95% CI: 1.008, 1.278; ); however, when two other cohort studies with data of EPA and DHA, both analyzed separately, were included into the pool, the association became not significant (RR: 1.034; 95% CI: 0.973, 1.096; ). Conclusion. Intake of n-3 PUFA and n-6 PUFA does not significantly affect risk of prostate cancer. High intake of ALA may reduce risk of prostate cancer, while intake of long-chain omega-3 fatty acids does not have a significant effect.

Androgen Metabolism Gene Polymorphisms, Associations with Prostate Cancer Risk and Pathological Characteristics: A Comparative Analysis between South African and Senegalese Men

Tue, 02 Oct 2012 13:27:05 +0000

Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls), Mixed Ancestry (207 cases; 167 controls), and Black (25 cases; 20 controls) men, as well as in Senegalese men (86 cases; 300 controls). Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men.

Current Challenges in Development of Differentially Expressed and Prognostic Prostate Cancer Biomarkers

Steven M. Lucas and Elisabeth I. Heath — Tue, 28 Aug 2012 07:23:52 +0000

Introduction. Predicting the aggressiveness of prostate cancer at biopsy is invaluable in making treatment decisions. In this paper we review the differential expression of genes and microRNAs identified through microarray analysis as potentially useful markers for prostate cancer prognosis and discuss some of the challenges associated with their development. Methods. A review of the literature was conducted through Medline. Articles were identified through searches of the following terms: “prostate cancer AND differential expression”, “prostate cancer prognosis”, and “prostate cancer AND microRNAs”. Results. Though numerous differentially expressed genes and microRNAs were identified as possible prognostic markers, the significance of several of these genes is either debated due to conflicting results or is not validated in other study populations. A few of the articles constructed predictive nomograms using a panel of biomarkers which require further validation. Challenges to the development of useful markers include different methodology, cancer heterogeneity, and sampling error. These can be overcome by categorizing prognostic factors into particular gene pathways or by supplementing biopsy information with blood or urine-based biomarkers. Conclusion. Though biomarkers based on differential expression offer the potential to improve decision making concerning prostate cancer, further validation of their utility and accuracy at the biopsy level is needed.

Emerging Putative Biomarkers: The Role of Alpha 2 and 6 Integrins in Susceptibility, Treatment, and Prognosis

James R. Marthick and Joanne L. Dickinson — Tue, 31 Jul 2012 10:47:31 +0000

The genetic architecture underpinning prostate cancer is complex, polygenic and despite recent significant advances many questions remain. Advances in genetic technologies have greatly improved our ability to identify genetic variants associated with complex disease including prostate cancer. Genome-wide association studies (GWASs) and microarray gene expression studies have identified genetic associations with prostate cancer susceptibility and tumour development. The integrins feature prominently in both studies examining the underlying genetic susceptibility and mechanisms driving prostate tumour development. Integrins are cell adhesion molecules involved in extracellular and intracellular signalling and are imperative for tumour development, migration, and angiogenesis. Although several integrins have been implicated in tumour development, the roles of integrin 𝛼2 and integrin 𝛼6 are the focus of this paper as evidence is now emerging that these integrins are implicit in prostate cancer susceptibility, cancer stem cell biology, angiogenesis, cell migration, and metastases to bone and represent potential biomarkers and therapeutic targets. There currently exists an urgent need to develop tools that differentiate indolent from aggressive prostate cancers and predict how patients will respond to treatment. This paper outlines the evidence supporting the use of 𝛼2 and 𝛼6 integrins in clinical applications for tailored patient treatment.

Hypofractionated Proton Boost Combined with External Beam Radiotherapy for Treatment of Localized Prostate Cancer

Sun, 08 Jul 2012 08:23:06 +0000

Proton boost of 20 Gy in daily 5 Gy fractions followed by external beam radiotherapy (EBRT) of 50 Gy in daily 2 Gy fractions were given to 278 patients with prostate cancer with T1b to T4N0M0 disease. Fifty-three percent of the patients received neoadjuvant androgen deprivation therapy (N-ADT). The medium followup was 57 months. The 5-year PSA progression-free survival was 100%, 95%, and 74% for low-, intermediate-, and high-risk patients, respectively. The toxicity evaluation was supported by a patient-reported questionnaire before every consultant visit. Cumulative probability and actuarial prevalence of genitourinary (GU) and gastrointestinal (GI) toxicities are presented according to the RTOG classification. N-ADT did not influence curability. Mild pretreatment GU-symptoms were found to be a strong predictive factor for GU-toxicity attributable to treatment. The actuarial prevalence declined over 3 to 5 years for both GU and GI toxicities, indicating slow resolution of epithelial damage to the genitourinary and gastrointestinal tract. Bladder toxicities rather than gastrointestinal toxicities seem to be dose limiting. More than 5-year followup is necessary to reveal any sign of true progressive late side effects of the given treatment. Hypofractionated proton-boost combined with EBRT is associated with excellent curability of localized PC and acceptable frequencies of treatment toxicity.

Hypofractionated Prostate Radiotherapy with or without Conventionally Fractionated Nodal Irradiation: Clinical Toxicity Observations and Retrospective Daily Dosimetry

Thu, 28 Jun 2012 08:24:34 +0000

Purpose. To evaluate toxicity associated with the addition of elective nodal irradiation (ENI) to a hypofractionated regimen for the treatment of prostate cancer. Methods and Materials. Fifty-seven patients received pelvic image-guided IMRT to 50.4 Gy in 28 fractions with a hypofractionated simultaneous boost to the prostate to 70 Gy. Thirty-one patients received prostate-only treatment to 70 Gy in 28 fractions. Results. Median followup was 41.1 months. Early grade ≥2 urinary toxicity rates were 49% (28 of 57) for patients receiving ENI and 58% (18 of 31) for those not (𝑃=0.61). Early grade ≥2 rectal toxicity rates were 40% (23 of 57) and 23% (7 of 31), respectively (𝑃=0.09). The addition of ENI resulted in a 21% actuarial rate of late grade ≥2 rectal toxicity at 4 years, compared to 0% for patients treated to the prostate only (𝑃=0.02). Retrospective daily dosimetry of patients experiencing late rectal toxicity revealed an average increase of 2.67% of the rectal volume receiving 70 Gy compared to the original plan. Conclusions. The addition of ENI resulted in an increased risk of late rectal toxicity. Grade ≥2 late rectal toxicity was associated with worse daily rectal dosimetry compared to the treatment plan.

Dose-Escalated Hypofractionated Intensity-Modulated Radiotherapy in High-Risk Carcinoma of the Prostate: Outcome and Late Toxicity

Wed, 20 Jun 2012 11:55:51 +0000

Background. The benefit of dose-escalated hypofractionated radiotherapy using intensity-modulated radiotherapy (IMRT) in prostate cancer is not established. We report 5-year outcome and long-term toxicity data within a phase II clinical trial. Materials and Methods. 60 men with predominantly high-risk prostate cancer were treated. All patients received neoadjuvant hormone therapy, completing up to 6 months in total. Thirty patients were treated with 57 Gy in 19 fractions and 30 patients with 60 Gy in 20 fractions. Acute and 2-year toxicities were reported and patients followed longitudinally to assess 5 year outcomes and long-term toxicity. Toxicity was measured using RTOG criteria and LENT/SOMA questionnaire. Results. Median followup was 84 months. Five-year overall survival (OS) was 83% and biochemical progression-free survival (bPFS) was 50% for 57 Gy. Five-year OS was 75% and bPFS 58% for 60 Gy. At 7 years, toxicity by RTOG criteria was acceptable with no grade 3 or above toxicity. Compared with baseline, there was no significant change in urinary symptoms at 2 or 7 years. Bowel symptoms were stable between 2 and 7 years. All patients continued to have significant sexual dysfunction. Conclusion. In high-risk prostate cancer, dose-escalated hypofractionated radiotherapy using IMRT results in encouraging outcomes and acceptable late toxicity.

Incidentally Found Prostate Cancer and Influence on Overall Survival after Radical Cystoprostatectomy

Sun, 03 Jun 2012 15:24:14 +0000

Objectives. To determine incidentally found prostate cancer frequency and impact on overall survival after RCP. Patients and Methods. The records of 81 men who underwent cystoprostatectomy from January 2000 to December 2009 were reviewed. The vital status of the study group was assessed as on September 1, 2009, by passive followup, using data from the population registry. Results. The 81 men underwent RCP. The incidental prostate cancer was found in the specimens of 27 (33.3%) patients. 13 (48.1%) of 27 prostate cancer cases were clinically significant. For 3 patients (11.1%) an extraprostatic extension was found. For 2 patients (7.4%)—positive margins, for 1 patient (3.7%)—Gleason sum 8, and for the rest 7 patients bigger than 0.5 cm3 volume tumor, and Gleason sum 7 was found. The mean follow-up time was 39.2±33.8 months (varies from 0.8 to 131.2 months). The patients with bladder cancer and incidentally found prostate cancer lived shorter (28.1±27.5 and 45.5±35.40 months). Higher overall survival (𝑃=0.03) was found in the patient group with bladder cancer without incidentally diagnosed prostate cancer. Conclusion. There are indications that in this small study prostate cancer has influenced on patients' survival with bladder cancer after radical cystoprostatectomy.

Expression of Neutral Endopeptidase, Endothelin-1, and Nuclear Factor Kappa B in Prostate Cancer: Interrelations and Associations with Prostate-Specific Antigen Recurrence after Radical Prostatectomy

Tue, 15 May 2012 10:54:23 +0000

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (𝑃<0.001), cytoplasmic ET-1 (𝑃=0.002), and cytoplasmic NFκB (𝑃<0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (𝑃<0.001) and NFκB (𝑃<0.001). ET-1 was also correlated with NFκB (𝑃<0.001). NEP expression (𝑃=0.017), pT stage (𝑃=0.013), and SMs (𝑃=0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.

Markers of Field Cancerization: Proposed Clinical Applications in Prostate Biopsies

Kristina A. Trujillo, Anna C. Jones, Jeffrey K. Griffith, and Marco Bisoffi — Mon, 14 May 2012 13:52:49 +0000

Field cancerization denotes the occurrence of genetic, epigenetic, and biochemical aberrations in structurally intact cells in histologically normal tissues adjacent to cancerous lesions. This paper tabulates markers of prostate field cancerization known to date and discusses their potential clinical value in the analysis of prostate biopsies, including diagnosis, monitoring progression during active surveillance, and assessing efficacy of presurgical neoadjuvant and focal therapeutic interventions.