The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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Molecular mechanisms of cholangiocarcinoma-cholangiocyte cell interactions in vitro

Cholangiocarcinoma is a highly aggressive cancer originating within the biliary tract. Whilst the role of the tumour microenvironment in CCA progression is well established, the function of surrounding cholangiocytes on CCA behaviour is often overlooked. Specifically, the effect of paracrine communication between cholangiocytes and cholangiocarcinoma cells has not been investigated previously. In this study, we provide evidence that cholangiocyte cells are a crucial paracrine modulator that influences the permissive or restrictive state to CCA progression. Indirect co-culture of cholangiocarcinoma cells with cholangiocyte cells causes a significant decrease in CCA cell viability, migratory behaviour, and cell cycle progression, associated with a demonstratable switch in the gene and protein expression of the EMT markers E-cadherin, Slug, Snail, and Vimentin. Moreover, co-culture triggered a metabolic shift in CCA cells, with enhanced branched chain amino acid (BCAA) metabolism, as well as a transcriptomic shift resulting in increased cytokine signalling gene expression, recapitulated in the secretome. In turn, cholangiocytes respond to this interaction with CCA cells, undergoing changes resulting in a growth advantage. Cholangiocytes experience an increase in creatine metabolism and ATP availability, linking to improved cell viability, increased cell cycle progression and reduced apoptosis, in conjunction with a reduction in gene and protein expression of p53 and apoptotic pathways. Moreover, a high-throughput screen of epigenetic inhibitors successfully identified two targets, UNC0642 and SGC3027, for further development against CCA. More crucially, although effective against our CCA cell lines, co-culture with cholangiocytes caused a significant increase in IC50 value for these epigenetic inhibitors, implicating cholangiocyte cells in CCA chemoresistance. We hypothesise the metabolic and genomic alterations triggered by this interaction contributes to CCA survival, invasiveness, and chemoresistance in the later stages of CCA development. Overall, our findings highlight the importance of cholangiocyte cells in modulating cholangiocarcinoma cells, impacting the development, progression, and treatment of cholangiocarcinoma

The Tumor Microenvironment of High Grade Serous Ovarian Cancer

The Special Issue on high grade serous ovarian cancer (HGSOC) and the contribution of the tumor microenviroment (TME) consists of reviews contributed by leaders in the OC field. As HGSOC metastases have a highly complex TME, there is an urgent need to better understand the TME in general, its distinct components in particular, and the role of the TME in the context of disease recurrence and development of chemoresistance. The Special Issue incorporates the current understanding of the different parts of thd TME components, including the cancer cells themselves, the cells surrounding the cancer cells or stromal cells, and the cells of the immune system, which are attracted to the site of metastases. In addition to these cells of the TME, the role of various cellular factors made by the cells of the TME are also the subject of the reviews. In addition, reviews in this Special Issue cover the complex relationships between the molecular mechanisms of HGSOC progression, including genomic, epigenomic and transcriptomic changes and changes in the immune cell landscape, as these may provide attractive new molecular targets for HGSOC therapy

Molecular investigation of anticancer genes

The lack of specificity of the therapeutic agents against cancer is one of the prime obstacles in developing effective therapies for the disease. The specificity of chemotherapeutic agents against cancer cells is primarily quantitative rather than qualitative. Despite the earlier success of targeted therapies, it is now clear that among an unselected population of patients, the response rate is usually limited to 10-20%. Further avenues need to be explored for the development of cancer-specific therapies. A recent concept towards such efforts is that of anticancer genes. When ectopically overexpressed, anticancer genes specifically destroy tumour cells without harming normal cells. The examples include TRAIL, MDA7, PAR4, apoptin and Orctl3. In addition, 22 novel anticancer genes were identified through systematic functional genetic screening. This thesis aimed at (i) deciphering the identity of these genes, (ii) investigating their regulation and (iii) exploring the mechanisms behind their cancer specific actions. Sanger sequencing and subsequent analyses revealed that these 22 novel anticancer genes included non-coding RNAs, novel transcripts and protein-coding genes, two among the latter are TMEFF2 and FBLN5. The expression levels of both these genes exhibit a positive correlation with the survival of breast cancer patients and both are positively regulated by FOXO3 in MCF-7 cells. FBLN5 and TMEFF2 cause cell death selectively in the COS-7 cells and not in their untransformed counterparts (CV-1 cells). Mechanistic gene expression profiling and elaborate comparison pathways analyses uncovered that FBLN5 undertakes this action putatively through the downregulation of the downstream targets of MYC and inhibition of oxidative phosphorylation. Additionally, TMEFF2 causes caspase-dependent and p53-independent apoptosis in MCF-7 cells. Gene expression profiling revealed that the TMEFF2 induces potent interferon signalling along with the upregulation of TRAIL in MCF-7 cells. TMEFF2 gives a perinuclear punctate cytoplasmic appearance in MCF-7 cells and does not co-localize with either mitochondria or α-tubulin.Open Acces

Advances and Novel Treatment Options in Metastatic Melanoma

The book presents several studies reporting advances on melanoma pathogenesis, diagnosis and therapy. It represents a milestone on the state of the art, updated at 2021, and also presents the current knowledge on the future developments in melanoma field

Polyphenols for Cancer Treatment or Prevention

Polyphenols are commonly found in fruits and vegetables, and have been suggested to have protective effects against chronic diseases, such as cancers. They are a diverse group of molecules, many of which possess antioxidant, anti-inflammatory, epigenetic, drug sensitization, and/or modulation of xenobiotic metabolizing enzyme properties. However, there is mixed evidence regarding their protective effects with respect to various cancers. Some of this controversy may be due to the combination of polyphenols administered, synergistic effects of accompanying compounds, bio-accessibility, bioavailability, effect of gut microbiota, and the type of cancer investigated. The purpose of this Special Issue is to present the recent evidence for the effect of polyphenol intake on cancer, as well as mechanisms of action. This Special Issue, entitled "Polyphenols for Cancer Treatment or Prevention", welcomes manuscript submissions of original research, meta-analyses, or reviews of the scientific literature. Authors should focus their manuscripts on polyphenol bioactives or dietary patterns naturally rich in polyphenols that have been identified and used for the prevention and or treatment of cancer