Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients.

The human microbiota shows pivotal roles in urologic health and disease. Emerging studies indicate that gut and urinary microbiomes can impact several urological diseases, both benignant and malignant, acting particularly on prostate inflammation and prostate cancer. Indeed, the microbiota exerts its influence on prostate cancer initiation and/or progression mechanisms through the regulation of chronic inflammation, apoptotic processes, cytokines, and hormonal production in response to different pathogenic noxae. Additionally, therapies’ and drugs’ responses are influenced in their efficacy and tolerability by microbiota composition. Due to this complex potential interconnection between prostate cancer and microbiota, exploration and understanding of the involved relationships is pivotal to evaluate a potential therapeutic application in clinical practice. Several natural compounds, moreover, seem to have relevant effects, directly or mediated by microbiota, on urologic health, posing the human microbiota at the crossroad between prostatic inflammation and prostate cancer development. Here, we aim to analyze the most recent evidence regarding the possible crosstalk between prostate, microbiome, and inflammation.

A major challenge in the clinical management of prostate cancer (PC) is to inhibit tumor growth and prevent metastatic spreading. In recent years, considerable efforts have been made to discover new compounds useful for PC therapy, and promising advances in this field were reached. Drugs currently used in PC therapy frequently induce resistance and PC progresses toward metastatic castration-resistant forms (mCRPC), making it virtually incurable. Curcumin, a commercially available nutritional supplement, represents an attractive therapeutic agent for mCRPC patients. In the present study, we compared the effects of chemotherapeutic drugs such as docetaxel, paclitaxel, and cisplatin, to curcumin, on two PC cell lines displaying a different metastatic potential: DU145 (moderate metastatic potential) and PC-3 (high metastatic potential). Our results revealed a dose-dependent reduction of DU145 and PC-3 cell viability upon treatment with curcumin similar to chemotherapeutic agents (paclitaxel, cisplatin, and docetaxel). Furthermore, we explored the EGFR-mediated signaling effects on ERK activation in DU145 and PC-3 cells. Our results showed that DU145 and PC-3 cells overexpress EGFR, and the treatment with chemotherapeutic agents or curcumin reduced EGFR expression levels and ERK activation. Finally, chemotherapeutic agents and curcumin reduced the size of DU145 and PC-3 spheroids and have the potential to induce apoptosis and also in Matrigel. In conclusion, despite different studies being carried out to identify the potential synergistic curcumin combinations with chemopreventive/therapeutic efficacy for inhibiting PC growth, the results show the ability of curcumin used alone, or in combinatorial approaches, to impair the size and the viability of PC-derived spheroids.

Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database (https://pubmed.ncbi.nlm.nih.gov) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented. Graphical Abstract

The association between diabetes and cardiovascular diseases is well known. Related diabetes macro‐ and microangiopathies frequently induce hypoxia and consequently energy failure to satisfy the jeopardized myocardium basal needs. Additionally, it is widely accepted that diabetes impairs endothelial nitric oxide synthase (eNOS) activity, resulting in diminished nitric oxide (NO) bioavailability and consequent endothelial cell dysfunction. In this study, we analyzed the embryonic heart‐derived H9c2 cell response to hypoxic stress after administration of a high glucose concentration to reproduce a condition often observed in diabetes. We observed that 24 h hypoxia exposure of H9c2 cells reduced cell viability compared to cells grown in normoxic conditions. Cytotoxicity and early apoptosis were increased after exposure to high glucose administration. In addition, hypoxia induced a RhoA upregulation and a Bcl‐2 downregulation and lowered the ERK activation observed in normoxia at both glucose concentrations. Furthermore, a significant cell proliferation rate increases after the 1400 W iNOS inhibitor administration was observed. Again, hypoxia increased the expression level of myogenin, a marker of skeletal muscle cell differentiation. The cardiomyocyte gene expression profiles and morphology changes observed in response to pathological stimuli, as hypoxia, could lead to improper ventricular remodeling responsible for heart failure. Therefore, understanding cell signaling events that regulate cardiac response to hypoxia could be useful for the discovery of novel therapeutic approaches able to prevent heart diseases.

Despite the improvements in diagnostic and therapeutic approaches, breast cancer still remains one of the world’s leading causes of death among women. Particularly, triple negative breast cancer (TNBC) is characterized by aggressiveness, metastatic spreading, drug resistance and a very high percentage of death in patients. Nowadays, identification of new targets in TNBC appears very compelling. TNBC are considered negative for the estrogen receptor alpha (ERα) expression. Nevertheless, they often express ERβ and its variants. As such, this TNBC subtype still responds to estrogens. While the ERβ1 variant seems to act as a tumor-suppressor, the two variants ERβ2 and 5 exhibit pro-oncogenic activities in TNBC. Thus, ERβ1 activation might be used to limit the growth and spreading as well as to increase the drug sensitivity of TNBC. In contrast, the pro-oncogenic properties of ERβ2 and ERβ5 suggest the possible development and clinical use of specific antagonists in TNBC treatment. Furthermore, the role of ERβ might be regarded in the context of the androgen receptor (AR) expression, which represents another key marker in TNBC. The relationship between AR and ERβ as well as the ability to modulate the receptor-mediated effects through agonists/antagonists represent a challenge to develop more appropriate therapies in clinical management of TNBC patients. In this review, we will discuss the most recent data in the field. Therapeutic implications of these findings are also presented in the light of the discovery of specific ERβ modulators.