Apoptotic cell death represents an important mechanism for the precise regulation of cell numbers, and a defence mechanism against tumoral cells. bcl‐2 and bax genes are known to be involved in the control of apoptotic pathways; in particular, the ratio between bcl‐2 and bax represents a cell rheostat that is able to predict a cell's response toward life or death to an apoptotic stimulus. In the present study we investigated the role of bcl‐2 and bax gene expression in a panel of 37 low‐grade tumours of the urinary bladder, and correlated the expression of these genes to the prognosis of patients in a follow‐up of more than one year. We found that levels of bax expression higher than bcl‐2 in bladder tumours well correlates to a better outcome for patients. Early relapses are much more frequently observed in those patients whose tumours express more bcl‐2 than bax mRNA. We conclude that the bcl‐2/bax expression ratio may be considered as a marker for disease progression in low grade bladder tumours, independently of clinical staging and histological grading.

Prostate cancer (PCa) is the most common cancer in men. The androgen receptor (AR) has a pivotal role in the pathogenesis and progression of PCa. Many therapies targeting AR signaling have been developed over the years. AR signaling inhibitors (ARSIs), including androgen synthesis inhibitors and AR antagonists, have proven to be effective in castration-sensitive PCa (CSPC) and improve survival, but men with castration-resistant PCa (CRPC) continue to have a poor prognosis. Despite a good initial response, drug resistance develops in almost all patients with metastatic CRPC, and ARSIs are no longer effective. Several mechanisms confer resistance to ARSI and include AR mutations but also hyperactivation of other pathways, such as PI3K/AKT/mTOR. This pathway controls key cellular processes, including proliferation and tumor progression, and it is the most frequently deregulated pathway in human cancers. A significant interaction between AR and the PI3K/AKT/mTOR signaling pathway has been shown in PCa. This review centers on the current scene of different AR and PI3K signaling pathway inhibitors, either as monotherapy or in combination treatments in PCa, and the treatment outcomes involved in both preclinical and clinical trials. A PubMed-based literature search was conducted up to November 2022. The most relevant and recent articles were selected to provide essential information and current evidence on the crosstalk between AR and the PI3K signaling pathways. The ClinicalTrials.gov registry was used to report information about clinical studies and their results using the Advanced research tool, filtering for disease and target.

Prostate is an immune-competent organ normally populated by inflammatory cells. Prostatic inflammation origin can be multi-factorial and there are some emerging evidences on its possible role as a factor involved in prostate cancer (PC) pathogenesis and progression. This review critically analyzes the role of inflammation as a prognostic factor for progression and aggressiveness of PC. We verified the last 10 years literature data on the association between inflammation and PC aggressiveness, or PC response to therapies. Several studies tried to correlate different inflammatory factors with the aggressiveness and metastatization of PC; all data sustain the role of inflammation in PC progression but they also produce confusion to identify a reliable clinical prognostic marker. Data on patients submitted to radical prostatectomy (RP) showed that cases with marked intraprostatic tissue inflammation are associated with higher rate of biochemical progression; systemic inflammation markers appear to have a significant prognostic value. Analyzing data on patients submitted to radiotherapy (RT) emerges a significant association between high neuthrophil to lymphocyte ratio (NLR) and decreased progression free survival and overall survival; also plateled to lymphocyte ratio (PLR) and C-reactive protein (CRP) have been proposed as significant prognostic factors for progression and overall survival. In patients submitted to androgen deprivation therapy (ADT), inflammation may drive castration resistant PC (CRPC) development by activation of STAT3 in PC cells. NLR has been proposed as independent predictor of overall survival in CRPC submitted to chemotherapy. Most of data are focused on markers related to systemic inflammation such as NLR and CRP, more than specifically to chronic prostatic inflammation. The suggestion is that these inflammatory parameters, also if not specific for prostatic inflammation and possibly influenced by several factors other than PC, can integrate with established prognostic factors.

In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa.

To analyze the expression at basal level of inflammation-related cytokines and chemokines and the activation status of the NF-κB pathway, together with the proliferation and apoptosis indexes in two widely used in vitro tumor models, the androgen-dependent human Prostate Cancer (PC) cell line LNCaP and the androgen-independent PC3 , and in primary cultures of human PC cells. To assess in these models and primary cultures, the effects of Serenoa repens (LSESr, Permixon®) on proliferation/apoptosis ratio, inflammation-related genes expression and NF-κB pathway activation. The expression of IL-6, CCL-5, CCL-2, COX-1, COX-2, iNOS inflammation-related genes has been evaluated at the mRNA level in two in vitro human PC models (LNCaP and PC3 cell lines) and in 40 independent human prostatic primary cultures obtained from PC patients undergoing radical prostatectomy. Tissue fragments were collected from both PC lesions and normal hyperplastic tissue counterparts for each case. All cultures were treated with two different amounts of Permixon® (44 and 88 μg/ml) for different time points (16, 24, 48 and 72 hours), depending on the cell type and the assay; the expression of inflammation-related genes, cell growth (proliferation/apoptosis ratio) and NF-κB activation has been analyzed in treated and untreated cells by means of semi-quantitative RNA-PCR, cell proliferation and immunofluorescence respectively. We detected a significant reduction (p <0.001) in PC and normal cells proliferation due to Permixon ® treatment. This result was related to an increase of the apoptotic activity showed by an increase in the number of anti-caspase-3 fluorescent cells. Almost all the inflammation-related genes (IL-6, CCL-5, CCL-2, COX-2 and iNOS) were expressed at the basal level in in vitro cultured cells and primary cultures and down-regulated by Permixon® treatment. This treatment interfered with NF-kB activation, detecting by the translocation of more than 30% of NF-κB p65 subunit to the nucleus. The present study confirms the expression of inflammatory pattern in PC. We showed the effect of Permixon® on down-regulation of inflammatory-related genes in cell lines and in primary cultures. The inhibitory effect of Permixon® on cell growth could be partly associated to the down-regulation of inflammatory-related genes and to the activation of NF-κB pathway in prostate tissue.

Prostate cancer (PCa) is the second most common cancer in men. As well in many other human cancers, inflammation and immune suppression have an important role in their development. We briefly describe the host components that interact with the tumor to generate an immune suppressive environment involved in PCa promotion and progression. Different tools provide to overcome the mechanisms of immunosuppression including vaccines and immune checkpoint blockades. With regard to this, we report results of most recent clinical trials investigating immunotherapy in metastatic PCa (Sipuleucel-T, ipilimumab, tasquinimod, Prostvac-VF, and GVAX) and provide possible future perspectives combining the immunotherapy to the traditional therapies.