Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

Until recently, ovarian cancer research has mainly focused on the tumor cell themselves ignoring for the most part the surrounding tumor environment. However, one of the major conceptual advances in oncology over the last few years has been the appreciation that major aspects of cancer biology are influenced by the tumor environment. Malignant ascites accumulates in the peritoneal cavity during ovarian cancer progression and constitutes a unique pro-inflammatory tumor environment providing a framework that orchestrates cellular and molecular changes contributing to aggressiveness and disease progression. The composition of ascites, which includes cellular and acellular components, constantly adapts during the course of the disease in response to various cellular cues originating from both tumor and stromal cells. Increasing evidence now supports an active role of ascites in the progression of ovarian cancer. Although much work is still needed to fully understand the contribution of ascites to ovarian cancer aggressiveness, this tumor environment potentially provides a wealth of opportunities for translational research including biomarker discovery and novel therapeutic target identification. In this review, we discuss recent advances in our understanding of ascites pathophysiology, the characterization of its cellular and acellular contents, the intercellular crosstalks, and how these data can be used to improve the outcome of ovarian cancer

Résolution d'une molécule d'ADN hybride virale-cellulaire dans des cellules de mammifères : rôle de la protéine virale grand T

Rml est une molécule hybride contenant 1,03 copie du génome du virus du polyome liée à une insertion cellulaire d'ADN de souris par des répétitions virales directes de 182 pb. Dans ce travail, nous avons examiné la recombinaison intramoléculaire de Rml en utilisant différents recombinants contenant cette molécule. Après transfection dans diverses lignées cellulaires, la recombinaison a été mise en évidence par la production de plages de lyse, ou directement par la méthode de Southern. Nous avons montré que des molécules de taille génomique étaient produites à une fréquence élevée dans des cellules de souris et qu'il s'agissait là d'un événement de recombinaison réciproque. Il semble que la présence de la protéine virale grand T soit nécessaire à cet événement de recombinaison

Prognostic significance of IL-6 and IL-8 ascites levels in ovarian cancer patients

<p>Abstract</p> <p>Background</p> <p>The acellular fraction of epithelial ovarian cancer (EOC) ascites promotes <it>de novo </it>resistance of tumor cells and thus supports the idea that tumor cells may survive in the surrounding protective microenvironment contributing to disease recurrence. Levels of the pro-inflammatory cytokines IL-6 and IL-8 are elevated in EOC ascites suggesting that they could play a role in tumor progression.</p> <p>Methods</p> <p>We measured IL-6 and IL-8 levels in the ascites of 39 patients with newly diagnosed EOC. Commercially available enzyme-linked immunosorbent assay (ELISA) was used to determine IL-6 and IL-8 ascites levels. Ascites cytokine levels were correlated with clinicopathological parameters and progression-free survival.</p> <p>Results</p> <p>Mean ascites levels for IL-6 and IL-8 were 6419 pg/ml (SEM: 1409 pg/ml) and 1408 pg/ml (SEM: 437 pg/ml) respectively. The levels of IL-6 and IL-8 in ascites were significantly lower in patients that have received prior chemotherapy before the surgery (Mann-Whitney U test, <it>P </it>= 0.037 for IL-6 and <it>P </it>= 0.008 for IL-8). Univariate analysis revealed that high IL-6 ascites levels (<it>P </it>= 0.021), serum CA125 levels (<it>P </it>= 0.04) and stage IV (<it>P </it>= 0.009) were significantly correlated with shorter progression-free survival. Including these variables in a multivariate analysis revealed that elevated IL-6 levels (<it>P </it>= 0.033) was an independent predictor of shorter progression-free survival.</p> <p>Conclusion</p> <p>Elevated IL-6, but not IL-8, ascites level is an independent predictor of shorter progression-free survival.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment