Raji Kooner

Prognostic significance of Gleason pattern in patients with Gleason score 7 prostate carcinoma

In the current study, the authors sought to further stratify the prognosis of patients with Gleason score (GS) 7 prostate carcinoma. They assessed the influence on outcome of a predominant poorly differentiated Gleason pattern (primary Gleason pattern [GP] 4) and/or a coincident small focus of poorly differentiated tumor of higher grade (tertiary GP 5).

Prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy

Predicting outcome for men with clinically localized prostate carcinoma treated with curative intent remains imprecise and further evaluation of accepted and potential predictive factors is 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.

Membranous Expression of Secreted Frizzled-Related Protein 4 Predicts for Good Prognosis in Localized Prostate Cancer and Inhibits PC3 Cellular Proliferation in Vitro

Purpose: Activation of the Wnt-signaling pathway is implicated in aberrant cellular proliferation in a variety of cancers. Secreted frizzled-related protein 4 (sFRP4) is a secreted protein with putative inhibitory activity of the Wnt-signaling cascade through binding and sequestering Wnt ligands. Because sFRP4 mRNA is overexpressed in prostate cancers (PCs), the aim of this study was to define the pattern of sFRP4 protein expression in normal and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and prognosis, as well as to define the phenotype of sFRP4-overexpression in an in vitro model of PC. Experimental Design: Polyclonal antibodies were raised against a COOH-terminal peptide of sFRP4, characterized and used to assess sFRP4 protein expression in benign prostate tissue and 229 patients with clinically localized PC (median follow-up 77 months, range 1–156). In vitro studies of the function of sFRP4 overexpression were performed using PC3 cells transfected with sFRP4. Results: Benign and malignant prostate tissue demonstrated cytoplasmic sFRP4 immunoreactivity, but there was a decrease in the expression of membranous sFRP4 in PCs compared with the hyperplastic lesions (P < 0.0001). Kaplan-Meier analysis revealed that patients whose PC expressed membranous sFRP4 in >20% of cells had improved relapse-free survival compared with those with ≤20% membranous expression (P = 0.002). Moreover, membranous sFRP4 expression (P = 0.04) was an independent predictor of relapse when modeled with Gleason score (P = 0.006), pathological stage (P = 0.002), and pre-operative prostate-specific antigen levels (P = 0.004). In addition, in vitro studies demonstrated a decrease in the proliferation rate of PC3 cells transfected with sFRP4 when compared with the control PC3-empty vector cells (P < 0.0001). Decreased levels of phosphorylated glycogen synthase kinase 3β in PC3-sFRP4 cells suggested that this phenotype is mediated by the “Wnt/β-catenin” pathway. Conclusions: These data suggest that sFRP4 expression may be prognostic for localized PC, potentially as a consequence of an inhibitory effect on PC cell proliferation.

Prognostic Significance of Pathologic Features in Localized Prostate Cancer Treated With Radical Prostatectomy: Implications for Staging Systems and Predictive Models

PURPOSE Although predicting outcome for men with clinically localized prostate cancer (PC) has improved, the staging system and nomograms used to do this are based on results from the North American health system. To be internationally applicable, these models require testing in cohorts from a variety of different health systems based on the predominant PC case identification methods used. PATIENTS AND METHODS We studied 732 men with localized PC treated with radical prostatectomy and no preoperative therapy between 1986 and 1999 at one Australian institution to determine the effect of clinicopathologic features on disease-free survival. RESULTS Preoperative serum prostate-specific antigen (PSA) concentration, Gleason score, pathologic stage, and year of surgery were independent predictors of outcome. Although margin status demonstrated only a trend toward significance in multivariate modeling overall, it proved to be independent in subgroups based on later year of surgery (1986 to 1994 v 1995 to 1998), preoperative PSA of less than 10 ng/mL, and Gleason score > or = 7. Adjuvant radiation therapy improved disease-free survival rates in patients with multiple surgical margin involvement. CONCLUSION This work confirms the prognostic significance of pathologic stage, Gleason score, and preoperative serum PSA. In the context of a contemporaneous screening effect in Australia, these findings may have implications for methods that predict outcome following surgery as screening becomes more prevalent in a population. The independent prognostic effect of margin status may alter with an increase in the proportion of screening-identified PCs. Staging systems and nomograms that predict outcome following surgery require validation in cohorts with different health practices before being universally applied.

Lower levels of nuclear β‐catenin predict for a poorer prognosis in localized prostate cancer

β‐catenin in its role as a nuclear signaling molecule has been implicated in prostate carcinogenesis primarily through modulation of androgen receptor activity. We defined the pattern of β‐catenin protein expression in the nuclei of normal, hyperplastic and malignant human prostate tissue and determined whether differences in expression were associated with disease progression and prognosis. Five normal prostates, 26 benign prostatic hypertrophy specimens, 232 radical prostatectomy specimens from patients with clinically localized prostate cancer (PC) and 20 cases of advanced PC were assessed for β‐catenin expression using immunohistochemistry. Nuclear β‐catenin expression in localized PC was significantly lower than that in benign prostate tissue (p < 0.001) and significantly higher than that in advanced PC tissue (p < 0.001). In addition, lower levels of nuclear β‐catenin expression (< 10% of cancer cells) predicted for a shorter biochemical relapse‐free survival in patients with localized PC (p = 0.008) and were inversely correlated with preoperative prostate‐specific antigen (PSA) levels (p = 0.01). Analysis of the low‐risk subgroup of patients with preoperative PSA levels < 10 ng/ml demonstrated that lower levels of nuclear β‐catenin expression (< 10% of cancer cells) again predicted for a poorer prognosis (p = 0.006). In conclusion, lower levels of nuclear β‐catenin expression are found in malignant compared to benign prostate tissue. In addition, lower nuclear β‐catenin expression is associated with a poorer prognosis in localized PC, in particular, in the low‐risk subgroup of patients with preoperative PSA levels < 10 ng/ml. Thus, the level of nuclear β‐catenin expression may be of clinical utility as a preoperative prognostic marker in low‐risk localized PC.

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)