PURPOSE: Transforming growth factor-beta (TGF-beta)-mediated epithelial-to-mesenchymal transition (EMT) has been shown to occur in some cancers; however, the pathway remains controversial and varies with different cancers. In addition, the mechanisms by which TGF-beta and the EMT contribute to prostate cancer recurrence are largely unknown. In this study, we elucidated TGF-beta-mediated EMT as a predictor of disease recurrence after therapy for prostate cancer, which has not been reported before. EXPERIMENTAL DESIGN: We analyzed TGF-beta-induced EMT using nuclear factor-kappaB (NF-kappaB) as an intermediate mediator in prostate cancer cell lines. A total of 287 radical prostatectomy specimens were evaluated using immunohistochemistry in a high-throughput tissue microarray analysis. Levels of TGF-beta signaling components and EMT-related factors were analyzed using specific antibodies. Results were expressed as the percentage of cancer cells that stained positive for a given antibody and were correlated with disease recurrence rates at a mean of 7 years following radical prostatectomy. RESULTS: In prostate cancer cell lines, TGF-beta-induced EMT was mediated by NF-kappaB signaling. Blockade of NF-kappaB or TGF-beta signaling resulted in abrogation of vimentin expression and inhibition of the invasive capability of these cells. There was high risk of biochemical recurrence associated with tumors that displayed high levels of expression of TGF-beta1, vimentin, and NF-kappaB and low level of cytokeratin 18. This was particularly true for vimentin, which is independent of patients' Gleason score. CONCLUSIONS: The detection of NF-kappaB-mediated TGF-beta-induced EMT in primary tumors predicts disease recurrence in prostate cancer patients following radical prostatectomy. The changes in TGF-beta signaling and EMT-related factors provide novel molecular markers that may predict prostate cancer outcomes following treatment.

The recent discovery of the overexpression of P504S/alpha-methylacyl coenzyme A racemase (AMACR) in prostate cancer is a successful example of translating an advanced molecular finding into clinical practice. AMACR (P504S) has been proven to be one of the few biomarkers that can help distinguish cancer from benign cells, with high sensitivity and specificity for prostate carcinoma. It is the first gene identified by the analysis of complementary DNA microarray profiles from prostate tissue to be used as a tissue tumor marker in clinical practice and to improve the diagnosis of prostate cancer. This review focuses on the study of AMACR (P504S) expression in prostate cancer, premalignant lesions, benign prostate tissues, and other normal and malignant tissues and a discussion of its clinical usefulness. We emphasize the interpretation of the AMACR immunohistochemical results in routine surgical pathology practice and also discuss the potential future applications of this marker and the possible role of AMACR in the pathogenesis of cancer development.

From 1.5% to 9.0% of prostatic needle biopsy specimens disclose atypical small acinar proliferations (ASAPs) suggestive of malignancy, carrying an approximate 45% predictive value for cancer. We applied keratin 34 beta E12 and P504S monoclonal immunostains to 93 cases that were judged as ASAP after HandE staining alone. Forty-one ASAP foci survived recutting for both immunostains. Three urologic pathologists independently assigned post-keratin 34 beta E12 diagnoses of cancer, ASAP, high-grade prostatic intraepithelial neoplasia, or benign and then reviewed P504S slides and assigned final diagnoses. Eight foci (20%) were resolved unanimously after keratin 34 beta E12 staining; 18 (44%) were resolved by 1 or 2 evaluators and 29 (71%) by at least 1. According to whether post-keratin 34 beta E12 ASAP designation was given by 3, 2, or 1 evaluator(s), P504S immunostaining unanimously resolved an additional 5 (12%), 10 (24%), or 23 (56%) of 41 ASAP foci and cumulatively, 31 foci (76%). Among 35 men (excluding 6 with cancer in other cores of the original biopsy), these immunostains could have permitted cancer diagnosis in 11 (31%), without repeated biopsy. Thus, the consensus diagnosis rate improved from poor to good after supplementing 34 beta E12 immunostaining with P504S.