Original article
Tumor necrosis factor-related apoptosis inducing ligand-R4 decoy receptor expression is correlated with high Gleason scores, prostate-specific antigen recurrence, and decreased survival in patients with prostate carcinoma

https://doi.org/10.1016/j.urolonc.2007.01.022Get rights and content

Abstract

Objective

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has recently been investigated because of its ability to selectively kill cancer cells. Despite recent publications mainly focusing on TRAIL resistance in cancer cells, little is known about how TRAIL contributes to the carcinogenesis process. Because the expression patterns of TRAIL and its receptors in patients with prostate carcinoma have recently been reported, this study investigated the significance of TRAIL and TRAIL receptor expression in connection to serum prostate-specific antigen (PSA) and Gleason scoring.

Materials and methods

A total of 98 patients were included in the study. Gleason scores, PSA, TRAIL, and TRAIL receptor expressions were used for the comparison purposes. The Spearman rho correlation test was administered to reveal the correlations among the variants. The Kruskal Wallis-Mann Whitney U or Friedman-Wilcoxon signed ranks test determined the statistical significance between the pairs. Multinomial and/or multiple binary logistic regression analyses were deployed to test whether TRAIL markers were independent variables to predict the prognosis of prostate cancer. Kaplan-Meier and log-rank tests were used to determine the survival rates.

Results

High-serum PSA levels were correlated with higher levels of TRAIL and TRAIL receptor expressions. Patients with high Gleason scores had higher levels of TRAIL-R4 decoy receptor expression but lower levels of TRAIL death ligand expression.

Conclusions

TRAIL-R4 decoy receptor expression is strongly correlated with PSA recurrence, which is suggestive of poor prognosis. High levels of TRAIL-R4 expression but low levels of TRAIL death ligand expression are connected to decreased survival.

Introduction

Prostate cancer is 1 of the most frequently diagnosed malignancies among men in the Western world, and 29,900 cases of death are expected this year in the United States alone [1]. The proper assessment of the prostate cancer progression is a pivotal step when counseling the patient for the curative versus palliative therapy. Stage, Gleason score, and serum prostate-specific antigen (PSA) are all well-established prognostic factors that are routinely used in the clinical decision-making process [2]. Despite the fact that numerous studies linked high-serum PSA levels to the clinically advanced stages of prostate carcinoma [3], in most cases, serum PSA measurement alone does not provide an accurate assessment of the disease progression for a given patient [4]. For example, preoperative evaluation of the serum PSA in patients with prostate cancer is confounded by both the volume of the benign prostate tissue present [5] and also the tumor grade [6]. Of the many histologic grading systems introduced to help to predict the pathologic stage and prognosis of prostate cancer, the most commonly used is the Gleason system [7], [8]. Despite this fact, even Gleason score alone is insufficient to predict accurately the pathologic stage because of a previously described phenomenon of histologic upgrading from biopsy to prostatectomy specimens [8], [9]. Currently, earlier staging systems of prostate carcinoma mainly rely on the digital rectal examination (DRE). However, its relative lack of sensitivity (52%) limits DRE [3]. Thus, traditional prognostic markers (grade, clinical stage, and pretreatment PSA) are of limited predictive value for the pathologic staging of the prostate carcinoma. Consequently, additional markers are strongly needed to define high-risk patients more accurately for both the pathologic staging and forthcoming therapies of prostate carcinoma.

Genes involved in the cellular proliferation such as tumor repressor genes (phosphatase and tensin homolog, etc.) [10], [11] and those genes controlling the cell death [12] are very attractive for investigation because of their potential to be used as prognostic markers to predict the disease progression. One such marker is the tumor necrosis factor-related apoptosis inducing ligand (TRAIL), which is an apoptosis-inducing member of the tumor necrosis factor family [13]. Investigations concerning TRAIL have become very popular because of its therapeutic potential as a result of selective apoptosis inducing properties on cancer cells [14]. However, it is still unclear how TRAIL and TRAIL receptor expression profiles influence the carcinogenesis process. TRAIL can interact with 4 distinct receptors. Two of these receptors, DR4 (TRAIL-R1) and DR5 (TRAIL-R2), are membrane-spanning proteins containing intracellular death domains essential for the transmission of the death signal upon TRAIL binding and receptor trimerization. Two other membrane receptors, DcR1 (TRAIL-R3) and DcR2 (TRAIL-R4), can also bind TRAIL but lack death domains and are unable to induce cell death [15]. Because the presence or absence of TRAIL decoy receptors were connected to the sensitivity of cancer cells to apoptotic ligands [16], [17], [18], the modulation of TRAIL and TRAIL receptor expression might be essential for the progression of prostate cancer [19]. Therefore, the aim of this study was to investigate the potential connection of TRAIL and its receptors to the currently known prognostic factors (serum PSA and Gleason scoring) for a better assessment of prostate carcinogenesis.

Section snippets

Clinical assessment of patients with prostate cancer

A total of 44 patients with benign prostate hyperplasia (BPH), 28 with organ-confined prostate carcinoma and 26 with advanced prostate carcinoma, admitted to the Urology Clinic of Akdeniz University Hospitals were included in the study. Pretreatment PSA levels were obtained from patient’s serum in the Central Laboratory of Akdeniz University Hospitals. Pathologists determined the Gleason score for each patient. Patients with advanced prostate cancer possessed clinical and radiologic evidence of

TRAIL and TRAIL receptor expressions are positively correlated with serum PSA levels

Serum PSA levels of 98 patients with prostate problems (44 patients with BPH, 28 with organ-confined prostate carcinoma, and 26 with advanced prostate carcinoma) were determined as described in the Materials and methods. Normality of the patient groups was tested using the Shapiro-Wilk method. Because neither group displayed a gaussian distribution, a nonparametric correlation analysis (Spearman rho correlation test) was applied to document any possible correlation between the serum PSA levels

Discussion

Prostate cancer is the most frequently diagnosed cancer type, and it is only the second to lung cancer in cancer-related deaths [1]. The widespread use of the PSA measurement as a diagnostic tool has resulted in a 20% increase in the detection of clinically localized prostate cancer. Despite this result, approximately one third of the newly diagnosed cases are regarded as locally advanced at diagnosis. Locally advanced prostate cancer encompasses a wide spectrum of tumor phenotypes with

Conclusions

A recombinant soluble form of TRAIL has recently been evaluated as a potential cancer therapeutic agent against a variety of solid tumors and hematologic malignancies in the clinical trials conducted by Genentech (South San Francisco, CA), in collaboration with Amgen (Thousand Oaks, CA). Moreover, a recombinant adenovirus encoding the human TRAIL complementary deoxyribonucleic acid (Ad5-TRAIL) [29], [30] has recently entered into Phase I clinical testing in patients with prostate cancer.

Acknowledgment

The authors thank Kemal H. Gulkesen, MD, PhD, for the statistical analysis.

References (30)

This study was supported by Akdeniz University Scientific Research Project Administration Division Grant.

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