A Central Role for Long Non-Coding RNA in Cancer

Long non-coding RNAs (ncRNAs) have been shown to regulate important biological processes that support normal cellular functions. Aberrant regulation of these essential functions can promote tumor development. In this review, we underscore the importance of the regulatory role played by this distinct class of ncRNAs in cancer-associated pathways that govern mechanisms such as cell growth, invasion, and metastasis. We also highlight the possibility of using these unique RNAs as diagnostic and prognostic biomarkers in malignancies

IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells

In high-grade serous ovarian cancer (OC), chemotherapy eliminates the majority of tumor cells, leaving behind residual tumors enriched in OC stem cells (OCSC). OCSC, defined as aldehyde dehydrogenase–positive (ALDH+), persist and contribute to tumor relapse. Inflammatory cytokine IL-6 is elevated in residual tumors after platinum treatment, and we hypothesized that IL-6 plays a critical role in platinum-induced OCSC enrichment. We demonstrate that IL-6 regulates stemness features of OCSC driven by ALDH1A1 expression and activity. We show that platinum induces IL-6 secretion by cancer-associated fibroblasts in the tumor microenvironment, promoting OCSC enrichment in residual tumors after chemotherapy. By activating STAT3 and upregulating ALDH1A1 expression, IL-6 treatment converted non-OCSC to OCSC. Having previously shown altered DNA methylation in OCSC, we show here that IL-6 induces DNA methyltransferase 1 (DNMT1) expression and the hypomethylating agent (HMA) guadecitabine induced differentiation of OCSC and reduced — but did not completely eradicate — OCSC. IL-6 neutralizing antibody (IL-6-Nab) combined with HMA fully eradicated OCSC, and the combination blocked IL-6/IL6-R/pSTAT3–mediated ALDH1A1 expression and eliminated OCSC in residual tumors that persisted in vivo after chemotherapy. We conclude that IL-6 signaling blockade combined with an HMA can eliminate OCSC after platinum treatment, supporting this strategy to prevent tumor recurrence after standard chemotherapy

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 micro-environment (TME) consisted of reviews contributed by leaders in the ovarian cancer (OC) field. [...]

Functional characterization of a panel of high-grade serous ovarian cancer cell lines as representative experimental models of the disease.

Genomic analysis of ovarian cancer cell lines has revealed a panel that best represents the most common ovarian cancer subtype, high-grade serous ovarian cancer (HGSOC). However, these HGSOC-like cell lines have not been extensively applied by ovarian cancer researchers to date, and the most commonly used cell lines in the ovarian cancer field do not genetically resemble the major clinical type of the disease. For the HGSOC-like lines to serve as suitable models, they need to be characterized for common functional assays. To achieve that objective, we systematically studied a panel of HGSOC cells CAOV3, COV362, Kuramochi, OVCAR4, OVCAR5, OVCAR8, OVSAHO and SNU119 for migration, invasion, proliferation, clonogenicity, EMT phenotype and cisplatin resistance. They exhibited a range of efficacies and OVCAR5, OVCAR8 and Kuramochi were the most aggressive. SNU119 and OVSAHO cells demonstrated the lowest functional activities. Wide differences in expression of EMT markers were observed between cell lines. SNU119 were the most epithelial and OVCAR8 had the most mesenchymal phenotype. COV362 was the most resistant to cisplatin while CAOV3 was the most sensitive. Taken together, our systematic characterization represents a valuable resource to help guide the application of HGSOC cells by the cancer research community

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

ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase

Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism of action is poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1 as the most upregulated member of the ETS family of TFs in metastasizing OC cells as they interacted with the microenvironment. ETS1 was regulated by p44/42 MAP kinase signaling activated in the OC cells interacting with mesothelial cells at the metastatic site. Human OC tumors had increased expression of ETS1, which predicted poor prognosis. ETS1 regulated OC metastasis both in vitro and in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis and functional rescue experiments revealed FAK as the key transcriptional target and downstream effector of ETS1. Taken together, our results indicate that ETS1 is an essential transcription factor induced in OC cells by the microenvironment, which promotes metastatic colonization though the transcriptional upregulation of its target FAK

Bladder Cancer Tissue-Based Biomarkers

This review aims to provide a practical update regarding the current role of tissue-based biomarkers in bladder cancer. Their prognostic and predictive role both in non-muscle-invasive (NMIBC) and in muscle-invasive disease (MIBC) has been reviewed with particular focus to their use in clinical practice. In summary, the literature on the prediction of disease recurrence in NMIBC is inconclusive, and there is little information on prediction of response to intravesical bacillus Calmette-Guerin (BCG). Concerning disease progression, external prospective validation studies suggest that FGFR3 mutation status and gene signatures may improve models that are based only on clinicopathologic information. In MIBC, tissue-based biomarkers are increasingly important, since they may predict the response to systemic chemotherapy and immunotherapy. In particular, the advent of molecular characterization promises to revolutionize the paradigm of decision-making in the treatment of MIBC. Molecular subtyping has been shown to improve the prediction of pathological stage at RC and to predict the response to systemic chemotherapy and immunotherapy. However, external and prospective validations are warranted to confirm these preliminary findings. Several different tissue-based biomarkers such as PD-1/PD-L1 expression, tumor mutational burden, and the analysis of tumor microenvironment, may in future play a role in selecting patients for systemic immunotherapy. However, to date, no pretreatment recommendations can be definitively made on the basis of any molecular predictors. In conclusion, despite the potential of tissue-based biomarkers, their use in bladder cancer should be limited to experimental settings

In vivo tumor growth of high-grade serous ovarian cancer cell lines

OBJECTIVE: Genomic studies of ovarian cancer (OC) cell lines frequently used in research revealed that these cells do not fully represent high-grade serous ovarian cancer (HGSOC), the most common OC histologic type. However, OC lines that appear to genomically resemble HGSOC have not been extensively used and their growth characteristics in murine xenografts are essentially unknown. METHODS: To better understand growth patterns and characteristics of HGSOC cell lines in vivo, CAOV3, COV362, KURAMOCHI, NIH-OVCAR3, OVCAR4, OVCAR5, OVCAR8, OVSAHO, OVKATE, SNU119 and UWB1.289 cells were assessed for tumor formation in nude mice. Cells were injected intraperitoneally (i.p.) or subcutaneously (s.c.) in female athymic nude mice and allowed to grow (maximum of 90 days) and tumor formation was analyzed. All tumors were sectioned and assessed using H&E staining and immunohistochemistry for p53, PAX8 and WT1 expression. RESULTS: Six lines (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, and OVSAHO) formed i.p xenografts with HGSOC histology. OVKATE and COV362 formed s.c. tumors only. Rapid tumor formation was observed for OVCAR3, OVCAR5 and OVCAR8, but only OVCAR8 reliably formed ascites. Tumors derived from OVCAR3, OVCAR4, and OVKATE displayed papillary features. Of the 11 lines examined, three (Kuramochi, SNU119 and UWB1.289) were non-tumorigenic. CONCLUSIONS: Our findings help further define which HGSOC cell models reliably generate tumors and/or ascites, critical information for preclinical drug development, validating in vitro findings, imaging and prevention studies by the OC research community

A novel precision-engineered microfiltration device for capture and characterisation of bladder cancer cells in urine

Background: Sensitivity of standard urine cytology for detecting urothelial carcinoma of the bladder (UCB) is low, attributable largely to its inability to process entire samples, paucicellularity and presence of background cells. Objective: Evaluate performance and practical applicability of a novel portable microfiltration device for capture, enumeration and characterisation of exfoliated tumour cells in urine, and compare it with standard urine cytology for UCB detection. Methods: A total of 54 urine and bladder wash samples from patients undergoing surveillance for UCB were prospectively evaluated by standard and microfilter-based urine cytology. Head-to-head comparison of quality and performance metrics, and cost effectiveness was conducted for both methodologies. Results: Five samples were paucicellular by standard cytology; no samples processed by microfilter cytology were paucicellular. Standard cytology had 33.3% more samples with background cells that limited evaluation (p < 0.001). Microfilter cytology was more concordant (κ = 50.4%) than standard cytology (κ = 33.5%) with true UCB diagnosis. Sensitivity, specificity and accuracy were higher for microfilter cytology compared to standard cytology (53.3%/100%/79.2% versus 40%/95.8%/69.9%, respectively). Microfilter-captured cells were amenable to downstream on-chip molecular analyses. A 40 ml sample was processed in under 4 min by microfilter cytology compared to 5.5 min by standard cytology. Median microfilter cytology processing and set-up costs were approximately 63% cheaper and 80 times lower than standard cytology, respectively. Conclusions: The microfiltration device represents a novel non-invasive UCB detection system that is economical, rapid, versatile and has potentially better quality and performance metrics than routine urine cytology, the current standard-of-care

Blue carbon stock of the Bangladesh Sundarban mangroves: what could be the scenario after a century?

The total blue carbon stock of the Bangladesh Sundarban mangroves was evaluated and the probable future status after a century was predicted based on the recent trend of changes in the last 30 years and implementing a hybrid model of Markov Chain and Cellular automata. At present 36.24 Tg C and 54.95 Tg C are stored in the above-ground and below-ground compartments respectively resulting in total blue carbon stock of 91.19 Tg C. According to the prediction 15.88 Tg C would be lost from this region by the year 2115. The low saline species composition classes dominated mainly by Heritiera spp. accounts for the major portion of the carbon sock at present (45.60 Tg C), while the highly saline regions stores only 14.90 Tg C. The prediction shows that after a hundred years almost 22.42 Tg C would be lost from the low saline regions accompanied by an increase of 8.20 Tg C in the high saline regions dominated mainly by Excoecaria sp. and Avicennia spp. The net carbon loss would be due to both mangrove area loss (~ 510 km2) and change in species composition leading to 58.28 Tg of potential CO2 emission within the year 2115