K. Rasiah

The Propeptide Mediates Formation of Stromal Stores of PROMIC-1: Role in Determining Prostate Cancer Outcome

The extracellular matrix (ECM) is a reservoir of cellular binding proteins and growth factors that are critical for normal cell behavior, and aberrations in the ECM invariably accompany malignancies such as prostate cancer. Carcinomas commonly overexpress macrophage inhibitory cytokine 1 (MIC-1), a proapoptotic and antitumorigenic transforming growth factor-beta superfamily cytokine. Here we show that MIC-1 is often secreted in an unprocessed propeptide containing form. It is variably processed intracellularly, with unprocessed forms being secreted from several tumor lines, including prostate carcinoma lines, PC-3 and LNCaP. Once secreted, only unprocessed proMIC-1 binds ECM, demonstrating for the first time the occurrence of extracellular stores of MIC-1. The propeptide mediates this association via its COOH-terminal 89 amino acids. Xenograft models bearing tumors secreting various engineered forms of MIC-1 show that the propeptide regulates the balance between ECM stores and circulating serum levels of mature MIC-1 in vivo. The absence of propeptide results in approximately 20-fold increase in serum MIC-1 levels. The significance of stromal MIC-1 stores was evaluated in prostate cancer tissue cores, which show major variation in stromal levels of MIC-1. Stromal MIC-1 levels are linked to prostate cancer outcome following radical prostatectomy, with decreasing stromal levels providing an important independent predictor of disease relapse. In low-grade localized prostate cancer (Gleason sum score < or = 6), the level of MIC-1 stromal stores was the best predictor of future relapse when compared with all other clinicopathologic variables. The secretion and ECM association of unprocessed proMIC-1 is likely to play a central role in modulating local bioavailability of MIC-1 which can affect patient outcome in prostate cancer and other epithelial tumors.

Superior Quality of Life and Improved Surgical Margins Are Achievable with Robotic Radical Prostatectomy After a Long Learning Curve: A Prospective Single-surgeon Study of 1552 Consecutive Cases

BACKGROUND Comparative studies suggest functional and perioperative superiority of robot-assisted radical prostatectomy (RARP) over open radical prostatectomy (ORP). OBJECTIVE To determine whether high-volume experienced open surgeons can improve their functional and oncologic outcomes with RARP and, if so, how many cases are required to surpass ORP outcomes and reach the learning curve plateau. DESIGN, SETTING, AND PARTICIPANTS A prospective observational study compared two surgical techniques: 1552 consecutive men underwent RARP (866) or ORP (686) at a single Australian hospital from 2006 to 2012, by one surgeon with 3000 prior ORPs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Demographic and clinicopathologic data were collected prospectively. The Expanded Prostate Cancer Index Composite quality of life (QoL) questionnaire was administered at baseline, 1.5, 3, 6, 12, and 24 mo. Multivariate linear and logistic regression modelled the difference in QoL domains and positive surgical margin (PSM) odds ratio (OR), respectively, against case number. RESULTS AND LIMITATIONS A total of 1511 men were included in the PSM and 609 in the QoL analysis. RARP sexual function scores surpassed ORP scores after 99 RARPs and increased to a mean difference at 861st case of 11.0 points (95% confidence interval [CI], 5.9-16.1), plateauing around 600-700 RARPs. Early urinary incontinence scores for RARP surpassed ORP after 182 RARPs and increased to a mean difference of 8.4 points (95% CI, 2.1-14.7), plateauing around 700-800 RARPs. The odds of a pT2 PSM were initially higher for RARP but became lower after 108 RARPs and were 55% lower (OR: 0.45; 95% CI, 0.22-0.92) by the 866th RARP. The odds of a pT3/4 PSM were initially higher for RARP but decreased, plateauing around 200-300 RARPs with an OR of 1.15 (0.68-1.95) at the 866th RARP. Limitations include single-surgeon data and residual confounding. CONCLUSIONS RARP had a long learning curve with inferior outcomes initially, and then showed progressively superior sexual, early urinary, and pT2 PSM outcomes and similar pT3 PSM and late urinary outcomes. Learning RARP was worthwhile for this high-volume surgeon, but the learning curve may not be justifiable for late-career/low-volume surgeons; further studies are needed.

Expression of the zinc transporter ZnT4 is decreased in the progression from early prostate disease to invasive prostate cancer.

We have utilized oligonucleotide microarrays to identify novel genes of potential clinical and biological importance in prostate cancer. RNA from 74 prostate cancers and 164 normal body samples representing 40 different tissues were analysed using a customized Affymetrix GeneChip® oligonucleotide microarray representative of over 90% of the expressed human genome. The gene for the zinc transporter ZnT4 was one of several genes that displayed significantly higher expression in prostate cancer compared to normal tissues from other organs. A polyclonal antipeptide antibody was used to demonstrate ZnT4 expression in the epithelium of all 165 elements of benign and 326 elements of localized prostate cancers examined and in nine of 10 advanced prostate cancer specimens by immunohistochemistry. Interestingly, decreased intensity of ZnT4 immunoreactivity occurred in the progression from benign to invasive localized prostate cancer and to metastatic disease. Immunofluorescence analysis and surface biotinylation studies of cells expressing ZnT4 localised the protein to intracellular vesicles and to the plasma membrane. These findings are consistent with a role for ZnT4 in vesicular transport of zinc to the cell membrane and potentially in efflux of zinc in the prostate.

High Gleason grade carcinoma at a positive surgical margin predicts biochemical failure after radical prostatectomy and may guide adjuvant radiotherapy.

Study Type – Prognosis (case series)

Aberrant Neuropeptide Y and Macrophage Inhibitory Cytokine-1 Expression Are Early Events in Prostate Cancer Development and Are Associated with Poor Prognosis

Studies to elucidate dysregulated gene expression patterns in premalignant prostate lesions have identified several candidate genes with the potential to be targeted to prevent the development and progression of prostate cancer and act as biomarkers of early disease. Herein, we explored the importance of two proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine-1 (MIC-1), as biomarkers of preinvasive prostate disease and investigated the relationship of expression to biochemical recurrence following treatment for localized prostate cancer. NPY and MIC-1 protein expression was determined by immunohistochemistry on tissue microarrays containing 1,626 cores of benign, low-grade prostatic intraepithelial neoplasia (PIN), high-grade PIN (HGPIN), and prostate cancer tissue from 243 radical prostatectomy patients. Both NPY and MIC-1 showed higher proportional immunostaining in HGPIN and prostate cancer compared with benign epithelium (P < 0.0001). NPY and MIC-1 immunostaining was higher in low-grade PIN compared with other benign tissues (both P < 0.0001) and was equivalent to immunostaining in HGPIN. NPY immunostaining of prostate cancer was independently associated with relapse, after adjusting for traditional prognostic factors, as a categorical variable in 20% intervals (P = 0.0449-0.0103) and as a continuous variable (P = 0.0017). Low MIC-1 immunostaining (20% categories) was associated with pathologic stage >2C after adjusting for predictors of pathologic stage (P = 0.3894-0.0176). This is the first study to show that altered NPY and MIC-1 expression are significantly associated with prostate cancer progression and suggests that these molecules be developed further as biomarkers in the management of prostate disease. (Cancer Epidemiol Biomarkers Prev 2006;15(4):711–6)

HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer

Steroid hormones and their metabolising enzymes have been studied extensively for their potential role in prostate cancer, with more recent interest in the androgen/estrogen inactivating enzyme 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4). Gene expression profiling showed HSD17B4 to be significantly overexpressed in prostate cancer compared to matched-benign epithelium. We therefore hypothesized that altered HSD17B4 expression may contribute to prostate cancer progression via altered hormone balance. In this study, HSD17B4 mRNA and protein expression were assessed by in situ hybridisation (ISH) and immunohistochemistry (IHC), respectively, in tissue arrays of prostate tissue from 172 patients treated by radical prostatectomy. Overexpression of HSD17B4 mRNA and protein was associated with prostate cancer (P<0.0001) and multivariate Cox proportional hazards analysis, adjusted for known prognostic indicators, demonstrated HSD17B4 mRNA and high protein expression were significant independent predictors of poor patient outcome as measured by time until PSA relapse (mRNA: hazards ratio [HR]=1.90, 95% confidence interval [CI]=1.15-3.12; P<0.0001; and protein: HR=2.09, 95% CI=1.31-3.33; P=0.0026). Here we provide strong evidence that both mRNA and protein overexpression of HSD17B4 is not only associated with the presence of prostate cancer, but is also a significant independent predictor of poor patient outcome.

Low AZGP1 expression predicts for recurrence in margin-positive, localized prostate cancer.

Men with positive margins after radical prostatectomy (RP) for localized prostate cancer (PC) have a 40–50% biochemical relapse rate at 5 years. Adjuvant radiotherapy improves biochemical progression‐free and overall survival in men with positive margins, but is associated with increased toxicity. There is an urgent need to identify new prognostic markers to define the group of patients who would benefit from multimodality therapy.

The impact of nerve sparing on incidence and location of positive surgical margins in radical prostatectomy

Study Type – Therapy (case series)

A multiparametric magnetic resonance imaging-based risk model to determine the risk of significant prostate cancer prior to biopsy

To develop and externally validate a predictive model for detection of significant prostate cancer.

High-dose rate brachytherapy compared with open radical prostatectomy for the treatment of high-risk prostate cancer: 10 year biochemical freedom from relapse

Objective •  To compare long‐term biochemical control of high‐risk prostate cancer in those men receiving high‐dose rate brachytherapy (HDRB) and radical prostatectomy (RP).