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Prostate cancer is the second most common cancer diagnosed in men worldwide; however, few patients are affected by clinically significant disease within their lifetime. Unfortunately, the means to discriminate between patients with indolent disease and those who progress to aggressive prostate cancer is currently unavailable, resulting in over-treatment of patients. We therefore aimed to determine biomarkers of prostate cancer that can be used in the clinic to aid the diagnosis and prognosis. Immunohistochemistry analysis was carried out on prostate cancer specimens with a range of Gleason scores. Samples were stained and analysed for intensity of the Seven Transmembrane Epithelial Antigen of the Prostate (STEAP)-1, -2, -3, -4 and the Divalent Metal Transporter 1 (DMT1) proteins to determine suitable biomarkers for classification of patients likely to develop aggressive prostate cancer. Additionally, these proteins were also analysed to determine whether any would be able to predict future relapse using Kaplan Meier analysis. Data generated demonstrated that the protein expression levels of STEAP2 correlated significantly with Gleason score; furthermore, STEAP4 was a significant predictor of relapse. This data indicates that STEAP2 could be potential prognostic candidate for use in combination with the current prostate cancer detection methods and the presence of STEAP4 could be an indicator of possible relapse.

Currently available methods for diagnosis and staging of prostate cancer lack the sensitivity to distinguish between patients with indolent prostate cancer and those requiring radical treatment. Alterations in key adherens (AJ) and tight junction (TJ) components have been hailed as potential biomarkers for prostate cancer progression but the majority of research has been carried out on individual molecules. To elucidate a panel of biomarkers that may help distinguish dormant prostate cancer from aggressive metastatic disease. We analysed the expression of 7 well known AJ and TJ components in cell lines derived from normal prostate epithelial tissue (PNT2), non-invasive (CAHPV-10) and invasive prostate cancer (LNCaP, DU145, PC-3) using gene expression, western blotting and immunofluorescence techniques. Claudin 7, α -catenin and β-catenin protein expression were not significantly different between CAHPV-10 cells and PNT2 cells. However, in PC-3 cells, protein levels for claudin 7, α -catenin were significantly down regulated (-1.5 fold, p = <.001) or undetectable respectively. Immunofluoresence showed β-catenin localisation in PC-3 cells to be cytoplasmic as opposed to membraneous. These results suggest aberrant Claudin 7, α - and β-catenin expression and/or localisation patterns may be putative markers for distinguishing localised prostate cancer from aggressive metastatic disease when used collectively.

Six-transmembrane epithelial antigen of the prostate-2 (STEAP2) expression is increased in prostate cancer when compared to normal prostate, suggesting STEAP2 may drive prostate cancer progression. This study aimed to establish the functional role of STEAP2 in prostate tumourigenesis and evaluate if its knockdown resulted in reduced invasive potential of prostate cancer cells. PC3 and LNCaP cells were transfected with STEAP2 siRNA and proliferation, migration, invasion and gene expression analyses were performed. STEAP2 immunohistochemistry was applied to assess the protein expression and localisation according to Gleason score in 164 prostate cancer patients. Invasion significantly decreased in both cell lines following STEAP2 knockdown. PC3 proliferation and migration capacity significantly reduced, while LNCaP cell morphology and growth characteristics were altered. Additionally, STEAP2 downstream targets associated with driving invasion were identified as MMP3, MMP10, MMP13, FGFR4, IL1β, KiSS1 and SERPINE1 in PC3 cells and, MMP7 in LNCaP cells, with CD82 altered in both. In patient tissues, STEAP2 expression was significantly increased in prostate cancer samples and this significantly correlated with Gleason score. These data demonstrate that STEAP2 drives aggressive prostate cancer traits by promoting proliferation, migration and invasion and significantly influencing the transcriptional profile of ten genes underlying the metastatic cascade.

Prostate adenocarcinoma is the second most frequent cancer worldwide and is one of the leading causes of male cancer-related deaths. However, it varies greatly in its behaviour, from indolent non-progressive disease to metastatic cancers with high associated mortality. The aim of this study was to identify predictive biomarkers for patients with localised prostate tumours most likely to progress to aggressive disease, to facilitate future tailored clinical treatment and identify novel therapeutic targets. The expression of 602 genes was profiled using oligoarrays, across three prostate cancer cell lines: CA-HPV-10, LNCaP and PC3, qualitatively identifying several potential prognostic biomarkers. Of particular interest was six transmembrane epithelial antigen of the prostate ( STEAP ) 1 and STEAP 2 which was subsequently analysed further in prostate cancer tissue samples following optimisation of an RNA extraction method from laser captured cells isolated from formalin-fixed paraffin-embedded biopsy samples. Quantitative analysis of STEAP1 and 2 gene expression were statistically significantly associated with the metastatic cell lines DU145 and PC3 as compared to the normal prostate epithelial cell line, PNT2. This expression pattern was also mirrored at the protein level in the cells. Furthermore, STEAP2 up-regulation was observed within a small patient cohort and was associated with those that had locally advanced disease. Subsequent mechanistic studies in the PNT2 cell line demonstrated that an over-expression of STEAP2 resulted in these normal prostate cells gaining an ability to migrate and invade, suggesting that STEAP2 expression may be a crucial molecule in driving the invasive ability of prostate cancer cells.

Purpose ARFs are a family of Ras-related GTP binding proteins, ARF6, in particular, is implicated in cancer invasion and metastasis. However, the role of ARF proteins in prostate cancer have yet to be investigated. Methods Immunohistochemical staining for ARF6 was performed on a prostate cancer tissue microarray with patient matched normal specimens. Results Antibody staining was significantly over-expressed in prostate cancer patient samples compared to normal patient tissue and a trend towards increased staining intensity in cancer samples with Gleason scores of 8 and above (metastatic disease). Conclusion Due to high homology between members of the ARF family we could not determine if ARF 6 was the only ARF over-expressed in the prostate cancer samples. However, we are the first to show that ARF-GTPases are over expressed in prostate cancer which provides further insight into the molecular biology of prostate cancer.

IntroductionRight ventricular (RV) function is a prognostic factor in patients with idiopathic PAH (iPAH). However at diagnosis, no factors differentiate those who will progress to RV dysfunction at 1 year. RV dysfunction in disease becomes more manifest on exercise and there is interest in the capacity of the RV to augment during exercise and its relationship with outcomes. Cardiac magnetic resonance imaging (CMR) is an accurate method of evaluating cardiac function during exercise. We aimed to study the ability of CMR to detect changes in RV and left ventricular (LV) function during exercise in healthy controls (HC) and patients with iPAH and hypothesised that RV dysfunction in iPAH becomes more apparent on exercise. Methods: Resting and exercise CMR was carried out on 10 HC (6 women, average age 36 ± 12) and 10 patients with iPAH (8 women, average age 37 ± 9) using a Philips 1.5T Achieva (Best, Netherlands) with a 32-channel cardiac coil. Supine exercise was performed using an MR compatible ergometer (Lode, Netherlands) at 40% of the watts achieved on cardiopulmonary exercise testing. Free breathing, real time LV short axis stack images were acquired during rest and exercise. LV and RV volumes were analysed using cvi42 (Circle Cardiovascular Imaging, Canada) using conventional endocardial surface segmentation. The Wilcoxon signed rank test was used to compare within groups and the Mann Whitney U test for between group analysis. Results: Results are summarised in Table 1. HCs exercised at a mean of 81 ± 25W and patients at a mean of 44 ± 11W. In HCs, RV and LV stroke volume (SV) increased on exercise, driven by a decrease in RV and LV end systolic volume (ESV). LV and RV ejection fraction (EF) increased. In patients, LVEDV and LVESV decreased on exercise, with an increase in LVSV and LVEF. RVEDV increased in size with a trend for ESV to be higher than at rest. RVSV and RVEF remained unchanged. Between groups, at rest, LVESV and LVSV were lower in patients with no significant differences in RV function. However, on exercise, patients had a significantly higher RVESV and lower RVSV and RVEF, compared to HCs. Conclusion: Exercise CMR is a sensitive, accurate test which can determine physiological changes in RV and LV function. We have shown that on exercise, when compared to HC, the LV in patients with iPAH decreases in size, the RV increases in size and RV dysfunction becomes apparent which was otherwise not present at rest. This could potentially be valuable in the assessment of response to treatment and prognosis in patients with iPAH.Abstract 125 Table 1Resting and Exercise cardiac parameters, values are expressed as mean ± standared deviation

Pulmonary arterial dilatation associated with pulmonary hypertension may result in significant compression of local structures. Left main coronary artery and left recurrent laryngeal nerve compression have been described. Tracheobronchial compression from pulmonary arterial dilatation is rare in adults, and there are no reports in the literature of its occurrence in idiopathic pulmonary arterial hypertension. Compression in infants with congenital heart disease has been well described. We report 2 cases of tracheobronchial compression: first, an adult patient with idiopathic pulmonary arterial hypertension who presents with symptomatic left main bronchus compression, and second, an adult patient with Eisenmenger ventricular septal defect and right-sided aortic arch, with progressive intermedius and right middle lobe bronchi compression in association with enlarged pulmonary arteries.