Markers Of Prostate Cancer Progression Research Articles

Detection of Extracellular Vesicle-Derived RNA as Potential Prostate Cancer Biomarkers: Role of Cancer-type SLCO1B3 and ABCC3.

Extracellular vesicles (EVs) provide a minimally invasive liquid biopsy source of tumor-specific markers for patients who have already undergone prostatectomies. Our laboratory has previously demonstrated enrichment of the cancer-type solute carrier organic anion transporter family 1B3 (ct-SLCO1B3) and the ATP Binding Cassette Subfamily Member C (ABCC3) in castration-resistant cell lines (CRPC). However, their expression in EVs has yet to be explored. Our study demonstrated that ct-SLCO1B3 and ABCC3 are highly detectable in CRPC cell line-derived EVs. We also showed that ct-SLCO1B3 and ABCC3 were detectable in a CRPC xenograft mouse model, both intratumorally and in plasma-derived EVs. Our results provide evidence for EV-contained ct-SLCO1B3 and ABCC3 as novel, EV-based tumor markers for prostate cancer progression.

Immunologic Assessment of Tumors from a Race-matched Military Cohort Identifies Mast Cell Depletion as a Marker of Prostate Cancer Progression.

Our findings demonstrate that there are immune-related genes and pathways that differ by race. Impaired intratumoral cellular immune composition, especially for TIL-normalized mast cells, may be vital in predicting and contributing to prostate cancer disease progression.

Inceptor correlates with markers of prostate cancer progression and modulates insulin/IGF1 signaling and cancer cell migration

ObjectiveThe insulin/insulin-like growth factor 1 (IGF1) pathway is emerging as a crucial component of prostate cancer progression. Therefore, we investigated the role of the novel insulin/IGF1 signaling modulator inceptor in prostate cancer. MethodsWe analyzed the expression of inceptor in human samples of benign prostate epithelium and prostate cancer. Further, we performed signaling and functional assays using prostate cancer cell lines. ResultsWe found that inceptor was expressed in human benign and malignant prostate tissue and its expression positively correlated with various genes of interest, including genes involved in androgen signaling. In vitro, total levels of inceptor were increased upon androgen deprivation and correlated with high levels of androgen receptor in the nucleus. Inceptor overexpression was associated with increased cell migration, altered IGF1R trafficking and higher IGF1R activation. ConclusionsOur in vitro results showed that inceptor expression was associated with androgen status, increased migration, and IGF1R signaling. In human samples, inceptor expression was significantly correlated with markers of prostate cancer progression. Taken together, these data provide a basis for investigation of inceptor in the context of prostate cancer.

P50 - Identification of markers for prostate cancer progression and aggressiveness through proteomic analysis of FFPE tissue samples

P50 - Identification of markers for prostate cancer progression and aggressiveness through proteomic analysis of FFPE tissue samples

Splice-disrupt genomic variants in prostate cancer

BackgroundSplice-disrupt genomic variants are one of the causes of cancer-causing errors in gene expression. Little is known about splice-disrupt genomic variants.Methods and resultsHere, pattern of splice-disrupt variants was investigated using 21,842,764 genomic variants in different types of prostate cancer. A particular attention was paid to genomic locations of splice-disrupt variants on target genes. HLA-A in prostate cancer, MSR1 in familial prostate cancer, and EGFR in both castration-resistant prostate cancer and metastatic castration-resistant had the highest allele frequencies of splice-disrupt variations. Some splice-disrupt variants, located on coding sequences of NCOR2, PTPRC, and CRP, were solely present in the advanced metastatic castration-resistant prostate cancer. High-risk splice-disrupt variants were identified based on computationally calculated Polymorphism Phenotyping (PolyPhen), Sorting Intolerant From Tolerant (SIFT), and Genomic Evolutionary Rate Profiling (GERP) + + scores as well as the recorded clinical significance in dbSNP database of NCBI. Functional annotation of damaging splice-disrupt variants highlighted important cancer-associated functions, including endocrine resistance, lipid metabolic process, steroid metabolic process, regulation of mitotic cell cycle, and regulation of metabolic process. This is the first study that profiles the splice-disrupt genomic variants and their target genes in prostate cancer. Literature mining based variant analysis highlighted the importance of rs1800716 variant, located on the CYP2D6 gene, involved in a range of important functions, such as RNA spicing, drug interaction, death, and urotoxicity.ConclusionsThis is the first study that profiles the splice-disrupt genomic variants and their target genes in different types of prostate cancer. Unravelling alternative splicing opens a new avenue towards the establishment of new diagnostic and prognostic markers for prostate cancer progression and metastasis.

Fresh tissue procurement and preparation for multicompartment and multimodal analysis of the prostate tumor microenvironment.

BackgroundProstatic cancers include a diverse microenvironment of tumor cells, cancer‐associated fibroblasts, and immune components. This tumor microenvironment (TME) is a known driving force of tumor survival after treatment, but the standard‐of‐care tissue freezing or fixation in pathology practice limit the use of available approaches/tools to study the TME's functionality in tumor resistance. Thus, there is a need for approaches that satisfy both clinical and laboratory endpoints for TME study. Here we present methods for clinical case identification, tissue processing, and analytical workflow that are compatible with standard histopathology while enabling molecular and functional interrogation of prostate TME components.MethodsWe first performed a small retrospective review to identify cases where submission of alternate prostate tissue slices and a parallel live tissue processing protocol complement traditional histopathology and enable viable multicompartment analysis of the TME. Then, we tested its compatibility with commonly employed methods to study the microenvironment including quantification of components both in situ and after tissue dissociation. We also evaluated tissue digestion conditions and cell isolation techniques to aid various molecular and functional endpoints.ResultsWe identified Gleason Grade Group 3+ clinical cases where tumor volume was sufficient to allow slicing of unfixed tissue and distribution of alternating tissue slices to standard‐of‐care histopathology and viable multi‐modal TME analyses. No single method was found that preserved cellular sub‐types for all downstream readouts; instead, tissues were further divided so techniques could be catered to each endpoint. For instance, we show that incorporating the protease dispase into tissue dissociation improves viability for culture and functional analyses but hinders immune cell analysis by flow cytometry. We also found that flow activated cell sorting provides highly pure cell populations for quantitative reverse‐transcription polymerase chain reaction and RNA‐seq while isolation using antibody‐labeled paramagnetic particles facilitated functional coculture experiments.ConclusionsThe identification of candidate cases and use of these techniques enable translational research and the development of molecular and functional assays to facilitate prostate TME study without compromising standard‐of‐care histopathological diagnosis. This allows bridging clinical histopathology and further interrogation of the prostate TME and promises to advance our understanding of tumor biology and unveil new predictive and prognostic markers of prostate cancer progression.

AT-rich interactive domain 1A (ARID1A) cannot be considered a morphological marker for prostate cancer progression: A pilot study

Prostate cancer (PCa) is one of the most common cancers worldwide but it presents many subtypes and patient heterogeneity. It is necessary to discriminate localised not aggressive PCa and metastatic cancer in order to better define the personalised treatment. The identification of an appropriate biomarker to combine with Gleason grading system, that is one of the most important prognostic factors in prostate cancer outcome, remains a major clinical issue. We have tested AT-rich interactive domain 1A (ARID1A) in prostate tissue is order to verify its possible role as morphological marker for prostate cancer progression. ARID1A is a tumour suppressor protein playing a pivotal role in chromatin remodelling during transcriptional regulation. It was decreased in many cancers correlating with tumour aggressiveness. Our data shown that ARID1A had a nuclear staining and that it is significantly decreased in prostate cancers suggesting that it can be involved in this neoplasm but it is not able to discriminate prostate cancer progression.

Tissue microarray profiling and integrative proteomics indicate the modulatory potential of Maytenus royleanus in inhibition of overexpressed TPD52 in prostate cancers

Maytenus roylanus (MEM) is a plant with anti-proliferative effects against prostate cancer. We aimed to explore the mechanism of action of MEM in prostate cancer (PCa) by employing an in vitro global proteome approach to get useful information of various signaling pathways and effected genes to define the mechanism of MEM action in prostate cancer. We conducted a global proteome analysis of CWR22Rv1after treatment with methanolic extract of MEM. The result of the proteomic profiling of in vitro PCa cells demonstrated the reduction in tumor protein D52 (TPD52) expression after treatment with methanolic extract of MEM. Down-regulation of TPD52 expression at mRNA level was observed by MEM treatment in CWR22Rν1 and C4-2 cells in a dose-dependent fashion probably by cleavage of Caspase 3 and PARP, or by modulation of cyclin-dependent kinases in CWR22Rν1 and C4-2 cells. The progressive character of the TRAMP model demonstrates a chance to evaluate the potential of chemo-preventive agents for both initial and late stages of prostate cancer development, and induction in TPD52 protein expression with development as well as the progression of prostate cancer was observed in the TRAMP model. Analyses of the tissue microarray collection of 25 specimens confirmed the clinical significance of our findings identifying TPD52 as a potential marker for PCa progression. We determined that knockdown of TPD52 (CWR22Rν1 cells), a considerable downregulation was seen at the protein level. Downregulation of TPD52 inhibited the migration and invasive behavior of prostate cancer cells as observed. Moreover, we observed that the siRNA-TPD52 transfection of CWR22Rν1 cells resulted in tumor growth inhibition with a marked reduction in the secretion of prostate-specific antigen (PSA) in the serum. Intraperitoneal injection of MEM considerably slowed tumor growth in athymic mice, inhibited TPD52 expression, and caused a marked reduction in PSA levels of serum as demonstrated by immunoblot screening and immune-histochemical staining. This report illustrates a molecular overview of pathological processes in PCa, indicating possible new disease biomarkers and therapeutic targets.

Expression of ERBB Family Members as Predictive Markers of Prostate Cancer Progression and Mortality.

Simple SummaryPatients diagnosed with prostate cancer are usually offered a standard treatment plan based on their Gleason score, stage, and prostate-specific antigen (PSA) level. However, studies on other cancers have shown the importance of using biomarkers in addition to clinical and pathologic parameters to personalize therapeutic decisions. Given the important heterogeneity in the natural history of localized prostate cancer, novel prognostic biomarkers would aid in patient stratification and decision making. Here, our study shows that members of the ERBB family are markers that have high prognostic value for predicting biochemical relapse, metastasis development, and even prostate cancer-related mortality. The integration of these markers into clinical practice may eventually lead to more appropriate therapeutic decisions in newly diagnosed patients and potentially reduce prostate cancer morbidity and mortality.Background: EGFR, ERBB2, ERBB3, and ERBB4 are growth receptors of the ERBB family implicated in the development of epithelial cancers. Studies have suggested a role for EGFR and ERBB3 in the development of prostate cancer (PC), while the involvement of ERBB2 and ERBB4 remains unclear. In this study, we evaluated the expression of all members of the ERBB family in PC tissue from a large cohort and determined their contribution, alone or in combination, as prognostic markers. Methods: Using immunofluorescence coupled with digital image analyses, we quantified the expression of EGFR, ERBB2, ERBB3, and ERBB4 on radical prostatectomy specimens (n = 285) arrayed on six tissue microarrays. By combining EGFR, ERBB2, and ERBB3 protein expression in a decision tree model, we identified an association with biochemical recurrence (log rank = 25.295, p < 0.001), development of bone metastases (log rank = 23.228, p < 0.001), and cancer-specific mortality (log rank = 24.586, p < 0.001). Conclusions: Our study revealed that specific protein expression patterns of ERBB family members are associated with an increased risk of PC progression and mortality.

Androgen Receptor Expression of Prostate Cancer Correlates with Gleason Score and Perineural Invasion in West Sumatera, Indonesia

Prostate cancer is the second most common and the fifth leading cause of death by cancer in men worldwide now. The failure of androgen deprivation therapy (ADT) for prostate cancer caused by activated androgen receptor (AR) signaling pathways mostly found. The role of AR in growth and progression of prostate cancer is still unclear. Analysis of AR expression in prostate cancer has never been done in West Sumatera. This study aims to determine AR expression of prostate cancer and correlate with Gleason score and perineural invasion. A total of 56 prostate cancer from department of anatomical pathology in West Sumatera. Hematoxylin and eosin (HE) stained slides and paraffin blocks were retrieved. Slides of all cases were evaluated to review Gleason score, histopathological grading, WHO grade group based on ISUP 2014/WHO 2016 and perineural invasion. Androgen receptor immunohistochemistry (IHC) was applied on all cases. High AR expression was the mostly found (51,79%). The mostly prostate cancer is Gleason score 9 (44,64%), histopathological grading poorly differentiated/undifferentiated (76,78%), WHO grade group 5 (48,21%). Perineural invasion was noted in 39,29%. There was significant statistical correlation between AR expression and Gleason score, but no significant correlation with perineural invasion. AR expression is the important marker of prostate cancer progression.

The metabolic role of PFKFB4 in androgen-independent growth in vitro and PFKFB4 expression in human prostate cancer tissue

BackgroundIt is well known that androgen-deprivation therapy (ADT) can inevitably drive prostate cancer (PCa) cells into a castration-resistant state. According to the “Warburg effect”, the metabolism of aggressive tumor cells increases significantly. The growth of cancer cells depends on glycolysis, which may be a potential target for cancer control. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) plays key roles in the proliferation and metastasis of PCa cells. However, there is very limited knowledge on the role of PFKFB4 in the conversion to castration resistance. The present study aimed to determine the changes in glucose consumption and PFKFB4 expression in LNCaP cells and androgen-independent LNCaP (LNCaP-AI) cells during the whole process of androgen-independent growth. Additionally, PFKFB4 expression in human PCa tissues was evaluated.MethodsWe established an androgen-independent LNCaP-AI cell line derived from LNCaP cells to mimic the traits of castration resistance in vitro. LNCaP-AI and LNCaP cells were cultured in the corresponding medium containing the same amount of glucose. At the end of experiments, the medium supernatant and blank medium were collected, and absorbance was measured. LNCaP-AI and LNCaP cells were harvested to detect PFKFB4 expression by Western blotting. Prostate tissue samples including PCa tissue, carcinoma-adjacent tissue and benign prostatic hyperplasia (BPH) tissue specimens were evaluated for PFKFB4 expression using immunohistochemistry.ResultsIn 18 h supernatant samples, the glucose consumption and lactate secretion of LNCaP-AI cells were higher than those of LNCaP cells. The Western blot results indicated that PFKFB4 expression was increased in LNCaP-AI cells compared with LNCaP cells. Immunohistochemistry revealed that the expression of PFKFB4 in PCa tissue specimens was higher than that in BPH and adjacent tissue specimens. However, the differences in PCa tissue before and after ADT were not statistically significant.ConclusionPFKFB4 may be associated with enhanced glycolysis during the androgen-independent growth of PCa cells in vitro. PFKFB4 may be a marker of PCa progression. Our results provide a rationale for further clinical investigation of PCa treatment focused on controlling PFKFB4 expression.

MiR-210 is induced by hypoxia and regulates neural cell adhesion molecule in prostate cells.

Hypoxia in prostate tumours has been associated with disease progression and metastasis. MicroRNAs are short noncoding RNA molecules that are important in several cell processes, but their role in hypoxic signalling is still poorly understood. miR-210 has been linked with hypoxic mechanisms, but this relationship has been poorly characterised in prostate cancer. In this report, the link between hypoxia and miR-210 in prostate cancer cells is investigated. Polymerase chain reactionanalysis demonstrates that miR-210 is induced by hypoxia in prostate cancer cells using in vitro cell models and an in vivo prostate tumour xenograft model. Analysis of The Cancer Genome Atlas prostate biopsy datasets shows that miR-210 is significantly correlated with Gleason grade and other clinical markers of prostate cancer progression. Neural cell adhesion molecule (NCAM) is identified as a target of miR-210, providing a biological mechanism whereby hypoxia-induced miR-210 expression can contribute to prostate cancer. This study provides evidence that miR-210 is an important regulator of cell response to hypoxic stress and proposes that its regulation of NCAM may play an important role in the pathogenesis of prostate cancer.

Identification of Novel Markers of Prostate Cancer Progression, Potentially Modulated by Vitamin D

Prostate cancer (PCa) is one of the most common cancers in men. The main risk factors associated with the disease include older age, family history of the disease, smoking, alcohol and race. Vitamin D is a pleiotropic hormone whose low levels are associated with several diseases and a risk of cancer. Here, we undertook microarray analysis in order to identify the genes involved in PCa. We analyzed three PCa microarray datasets, overlapped all genes significantly up-regulated, and subsequently intersected the common genes identified with the down-regulated genes transcriptome of LNCaP cells treated with 1α,25(OH)2D3, in order to identify the common genes involved in PCa and potentially modulated by Vitamin D. The analysis yielded 43 genes potentially involved in PCa and significantly modulated by Vitamin D. Noteworthy, our analysis showed that six genes (PRSS8, SOX4, SMYD2, MCCC2, CCNG2 and CD2AP) were significantly modulated. A Pearson correlation analysis showed that five genes out of six (SOX4 was independent), were statistically correlated with the gene expression levels of KLK3, and with the tumor percentage. From the outcome of our investigation, it is possible to conclude that the genes identified by our analysis are associated with the PCa and are potentially modulated by the Vitamin D.

Mouse glutamate carboxypeptidaseII (GCPII) has a similar enzyme activity and inhibition profile but a different tissue distribution to human GCPII.

Glutamate carboxypeptidase II (GCPII), also known as prostate‐specific membrane antigen (PSMA) or folate hydrolase, is a metallopeptidase expressed predominantly in the human brain and prostate. GCPII expression is considerably increased in prostate carcinoma, and the enzyme also participates in glutamate excitotoxicity in the brain. Therefore, GCPII represents an important diagnostic marker of prostate cancer progression and a putative target for the treatment of both prostate cancer and neuronal disorders associated with glutamate excitotoxicity. For the development of novel therapeutics, mouse models are widely used. However, although mouse GCPII activity has been characterized, a detailed comparison of the enzymatic activity and tissue distribution of the mouse and human GCPII orthologs remains lacking. In this study, we prepared extracellular mouse GCPII and compared it with human GCPII. We found that mouse GCPII possesses lower catalytic efficiency but similar substrate specificity compared with the human protein. Using a panel of GCPII inhibitors, we discovered that inhibition constants are generally similar for mouse and human GCPII. Furthermore, we observed highest expression of GCPII protein in the mouse kidney, brain, and salivary glands. Importantly, we did not detect GCPII in the mouse prostate. Our data suggest that the differences in enzymatic activity and inhibition profile are rather small; therefore, mouse GCPII can approximate human GCPII in drug development and testing. On the other hand, significant differences in GCPII tissue expression must be taken into account when developing novel GCPII‐based anticancer and therapeutic methods, including targeted anticancer drug delivery systems, and when using mice as a model organism.

Vitamin D receptor-binding site variants affect prostate cancer progression.

Vitamin D is an important modulator of cellular proliferation through the vitamin D receptor (VDR) that binds to DNA in the regulatory sequences of target genes. We hypothesized that single nucleotide polymorphisms (SNPs) in VDR-binding sites might affect target gene expression and influence the progression of prostate cancer. Using a genome-wide prediction database, 62 SNPs in VDR-binding sites were selected for genotyping in 515 prostate cancer patients and the findings were replicated in an independent cohort of 411 patients. Prognostic significance on prostate cancer progression was assessed by Kaplan-Meier analysis and the Cox regression model. According to multivariate analyses adjusted for known predictors, HFE rs9393682 was found to be associated with disease progression for localized prostate cancer, and TUSC3 rs1378033 was associated with progression for advanced prostate cancer in both cohorts. Vitamin D treatment inhibited HFE mRNA expression, and down-regulation of HFE by transfecting small interfering RNA suppressed PC-3 human prostate cancer cell proliferation and wound healing ability. In contrast, vitamin D treatment induced TUSC3 expression, and silencing TUSC3 promoted prostate cancer cell growth and migration. Further analysis of an independent microarray dataset confirmed that low TUSC3 expression correlated with poor patient prognosis. Our results warrant further studies using larger cohorts. This study identifies common variants in VDR-binding sites as prognostic markers of prostate cancer progression and HFE and TUSC3 as plausible susceptibility genes.

A lifestyle intervention among elderly men on active surveillance for non-aggressive prostate cancer: a randomised feasibility study with whole-grain rye and exercise

BackgroundThe prognosis for men with non-aggressive prostate cancer is good, and several studies have investigated the impact of lifestyle changes including physical activity and diet on the prognosis. Despite positive results in animal studies and a few human interventions with whole-grain rye on markers of prostate cancer progression, the feasibility of trials investigating such dietary changes in combination with physical activity remains largely unstudied. The primary aim was to investigate the feasibility of an intervention with high whole-grain rye intake and vigorous physical activity for 6 months in men diagnosed with prostate cancer.MethodsIn total, 26 men (53–72 years) recently diagnosed with non-aggressive prostate cancer and on active surveillance, were enrolled in 2011–2012 and randomly assigned to an intervention or a control group. The intervention included 170 g/day of whole-grain rye and 3 × 45 minutes/week of vigorous physical activity. The duration of the intervention was 6 months and end of follow-up 12 months after baseline. Clinic visits were scheduled at baseline and 3, 6 and 12 months after baseline. Compliance with the intervention was evaluated by diaries, food frequency questionnaires, biomarkers, and heart rate monitor data. The effect of the intervention was evaluated by linear multiple regression analysis.ResultsIn the intervention group, the mean daily intake of whole-grain rye measured from diaries was 146 g (SD: 19) for the first 3 months and 125 g (SD: 40) for the last 3 months of the intervention. The median level (5th and 95th percentiles) of vigorous physical activity was 91 (17, 193) min/week for the first 3 months and 66 (13, 259) min/week for the last 3 months. No recordings of physical activity were done for the control group. Aerobic fitness (VO2 peak) increased in the intervention group compared to the control group after the intervention. No effects were found on other cardio-metabolic outcomes or prostate cancer progression.ConclusionsThe lifestyle intervention appeared feasible for 6 months among Danish men and the results are encouraging for conducting full-scale studies, where the impact of whole-grain rye and vigorous physical activity on prostate cancer progression and metabolic parameters can be evaluated.Trial registrationClinicalTrials.gov, NCT01300104. Registered on 18 February 2011.

Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression.

Prostate cancer is a heterogeneous disease. MiR-375 is a marker for prostate cancer progression, but its cellular function is not characterized. Here, we provide the first comprehensive investigation of miR-375 in prostate cancer. We show that miR-375 is enriched in prostate cancer compared to normal cells. Furthermore, miR-375 enhanced proliferation, migration and invasion in vitro and induced tumor growth and reduced survival in vivo showing that miR-375 has oncogenic properties in prostate cancer. On the molecular level, we provide the targetome and genome-wide transcriptional changes of miR-375 expression by applying a generalized linear model for Ago-RIP-Seq and RNA-Seq, and show that miR-375 is involved in tumorigenic networks and Polycomb regulation. Integration of tissue and gene ontology data prioritized miR-375 targets and identified the tumor suppressor gene CBX7, a member of Polycomb repressive complex 1, as a major miR-375 target. MiR-375-mediated repression of CBX7 was accompanied by increased expression of its homolog CBX8 and activated transcriptional programs linked to malignant progression in prostate cancer cells. Tissue analysis showed association of CBX7 loss with advanced prostate cancer. Our study indicates that miR-375 exerts its tumor-promoting role in prostate cancer by influencing the epigenetic regulation of transcriptional programs through its ability to directly target the Polycomb complex member CBX7.

Dynamic correlation of serum C-reactive protein (CRP) levels with serum prostate-specific antigen (PSA) levels in patients with prostate cancer (PCa) on androgen deprivation therapy (ADT).

181 Background: CRP, a marker of inflammation, has been associated with disease extent and prognosis in urologic cancers (Huang J, et al. Mol Aspects Med, 2015). In this study we wanted to see whether CRP is dynamically correlated with PSA in patients with PCa when they were on ADT. Methods: 83 patients on ADT were included in this analysis. Their CRP and PSA were recorded longitudinally and the range of length of follow up time is from 3 to 47 (median 16) months. All patients had at least 3 pairs of CRP and PSA measurements available. Statistical analysis was conducted using Dynamic Correlation (Dubin JA, Muller H-G. J Am Stat Assoc, 2005) package ‘dynCorr’ in R 3.1.2, and SAS Version 9.4. Significance levels were set at 0.05. We calculated dynamical correlation as function of time lag between CRP and PSA measurements along with 95% bootstrap confidence intervals and p value. Results: See below table. Conclusions: We found that at lag = 30 days (CRP leads PSA by 30 days), the correlation is significant at level of &lt; 0.05, which means any increase or decrease of CRP at a given time point will lead to about same change in PSA 30 days later. Though these findings must be verified in a larger setting, our results support, in the setting of ADT use, the role of CRP as an early marker of PCa progression and treatment response. [Table: see text]

Significance of p53 and ki-67 expression in prostate cancer.

Background:Prostate cancer is a major health problem throughout the developed world. Tumor grade is one of the most important prognostic factors of prostate cancer. At present, adequate prognostic markers for prostate cancer progression are still lacking, in spite of intensive investigation. Accordingly, we studied the role of immunohistochemical (IHC) expression of p53 and Ki-67 as a prognostic factor in carcinoma prostate and correlated their expression with Gleason's grade.Materials and Methods:In this prospective study, a total of 60 cases including 50 cases of prostate carcinoma and 10 of benign prostatic hyperplasia (BPH) were taken. Tumor grade was determined according to Gleason's grading system. p53 and Ki-67 expressions were determined by IHC staining. The obtained results were analyzed and evaluated using Spearman's statistical test (SPSS version 20).Results:In BPH, p53 was expressed in only 2 of 10 (20%) cases while in carcinoma it was expressed in 38 of 50 (76%) cases. Ki-67 was expressed in only 1 of 10 (10%) BPH cases while in carcinoma it was expressed in 32 of 50 (64%) cases. In present study, 1 of 4 (25%) well differentiated, 23 of 31 (74.19%) moderately differentiated and 14 of 15 (93.33%) poorly differentiated tumors revealed p53 immunopositivity and a statistically significant correlation was observed between p53 expression and increased Gleason's grade (P = 0.038). All 4 (100%) cases of well-differentiated carcinoma were negative for Ki-67 expression. Nineteen of 31 (61.29%) moderately differentiated and 13 of 15 (86.66%) poorly differentiated tumors were positive for Ki-67 and a statistically significant correlation was observed between Ki-67 positivity and increased Gleason's grade (P = 0.002).Conclusions:Both p53 and Ki-67 were significantly up-regulated in malignant lesions as compared to benign lesions and a strong relationship with the Gleason's grading was noticed, therefore, we propose that these markers can be applied along with other prostate cancer prognostic factors.

Abstract 4971: Splicing factor kinase regulates metastatic dissemination of human prostate cancer

Abstract Metastasis causes the vast majority of cancer-associated deaths. Despite its clinical significance, the molecular mechanisms that regulate this multi-step process are poorly understood. To successfully disseminate a cancer cell must escape the primary tumor, travel to a distant site, arrest, enter the stroma and grow in a new microenvironment. The presence of circulating tumor cells in patients with metastatic disease and experimental animals with metastatic cancers suggests that tumor invasion is a critical, rate-limiting step in the metastatic process. To identify the key molecular determinants that regulate invasive metastatic lesion formation we performed the first whole-genome, in vivo RNAi screen in an avian embryo model using advanced intravital imaging techniques. We identified numerous novel regulators of cancer cell invasion, including JL1, a splicing factor kinase. In secondary assays, we demonstrated that JL1-depletion inhibits migration of several human cancer cell lines with no effect on proliferation or survival. Furthermore, JL1-deficient human cancer cells display diminished metastatic potential in chicken embryo and mouse models of metastasis. Cancer microarray database mining shows that JL1 gene expression is strongly associated with indicators of poor clinical outcome in prostate cancer, including pathological Gleason score and metastasis. To experimentally determine JL1 association with advanced disease we performed histological examinations of prostate cancer tissue and determined that JL1 staining strongly correlates with prostate cancer progression. JL1 kinase regulates alternative splicing of numerous cellular transcripts in response to stress and growth signals. To examine the molecular mechanism behind JL1 regulation of cancer cell metastasis, we performed exon level microarray analysis on JL1-depleted cancer cell lines. Subsequent interactome analysis identified an enrichment of key regulatory proteins in pro-metastatic networks. Therefore, we hypothesize that abrogated JL1 activity directly promotes prostate cancer cell migration and invasion. In summary, JL1 is a novel regulator of cancer cell metastasis that represents a potential pathological marker for prostate cancer progression, and novel drug target to block invasion and metastasis. Citation Format: David J. Bond, Konstantin Stoletov, Hon Sing Leong, Emma Woolner, Shuhong Liu, Tarek Bismar, Andries Zijlstra, John D. Lewis. Splicing factor kinase regulates metastatic dissemination of human prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4971. doi:10.1158/1538-7445.AM2014-4971