Problem Of Prostate Cancer Research Articles

Chromosome-specific segment size alterations are determinants of prognosis in prostate cancer

Currently, risk stratification is the most difficult problem in prostate cancer (PCa) management. Gleason grading cannot adequately predict cancer progression. This study aimed to identify chromosome-specific segment size alterations that could aid risk stratification and predict metastasis using a retrospective cohort-study strategy. A binary logistic regression model was generated using 16 chromosome-specific segments with size alterations (deletions and amplifications) that showed associations with disease stage (primary versus metastatic). The regression model was trained with the MSKCC PIK3R1 PCa cohort (n = 1417), and validated with the TCGA Firehose Legacy (n = 500), MSKCC Prostate Oncogenome Project (n = 218), and the SU2C/PCF Dream Team (n = 150) PCa cohorts. Furthermore, the capacity of the model to predict metastasis between primary tumours with metastasis (n = 54) and primary tumours without metastasis (n = 54) was tested. The accuracy, sensitivity, and specificity of the model at disease stage stratification ranged from 69.02% to 88.55%, 72.8% to 86.00% and 66.30% to 89.50%, respectively. The model also showed good performance at metastasis prediction with accuracy, sensitivity, and specificity of 57.41%, 62.96% and 51.85%, respectively. The study conclusion was that chromosome-specific segment size alterations can aid risk stratification and metastasis prediction. The significance of the study findings is that in combinations with clinical, biochemical, and histopathological variables, chromosome-specific alterations could improve current risk stratification and prediction models for PCa.

Overdiagnosis in urologic cancer : For World Journal of Urology Symposium on active surveillance in prostate and renal cancer.

Cancer, which historically was diagnosed at late and incurable stages, has expanded to a heterogeneous group of conditions that vary from clinically insignificant to rapidly aggressive and lethal. This evolution is due to the widespread use of screening tests for early detection of cancer, both directed (i.e., PSA, mammography, colonoscopy) and undirected (abdominal imaging). The use of these tests has resulted in both benefits and harms. The benefits are a reduction in survival and mortality, due to significant cancers being diagnosed at a more curable stage. The harms are an increase, in some cases dramatic, in the diagnosis of clinically insignificant disease. These are called 'cancer' but not destined to affect the patient's life, even in the absence of treatment. Non-explicit summary of the literature on overdiagnosis of cancer. The phenomenon of overdiagnosis requires two factors: the presence of a common reservoir of microfocal disease and a screening test to find it. These factors exist for breast, prostate, skin, renal, and thyroid cancers, and to a lesser degree for lung cancer. The problem of cancer overdiagnosis and overtreatment is complex, with numerous etiologies and many tradeoffs. It is a particular problem in prostate cancer but is a major issue in many other cancer sites. Screening for prostate cancer based on the best data from prospective randomized trials significantly reduces cancer mortality. However, reducing overtreatment in patients diagnosed with indolent disease is critical to the success of screening. Active surveillance, the focus of this series of articles, is an important strategy to reduce overtreatment. This article reviews the pathological, clinical, social, and psychological aspects of overdiagnosis in cancer.

Xenograft-derived mRNA/miR and protein interaction networks of systemic dissemination in human prostate cancer

BackgroundDistant metastasis formation is the major clinical problem in prostate cancer (PCa) and the underlying mechanisms remain poorly understood. Our aim was to identify novel molecules that functionally contribute to human PCa systemic dissemination based on unbiased approaches. MethodsWe compared mRNA, microRNA (miR) and protein expression levels in established human PCa xenograft tumours with high (PC-3), moderate (VCaP) or weak (DU-145) spontaneous micrometastatic potential. By focussing on those mRNAs, miRs and proteins that were differentially regulated among the xenograft groups and known to interact with each other we constructed dissemination-related mRNA/miR and protein/miR networks. Next, we clinically and functionally validated our findings. ResultsBesides known determinants of PCa progression and/or metastasis, our interaction networks include several novel candidates. We observed a clear role of epithelial-to-mesenchymal transition (EMT) pathways for PCa dissemination, which was additionally confirmed by an independent human PCa model (ARCAP-E/-M). Two converging nodes, CD46 (decreasing with metastatic potential) and DDX21 (increasing with metastatic potential), were used to test the clinical relevance of the networks. Intriguingly, both network nodes consistently added prognostic information for patients with PCa whereas CD46 loss predicted poor outcome independent of established parameters. Accordingly, depletion of CD46 in weakly metastatic PCa cells induced EMT-like properties in vitro and spontaneous micrometastasis formation in vivo. ConclusionsThe clinical and functional relevance of the dissemination-related interaction networks shown here could be successfully validated by proof-of-principle experiments. Therefore, we suggest a direct pro-metastatic, clinically relevant role for the multiple novel candidates included in this study; these should be further exploited by future studies.

Cell surface Thomsen-Friedenreich proteome profiling of metastatic prostate cancer cells reveals potential link with cancer stem cell-like phenotype.

The tumor-associated Thomsen-Friedenreich glycoantigen (TF-Ag) plays an important role in hematogenous metastasis of multiple cancers. The LTQ Orbitrap LC-MS/MS mass spectrometry analysis of cell surface TF-Ag proteome of metastatic prostate cancer cells reveals that several cell surface glycoproteins expressing this carbohydrate antigen in prostate cancer (CD44, α2 integrin, β1 integrin, CD49f, CD133, CD59, EphA2, CD138, transferrin receptor, profilin) are either known as stem cell markers or control important cancer stem-like cell functions. This outcome points to a potential link between TF-Ag expression and prostate cancer stem-like phenotype. Indeed, selecting prostate cancer cells for TF-Ag expression resulted in the enrichment of cells with stem-like properties such as enhanced clonogenic survival and growth, prostasphere formation under non-differentiating and differentiating conditions, and elevated expression of stem cell markers such as CD44 and CD133. Further, the analysis of the recent literature demonstrates that TF-Ag is a common denominator for multiple prostate cancer stem-like cell populations identified to date and otherwise characterized by distinct molecular signatures. The current paradigm suggests that dissemination of tumor cells with stem-like properties to bone marrow that occurred before surgery and/or radiation therapy is largely responsible for disease recurrence years after radical treatment causing a massive clinical problem in prostate cancer. Thus, developing means for destroying disseminated prostate cancer stem-like cells is an important goal of modern cancer research. The results presented in this study suggest that multiple subpopulation of putative prostate cancer stem-like cells characterized by distinct molecular signatures can be attacked using a single target commonly expressed on these cells, the TF-Ag.

Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis.

Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3) promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR (qMSP) analysis of a large radical prostatectomy (RP) cohort (n = 292), we found that the TFF3 promoter was significantly hypomethylated in PC compared to non-malignant (NM) prostate tissue samples (p < 0.001) with an AUC (area under the curve) of 0.908 by receiver operating characteristics (ROC) curve analysis. Moreover, significant TFF3 promoter hypomethylation (p ≤ 0.010) as well as overexpression (p < 0.001) was found in PC samples from another large independent patient sample set (498 PC vs. 67 NM) analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. TFF3 promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression was significantly associated with high ERG, ETS transcription factor (ERG) expression (p < 0.001), as well as with high Gleason score (p < 0.001), advanced pathological T-stage (p < 0.001), and prostate-specific antigen (PSA) recurrence after RP (p = 0.013; univariate Cox regression analysis). There were no significant associations between TFF3 promoter methylation levels, ERG status, or PSA recurrence in these RP cohorts. In conclusion, our results demonstrated diagnostic biomarker potential of TFF3 promoter hypomethylation for PC as well as prognostic biomarker potential of TFF3 RNA expression. To the best of our knowledge, this is the most comprehensive study of TFF3 promoter methylation and transcriptional expression in PC to date.

THE USE OF MODERN ANALOGUES OF LUTEINIZING HORMONE RELEASING HORMONE IN THE HORMONAL THERAPY IN PATIENTS WITH PROSTATE CANCER

The urgency of the problem of prostate cancer (PC) remains extremely high due to the continued growth of morbidity and mortality from this disease. Despite the introduction of diagnostics with the use of prostate specific antigen (PSA) and the increase in the number of cases of detection of localized forms of the disease, frequency of detection in the primary treatment of patients with advanced and metastatic prostate cancer remains high. Therapy aimed at reducing testosterone levels in the body of the patient with metastatic prostate cancer is the gold standard of treatment, so surgical or pharmacological castration to reduce testosterone levels, are generally accepted methods of therapy. Hormone therapy (HT) using a pharmacological castration is the major and most commonly used method of treatment of patients with metastatic prostate cancer, the effectiveness of which is comparable with surgical castration. The article presents a review of studies that compared the effectiveness and side effects of HT with the use of surgical and medical castration, as well as the results of domestic studies evaluated the effectiveness of the application of the drug buserelin-domestic analogue of LHRH.

Stimulation of cellular senescent processes, including secretory phenotypes and anti-oxidant responses, after androgen deprivation therapy in human prostate cancer

Endocrine resistance is a major problem in prostate cancer. Recent studies suggest that cellular plasticity plays a key role in therapy resistance. Yet little is known about the cellular changes of human prostate cancer after androgen deprivation therapy (ADT). In this study, we investigated cellular senescence, senescence-associated secretory phenotypes (SASPs), and anti-oxidant responses. Hormone ablation upregulated senescence-associated (SA)-β-Gal activity in prostate glands, as well as the expressions of p27KIP1 and p53, in a mouse castration model. In line with this, the expressions of p21CIP1 and p27KIP1 were significantly more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. In a study of SASP markers, the expressions of IL6 and IL8 were also more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. IL6, IL8, and MMP2 were expressed more strongly in human prostate cancer specimens resected after ADT than in untreated tumors. Of note, treatment with the anti-oxidant reagent NAC significantly suppressed SA-β-Gal activity in androgen-sensitive human prostate cancer LNCaP cells. In immunohistochemical analyses on anti-oxidant response genes, NRF2 and NQO1 were more upregulated after hormone ablation in human prostate gland and carcinoma specimens after ADT than in untreated specimens or in murine prostate glands after castration. Taken together, these findings suggest that ADT induces cellular senescence processes accompanied by secretory phenotypes and anti-oxidant responses in prostate. These cellular changes may be attractive targets for preventing endocrine resistance in prostate cancer.

Abstract A283: PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance.

Abstract Purpose: Radioresistance is a major problem in prostate cancer (CaP) radiotherapy (RT). The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway plays a central role in cancer metastasis and radioresistance. This study aimed to evaluate the effects of combination of dual or single inhibitors targeting PI3K/Akt/mTOR pathway proteins with RT in CaP radioresistant (RR) cells in vitro. Experimental Design: Three CaP-RR cell lines (PC-3RR, DU145RR, and LNCaPRR) were established in our laboratory by radiation treatment and their radioresistance was confirmed by colony assay. The half maximal inhibitory concentration (IC50) values of four inhibitors including two dual inhibitors (BEZ235 and PI103) and two single inhibitors (BKM120 and Rapamycin) were tested by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in CaP RR cells. Combination of 1/2 IC50 doses of each inhibitor with RT was examined to decide which inhibitor has a better capability to improve radiosensitivity of CaP-RR cells by cologenic assay and apoptosis assays. Results: We found that CaP-RR cells are associated with epithelial-mesenchymal transition (EMT) and enhanced cancer stem cell phenotypes, and the activation of PI3K/Akt/mTOR signaling pathway. We also found that the combination of single inhibitor either BKM120 (targeting PI3k) or rapamycin (Targeting mTOR) with RT had limited capability to improve radiosensitivity, including less regression of colony formation and inducing less apoptosis in CaP RR cells, whereas dual inhibitor BEZ235 or PI103 combined with RT could effectively improve radiosensitivity, obviously inhibit CaP RR cells in colony ability (P&amp;lt;0.05), and induce more apoptosis (P&amp;lt;0.05). Conclusions: Our findings suggest that PI3K/Akt/mTOR pathway is actively involved in CaP radioresistance and the dual PI3K/Akt/mTOR inhibitors (BEZ235 and PI103) have obvious advantages over single inhibitors in sensitizing radiation therapy and overcome CaP radioresistance. Using a PI3K/mTOR dual inhibitor with RT is a promising modality for the treatment of CaP to overcome radioresistance and this combination approach is worthwhile for future animal study and clinical trials. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A283. Citation Format: Lei Chang, Peter Graham, Jingli Hao, Jie Ni, Joseph Bucci, Paul Cozzi, John Kearseley, Yong Li. PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A283.

Team science on a smaller scale

Team science on a smaller scale

Abstract 1503: Cancer testis antigen SPANXB2 and prostate cancer progression: Human prostate stroma promotes SPANXB2 expression

Abstract A critical problem in prostate cancer is our inability to reliably distinguish indolent from aggressive disease. Recent evidence has implicated a class of genes, termed Cancer Testis Antigens (CTA) that uniquely expressed on malignant tissue, in cancer progression. CTA SPANXB2 was reported to be associated with aggressive and metastasis of melanoma and other cancers. The role of SPANXB2 in prostate cancer is still uncertain. In preliminary studies, we observed that the CTA SPANXB2 is up-regulated in mRNA level in metastatic prostate cancer xenograft models (PC3 cells injected in mouse dorsal prostate with Matrigel). Compared with other injection sites, mouse dorsal prostate enriched prostate stroma. Therefore, we further tested whether prostate stroma is the key factor to influence SPANXB2 expression and enhance the metastasis potential of prostate cancer cells. We validated this through an in vitro epithelial-stroma interaction models: GFP labeled PC3 cells were placed on the top of human prostate stromal cells (HPS-19I); two days later PC3-GFP cells were isolated through flow cytometry with high purity (&amp;gt; 99%). By real time PCR, the expression level of SPANXB2 in these purified PC3-GFP cells was found to be upregulated up to 10 folds. We also tested DU145 and LNCaP in this same model, and similar results were obtained. We further examined the migration and invasion ability of these cells and found that stromal exposed cells gained an enhanced ability to migrate and invade. Interestingly, we also observed that the stem cells marker, CD24 was highly up -regulated up to 6 folds in PC3 cells after co-culture with HPS-19I. In addition, we treated PC3 cells with TGF-β1 and TGF-β2, and noted that SPANXB2 and CD24 were significantly increased in PC3 cells after 24 hours treatment with TGF-β2. Our results reveal that i) the interaction between human prostate stromal cells and prostate cancer cells promote CTA-SPANXB2 and CD24 expression in prostate cancer cells, ii) these interactions further enhance the migration and invasion ability of prostate cancer cells and iii) TGF-β2 may regulate SPANXB expression relevant cells. These data provide rationale for studying SPANXB2 in stromal-epithelial interactions and may be potentially used to pinpoint druggable targets that drive metastasis and that distinguish indolent from aggressive prostate cancer. Keywords: Cancer testis antigen, SPANXB2, Prostate cancer, Metastasis, Stoma Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1503. doi:1538-7445.AM2012-1503

Underdiagnosis More of a Problem in Prostate Cancer Than Overdiagnosis

Underdiagnosis More of a Problem in Prostate Cancer Than Overdiagnosis

Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of skeletal changes in prostate cancer

Skeletal metastases are a significant problem in prostate cancer (PC). The patients are also exposed to treatment-related skeletal changes. This cross-sectional study evaluated a marker of bone resorption, TRACP 5b in relation to the standard analyte total alkaline phosphatase (tALP) as a marker of skeletal changes. Serum levels of TRACP 5b, tALP and PSA were measured in 130 prostate cancer patients. Comparison was made between patients with (BM+, n = 25) and without (BM−, n = 105) skeletal metastases, and between those treated with (n = 64) or without (n = 66) androgen deprivation (AD). Sensitivities and specificities were calculated for each marker and diagnostic accuracy was evaluated by ROC curve analysis. ROC curves indicated the superior accuracy of tALP, whereas TRACP 5b and PSA were comparable. With tALP the best combination of sensitivity (96%) and specificity of (91%) was reached at a cut-off point 224 U/L, the corresponding values were for TRACP 5b sensitivity (76%), specificity (89%) with a cut-off point 4.89 U/L, and for PSA sensitivity (65%), specificity (81%) at 23 ng/L for skeletal metastases. Patients treated with AD showed with increasing duration an increase in TRACP 5b values. TRACP 5b was less specific than tALP as a marker of skeletal metastases. TRACP 5b may have a role in the diagnostics of skeletal changes in PC with a focus on treatment-related skeletal changes.

Natural history of prostate cancer--epidemiologic considerations.

Multicentricity, heterogeneity, and sampling error complicate the study of the natural history of prostate cancer. Carcinomas previously termed "latent" are probably similar to those detected clinically. The diagnosis of carcinoma is only made following biopsy and histologic confirmation. Estimates of grade and stage made at the time of detection are prone to sampling error and are likely to change following examination of radical prostatectomy specimens. In regions with lower life expectancies, the problem of prostate cancer becomes a lower priority due to its association with aging. Access to care, numbers of medical facilities, and differing public health priorities make international rates difficult to compare. However, in view of the high worldwide prevalence of the disease, further epidemiologic studies of prostate cancer are warranted.

Incidence of prostate cancer will double by the year 2030: the argument for.

Prostate cancer is a frequent cancer in old men which increases with age and is associated with wide geographical variation. Even if age-specific incidence rates remain stable, the problem of prostate cancer seems certain to increase in absolute terms simply because of the ageing of the population. This will have major economic implications for the future, particularly in Westernised societies, with any temporal trend in risk serving only to further compound the problem. However, since the risk of dying from prostate cancer has remained unchanged in many countries throughout this century, it may be that the increased incidence may be the result of increasing transurethral resection of the prostate procedures or screening techniques which have increased the detection and reporting of prostate cancer.

The optimization and inherent limitations of 3D conformal radiotherapy treatment plans of the prostate.

This paper describes the applications of an inverse planning optimization algorithm to the real clinical problem of prostate cancer. The algorithm has been designed to compute optimized beam-weights taking full account of three-dimensional spatial information of dose inside the patient. The algorithm is based on fast simulated annealing, utilizing a cost-function containing both linear and quadratic terms. The linear part of the cost function allows for the implementation of "short-cuts" in the cost-function computation, which reduces the calculation time by a factor of about 30. It has been applied to compute optimized beam-weights for a three-field and a seven-field prostate treatment plan. It is shown for the three-field plan that the optimization algorithm can reproduce, and even slightly improve on, the results of an experienced human planner. For the seven-field plan, the human planner experienced difficulty finding beam-weights that gave an acceptable dose distribution. It is shown that the optimization algorithm can achieve good results in this case. The outcome of the optimization of the seven-field plan prompted an investigation into the best results that could be achieved by an "ideal" conformal radiotherapy technique. The results of this investigation are presented and it is shown that the limiting factor for conformal therapy of the prostate is the size of the overlap volume between the planning target volume (PTV) and the rectum. Finally, the efficiency and accuracy of fast simulated annealing is compared with that of classical simulated annealing. The former was found to be at least 10 times faster for the problem studied.

Problem of Prostate Cancer

Problem of Prostate Cancer

Editorial: Perspectives on the Problem of Prostate Cancer

Editorial: Perspectives on the Problem of Prostate Cancer

Prostate cancer in blacks: an update from the American College of Surgeons' patterns of care studies.

Data from the American College of Surgeons' prostate cancer surveys covering nearly a decade of experience demonstrate that the problem of prostate cancer is unique among black men in the United States. These data show that the distribution of stage at diagnosis changed across the 10-year interval. The data indicate that there have been improvements in the 5-year survival rates of both black and white patients, but the prostate cancer-specific survival of black patients remains significantly poorer than that of whites.