Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer.

Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells.

Preclinical Models of Neuroendocrine Prostate Cancer.

Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer-related death amongst men in the United States. Neuroendocrine prostate cancer (NEPC) can either arise de novo or emerge as a consequence of therapy. De novo NEPC is rare, with an incidence of <2% of all PCa cases.

Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.

Lin28 RNA-binding proteins are stem-cell factors that play key roles in development. Lin28 suppresses the biogenesis of let-7 microRNAs and regulates mRNA translation. Notably, let-7 inhibits Lin28, establishing a double-negative feedback loop.

A functional SNP regulates E-cadherin expression by dynamically remodeling the 3D structure of a promoter-associated non-coding RNA transcript.

Transcription of E-cadherin, a tumor suppressor that plays critical roles in cell adhesion and the epithelial-mesenchymal transition, is regulated by a promoter-associated non-coding RNA (paRNA). The sense-oriented paRNA (S-paRNA) includes a functional C/A single nucleotide polymorphism (SNP rs16260). The A-allele leads to decreased transcriptional activity and increased prostate cancer risk.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ Receptor Ligands with Antiproliferative Properties.

A series of novel σ receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents.

Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma.

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug.

Inflammatory metabolic profile of South African patients with prostate cancer.

Background: Men with African ancestry are more likely to develop aggressive prostate cancer (PCa) and to die from this disease. The study of PCa in the South African population represents an opportunity for biomedical research due to the high prevalence of aggressive PCa. While inflammation is known to play a significant role in PCa progression, its association with tumor stage in populations of African descent has not been explored in detail.

EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer.

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity.

Chemoenzymatic synthesis of 2,6-disubstituted tetrahydropyrans with high σ receptor affinity, antitumor and analgesic activity.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g.

Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer.

Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH.

Novel σ antagonists designed for tumor therapy: Structure - activity relationships of aminoethyl substituted cyclohexanes.

Depending on the substitution pattern and stereochemistry, 1,3-dioxanes 1 with an aminoethyl moiety in 4-position represent potent σ receptor antagonists. In order to increase the stability, a cyclohexane ring first replaced the acetalic 1, 3-dioxane ring of 1. A large set of aminoethyl substituted cyclohexane derivatives was prepared in a six-step synthesis.

Pharmacodynamic and Pharmacokinetic Properties of Full Phosphorothioate Small Interfering RNAs for Gene Silencing .

State-of-the-art small interfering RNA (siRNA) therapeutics such as givosiran and fitusiran are constructed from three variable components: a fully-modified RNA core that conveys metabolic stability, a targeting moiety that mediates target-cell uptake, and a linker. This structural complexity poses challenges for metabolite characterization and risk assessment after long-term patient exposure. In this study, we show that basic phosphorothioate modification of a siRNA targeting the oncoprotein Lin28B provides a useful increase in metabolic stability, without greatly compromising potency.

A Novel Prostate Cell Type-Specific Gene Signature to Interrogate Prostate Tumor Differentiation Status and Monitor Therapeutic Response (Running Title: Phenotypic Classification of Prostate Tumors).

In this study, we extracted prostate cell-specific gene sets (metagenes) to define the epithelial differentiation status of prostate cancers and, using a deconvolution-based strategy, interrogated thousands of primary and metastatic tumors in public gene profiling datasets. We identified a subgroup of primary prostate tumors with low luminal epithelial enrichment (LumE). LumE tumors were associated with higher Gleason score and mutational burden, reduced relapse-free and overall survival, and were more likely to progress to castration-resistant prostate cancer (CRPC).

Mitochondrial fission promotes self-renewal and tumorigenic potential in prostate cancer.

The emergence of therapy-resistant cancer stem cells (CSCs) limit the efficacy of prostate cancer treatment. Using genetic knockdown and chemical inhibitors, we demonstrate the critical role of Bromodomain Containing 4 (BRD4) in promoting mitochondrial fission and sustaining CSC expansion. These findings provide a new paradigm for developing novel treatment strategies for prostate cancer.

The Prospect and Challenges to the Flow of Liquid Biopsy in Africa.

Liquid biopsy technologies have the potential to transform cancer patient management as it offers non-invasive diagnosis and real-time monitoring of disease progression and treatment responses. The use of liquid biopsy for non-invasive cancer diagnosis can have pivotal importance for the African continent where access to medical infrastructures is limited, as it eliminates the need for surgical biopsies. To apply liquid biopsy technologies in the African setting, the influence of environmental and population genetic factors must be known.

Efficacy of Novel Bromodomain and Extraterminal Inhibitors in Combination with Chemotherapy for Castration-Resistant Prostate Cancer.

Background: Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor-targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients.

Transcriptional Reprogramming and Inhibition of Tumor-propagating Stem-like Cells by EC-8042 in ERG-positive Prostate Cancer.

Background: The TMPRSS2-ERG gene fusion is the most frequent genetic rearrangement in prostate cancers and results in broad transcriptional reprogramming and major phenotypic changes. Interaction and cooperation of ERG and SP1 may be instrumental in sustaining the tumorigenic and metastatic phenotype and could represent a potential vulnerability in ERG fusion-positive tumors.

Objective: To test the activity of EC-8042, a compound able to block SP1, in cellular and mouse models of ERG-positive prostate cancer.

Transcriptional Reprogramming and Novel Therapeutic Approaches for Targeting Prostate Cancer Stem Cells.

Prostate cancer is the most common malignancy in men and the second cause of cancer-related deaths in western countries. Despite the progress in the treatment of localized prostate cancer, there is still lack of effective therapies for the advanced forms of the disease. Most patients with advanced prostate cancer become resistant to androgen deprivation therapy (ADT), which remains the main therapeutic option in this setting, and progress to lethal metastatic castration-resistant prostate cancer (mCRPC).

Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer.

Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies.

Erratum to "Prostate Osteoblast-Like Cells: A Reliable Prognostic Marker of Bone Metastasis in Prostate Cancer Patients".

[This corrects the article DOI: 10.1155/2018/9840962.].