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Purpose: Because TRAIL (tumor necrosis factor related apoptosis inducing ligand) selectively kills cancer cells without damaging normal cells, a gene therapy approach using TRAIL is feasible for treating patients with cancer. However, recent publications suggest that significant portions of human tumors appear to be TRAIL resistant. Furthermore, there is some controversy about whether TRAIL receptor composition influences TRAIL sensitivity in cancer cells. Our recent studies suggest that TRAIL receptor composition is the major modulator of TRAIL sensitivity, as demonstrated using prostate, breast and lung cancer cells. We investigated TRAIL and TRAIL receptor expression profiles during prostate carcinogenesis to evaluate their potential as biomarkers and predict the feasibility of a related gene therapy approach., Materials and Methods: Paraffin embedded prostate tissues of 44 patients with benign prostatic hyperplasia, 28 with organ confined prostate carcinoma and 26 with advanced prostate carcinoma were analyzed using immunohistochemical staining procedures., Results: Significant levels of TRAIL-R4 decoy receptor expression were detected in patients with benign prostatic hyperplasia, and organ confined and advanced prostate carcinoma. All TRAIL markers tested appear to be valuable markers for separating patients with benign prostatic hyperplasia from patients with organ confined prostate carcinoma or advanced prostate carcinoma., Conclusions: Due to high TRAIL-R4 expression in all patient groups complementary gene therapy modalities might be needed to bypass potential TRAIL-R4 induced resistance.

AIDIT (Advancing International Co-operation and Developing Infrastructure for Targeted Screening of Prostate Cancer in Men with Genetic Predisposition) is a project funded by the Sixth Framework Programme of the European Community which is endeavouring to facilitate co-operation between European countries in the field of cancer research. The project also aims to raise awareness of familial prostate cancer among health professionals and the public within the associated candidate countries (ACCs) and new member states of the European Union (EU). AIDIT will focus on linking clinical and research teams in the ACCs and new member states with the IMPACT Consortium (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), an international team investigating screening and diagnosis for men with a genetic risk of prostate cancer predisposition genes BRCA1 or BRCA2). Cancer research has been targeted as a high priority for the European Community; however, research is most successful when centralised and well coordinated, avoiding the duplication and fragmentation associated with smaller, isolated studies. AIDIT will consolidate the current IMPACT consortium and allow research partners from across the world to benefit from shared knowledge and experience. To date, the AIDIT team has established a website to facilitate communication between project collaborators (www.impact-study.co.uk), has been represented at several international meetings and has facilitated a conference for the IMPACT study to bring together international research teams, clinicians and policy makers.

Despite the fact that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells, TRAIL resistance in cancer cells has challenged the use of TRAIL as a therapeutic agent. First, prostate carcinoma cell lines (DU145, LNCaP and PC3) were screened for sensitivity to adenovirus delivery of TRAIL (Ad5hTRAIL). As amplified Ikappa B kinase (IKK) activity is responsible for the constitutive nuclear factor-kappaB (NF-kappaB) activation leading to uncontrolled cell growth and metastasis, a dual vector approach using both an adenovirus vector (Ad) expressing the dominant-negative mutant of IKKbeta (AdIKKbetaKA) and Ad5hTRAIL was employed to determine if prostate cancer cells were sensitized to TRAIL in the setting of IKK inhibition. Inhibition of the NF-kappaB pathway through IKK blockade sensitized all three prostate cancer cell lines to TRAIL, regardless of NF-kappaB activation or decoy receptor gene expression. Moreover, a novel quantitative real-time RT-PCR assay and conventional flow cytometry analysis indicated that TRAIL-resistant DU145 and LNCaP cells, but not TRAIL-sensitive PC3 cells, expressed substantial amounts of TRAIL Decoy Receptor 4. In conclusion, TRAIL decoy receptor expression appeared to be the chief determinant of TRAIL resistance encountered in prostate carcinoma cell lines.

Objective: The purpose of the study was to determine if the tumor suppressor gene phosphate and tensin homolog (PTEN) (mutated in multiple advanced cancers 1) in combination with Gleason scoring and serum prostate specific antigen (PSA) could be employed to better predict the progression of prostate carcinoma., Materials and Methods: The study group consisted of 43 patients with benign prostate hyperplasia (BPH), 15 with organ confined prostate carcinoma (OCPCa), and 18 with advanced prostate carcinoma (APCa). Prostate tissue samples were obtained from radical prostatectomy, transurethral resection, and TRUS guided trans-rectal needle biopsy and then evaluated for biomarker expression. The clinical stage was assessed according to tumor node metastasis classification and grade according to Gleason system. Serum PSA was measured by conventional techniques and Western blotting analysis was used to determine PTEN expression in the primary tissue. Multivariate analysis was performed to analyze whether these markers could individually predict the progression of prostate carcinoma., Results: APCa patients displayed higher Gleason scores and serum PSA levels. But much lower PTEN expression was detected in prostate of APCa patients compared to patients with BPH or OCPCa. Hormone refractory (HR) and hormone sensitive (HS) APCa cases did not yield any significant differences in terms of Gleason scoring, serum PSA and PTEN expression. PSA levels were significantly higher in patients with OCPCa or APCa compared to patients with BPH., Conclusion: Our results suggested that both PTEN and serum PSA appeared to be useful as independent markers to depict the nature of tumor behavior as benign or malign. In addition, PTEN also appeared to be useful as an independent marker to predict the progression of prostate carcinoma., (Copyright 2004 Elsevier Inc.)