The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells

BACKGROUND: Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer. The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells.METHODS: NE differentiation of prostate cancer LNCaP cells was induced by serum deprivation or by incubation with interleukin-6, for 6 days. Levels of NE markers and signaling proteins were determined by western blotting. Levels of cannabinoid receptors were determined by quantitative PCR. The involvement of signaling cascades was investigated by pharmacological inhibition and small interfering RNA.RESULTS: The differentiated LNCaP cells exhibited neurite outgrowth, and increased the expression of the typical NE markers neuron-specific enolase and βIII tubulin (βIII Tub). Treatment with 3 μM WIN inhibited NK differentiation of LNCaP cells. The cannabinoid WIN downregulated the PI3K/Akt/mTOR signaling pathway, resulting in NE differentiation inhibition. In addition, an activation of AMP-activated protein kinase (AMPK) was observed in WIN-treated cells, which correlated with a decrease in the NE markers expression. Our results also show that during NE differentiation the expression of cannabinoid receptors CB1 and CB2 dramatically decreases.CONCLUSIONS: Taken together, we demonstrate that PI3K/Akt/AMPK might be an important axis modulating NE differentiation of prostate cancer that is blocked by the cannabinoid WIN, pointing to a therapeutic potential of cannabinoids against NE prostate cancer.Prostate Cancer and Prostatic Diseases advance online publication, 21 June 2016; doi:10.1038/pcan.2016.19.</p

The oncologic role of local treatment in primary metastatic prostate cancer.

PURPOSE: To determine the oncologic benefit or otherwise of local treatment of the prostate in patients with primary metastatic prostate cancer. METHODS: A review of the literature was performed in April 2014 using the Medline/PubMed database. Studies were identified using the search terms "prostate cancer," "metastatic," "metastasis," "high risk," "radiation therapy," "radiotherapy" and "prostatectomy" from 1990 until April, 2014. Articles were also identified through searches of references of these articles. RESULTS: Retrospective series and population-based data suggest that the use of local treatment of the prostate in patients with primary metastatic prostate cancer may improve cancer-specific survival and overall survival compared with treating these patients with androgen deprivation therapy alone. The clinical outcome in metastatic prostate cancer is largely determined by the extent of lymph node involvement and overall metastatic burden. Contemporary data are lacking to recommend one alternative of local therapy (radiotherapy or radical prostatectomy) over the other. The primary limitation of this literature review is the lack of published randomized trial assessing the role of local treatment in addition to systemic therapy. CONCLUSIONS: Local treatment appears to improve oncologic outcomes in metastatic prostate cancer patients. Nevertheless, due to the lack of high-quality evidence, its role needs to be confirmed in future prospective trials. The selection of ideal candidates and optimal treatment alternative (radiotherapy, radical prostatectomy or other) warrants further investigation

What is the optimal definition of misclassification in patients with very low-risk prostate cancer eligible for active surveillance? Results from a multi-institutional series

Background: The risk of unfavorable prostate cancer in active surveillance (AS) candidates is nonnegligible. However, what represents an adverse pathologic outcome in this setting is unknown. We aimed at assessing the optimal definition of misclassification and its effect on recurrence in AS candidates treated with radical prostatectomy (RP). Materials and methods: Overall, 1,710 patients eligible for AS according to Prostate Cancer Research International: Active Surveillance criteria treated with RP between 2000 and 2013 at 3 centers were evaluated. Patients were stratified according to pathology results at RP: organ-confined disease and pathologic Gleason score 6 (group 1); organ-confined disease and Gleason score 3 + 4 (group 2); and non organ -confined disease, Gleason score >= 4 + 3, and nodal invasion (group 3). Biochemical recurrence (BCR) was defined as 2 consecutive prostate specific antigen (PSA) >= 0.2 ng/ml. Kaplan-Meier curves assessed time to BCR. Multivariable Cox regression analyses tested the association between pathologic features and BCR. Multivariable logistic regression analyses identified the predictors of adverse pathologic characteristics. Results: Overall, 926 (54.2%), 653 (33.0%), and 220 (12.9%) patients were categorized in groups 1, 2, and 3, respectively. Median followup was 32.2 months. The 5-year BCR-free survival rate was 94.2%. Patients in group 3 had lower BCR-free survival rates compared with those in group 1 (79.1% vs. 97.0%, P = 10 ng/ml/ml were associated with higher risk of unfavorable pathologic characteristics (i.e., inclusion in group 3; all P = 4 + 3 or non organ-confined disease at final pathology were at increased risk of BCR. These individuals represent the real misclassified AS patients, who can be predicted based on older age and higher PSA density. (C) 2015 Elsevier Inc. All rights reserved