scholarly journals Characterization of Candidate Factors Associated With the Metastasis and Progression of High Grade Serous Ovarian Cancer

2021 ◽  
Author(s):  
Huiping Liu ◽  
Ling Zhou ◽  
Hongyan Cheng ◽  
Shang Wang ◽  
Wenqing Luan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Primary Tumor ◽  
Gynecological Cancer ◽  
Wnt Signaling Pathway ◽  
The Cancer Genome Atlas ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Hub Genes ◽  
Bioinformatics Analyses ◽  
Factors Associated

Abstract Background. High grade serous ovarian cancer (HGSOC) is the highest cause of gynecological cancer-related mortality due to the extremely metastatic nature of this disease. The goal of this study is to explore and evaluate the profiles and characteristics of candidate factors associated with metastasis and progression of HGSOC.Methods. Transcriptomic data of HGSOC patients’ samples collected from the primary tumor and matched omental metastatic tumor were obtained from three independent studies in the NCBI GEO database. Genes significantly up-regulated and down-regulated were selected to evaluate the effects to prognosis and progression of ovarian cancer using data of ovarian cancer patients from The Cancer Genome Atlas (TCGA) database. Enrichment analysis for biological processes and pathways was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis. Furthermore, the hub genes immune landscapes were estimated by Tumor Immune Estimation Resource (TIMER) database.Results. 14 candidate genes included ADIPOQ, ALPK2, BARX1, CD37, CNR2, COL5A3, FABP4, FAP, GPR68, ITGBL1, MOXD1, PODNL1, SFRP2 and TRAF3IP3 were selected as up-regulated genes in metastatic tumors in every database while CADPS, GATA4, STAR and TSPAN8 were down-regulated. These 14 genes were significantly enriched for negative regulation of Wnt signaling pathway, fat cell differentiation, extracellular matrix organization. Finally, ALPK2, FAP, SFRP2 and GATA4, STAR, TSPAN8 were selected as hub genes that were found to be significantly associated with the survival and recurrence. All hub genes were correlated with several types of tumor microenvironmental cells infiltration significantly, especially for cancer associated fibroblasts and NK cells.Conclusions. This study indicates that screening for differentially expressed genes and pathways in HGSOC primary tumor and matched metastasis tumor using integrated bioinformatics analyses. In sum, we identify six hub genes correlated with the progression of HGSOC in our study, which might provide effective targets to predict prognosis and provide novel insights into immune-based therapy strategies of HGSOC well.

scholarly journals Immune Modeling Analysis Reveals Immunologic Signatures Associated With Improved Outcomes in High Grade Serous Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Nicole E. James ◽  
Katherine Miller ◽  
Natalie LaFranzo ◽  
Erin Lips ◽  
Morgan Woodman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Cell ◽  
Immune Escape ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Immunological Responses ◽  
Modeling Analysis ◽  
Immune Cell Subsets

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide, as patients are typically diagnosed at a late stage and eventually develop chemoresistant disease following front-line platinum-taxane based therapy. Only modest results have been achieved with PD-1 based immunotherapy in ovarian cancer patients, despite the fact that immunological responses are observed in EOC patients. Therefore, the goal of this present study was to identify novel immune response genes and cell subsets significantly associated with improved high grade serous ovarian cancer (HGSOC) patient prognosis. A transcriptomic-based immune modeling analysis was employed to determine levels of 8 immune cell subsets, 10 immune escape genes, and 22 co-inhibitory/co-stimulatory molecules in 26 HGSOC tumors. Multidimensional immune profiling analysis revealed CTLA-4, LAG-3, and Tregs as predictive for improved progression-free survival (PFS). Furthermore, the co-stimulatory receptor ICOS was also found to be significantly increased in patients with a longer PFS and positively correlated with levels of CTLA-4, PD-1, and infiltration of immune cell subsets. Both ICOS and LAG-3 were found to be significantly associated with improved overall survival in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Finally, PVRL2 was identified as the most highly expressed transcript in our analysis, with immunohistochemistry results confirming its overexpression in HGSOC samples compared to normal/benign. Results were corroborated by parallel analyses of TCGA data. Overall, this multidimensional immune modeling analysis uncovers important prognostic immune factors that improve our understanding of the unique immune microenvironment of ovarian cancer.

scholarly journals Role of integrins in the metastatic spread of high-grade serous ovarian cancer

2021 ◽  
Author(s):  
Slavomir Krajnak ◽  
Jörg Jäkel ◽  
Katharina Anić ◽  
Roxana Schwab ◽  
Marcus Schmidt ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Primary Tumor ◽  
High Expression ◽  
Metastatic Spread ◽  
Clinicopathological Parameters ◽  
Integrin Expression ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Integrin Α4 ◽  
Integrin Α2

Abstract Purpose Integrins may be involved in the metastatic spread of high-grade serous ovarian cancer (HGSOC) which determines the therapeutical approach and prognosis. We investigated the integrin expression in primary tumor and metastases of advanced HGSOC. Methods The expression of integrin α2, α4, α5, α6, and β1 was assessed by immunostaining in tumor samples of the ovary, omentum, and peritoneum of each patient. Differences in integrin expression among tumor localizations and their association with clinicopathological parameters were examined by Fisher’s exact test. The impact of integrin expression on progression-free survival (PFS) and overall survival (OS) was examined by Cox regression and Kaplan–Meier analyses. Results Hundred and thirteen tumor samples of 40 HGSOC patients were examined. The expression of the integrins did not differ between the three tumor localizations (all p values > 0.05) with the exception of high expression of integrin α4 in primary tumor and omentum (52.5% versus 47.5%, p = 0.008) and primary tumor and peritoneum (52.5% versus 47.5%, p = 0.050). High expression of integrin α4 in peritoneum was associated with poorer PFS (HR 2.02 95% CI 1.01–4.05, p = 0.047), younger age (p = 0.047), and death (p = 0.046). Median PFS in patients with high expression of integrin α4 was 13.00 months, whereas median PFS in patients without high expression of integrin α4 was 21.00 months (p = 0.040). Expression of other integrins did not correlate with PFS or OS. Conclusion Expression of integrin α4 may be altered during the metastatic spread of HGSOC and affect prognosis, whereas expression of integrin α2, α5, α6, and β1 did not reveal any prognostic value.

scholarly journals Focal Recurrent Copy Number Alterations Characterize Disease Relapse in High Grade Serous Ovarian Cancer Patients with Good Clinical Prognosis: A Pilot Study

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 678 ◽  
Author(s):  
Dugo ◽  
Devecchi ◽  
De Cecco ◽  
Cecchin ◽  
Mezzanzanica ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Molecular Heterogeneity ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Disease Relapse ◽  
Clinical Prognosis ◽  
Primary Surgery ◽  
Altered Gene

High grade serous ovarian cancer (HGSOC) retains high molecular heterogeneity and genomic instability, which currently limit the treatment opportunities. HGSOC patients receiving complete cytoreduction (R0) at primary surgery and platinum-based therapy may unevenly experience early disease relapse, in spite of their clinically favorable prognosis. To identify distinctive traits of the genomic landscape guiding tumor progression, we focused on the R0 patients of The Cancer Genome Atlas (TCGA) ovarian serous cystadenocarcinoma (TCGA-OV) dataset and classified them according to their time to relapse (TTR) from surgery. We included in the study two groups of R0-TCGA patients experiencing substantially different outcome: Resistant (R; TTR ≤ 12 months; n = 11) and frankly Sensitive (fS; TTR ≥ 24 months; n = 16). We performed an integrated clinical, RNA-Sequencing, exome and somatic copy number alteration (sCNA) data analysis. No significant differences in mutational landscape were detected, although the lack of BRCA-related mutational signature characterized the R group. Focal sCNA analysis showed a higher frequency of amplification in R group and deletions in fS group respectively, involving cytobands not commonly detected by recurrent sCNA analysis. Functional analysis of focal sCNA with a concordantly altered gene expression identified in R group a gain in Notch, and interferon signaling and fatty acid metabolism. We are aware of the constraints related to the low number of OC cases analyzed. It is worth noting, however, that the sCNA identified in this exploratory analysis and characterizing Pt-resistance are novel, deserving validation in a wider cohort of patients achieving complete surgical debulking.

scholarly journals Engineered EV-Mimetic Nanoparticles as Therapeutic Delivery Vehicles for High-Grade Serous Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3075
Author(s):  
Amal A. Al-Dossary ◽  
Essam A. Tawfik ◽  
Adaugo C. Isichei ◽  
Xin Sun ◽  
Jiahe Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gynecological Cancer ◽  
Treatment Options ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Delivery Vehicle ◽  
Platinum Drug ◽  
Gynecological Malignancy ◽  
Cancer Chemotherapeutics ◽  
Drug Resistant Strains

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy among women. Several obstacles impede the early diagnosis and effective treatment options for ovarian cancer (OC) patients, which most importantly include the development of platinum-drug-resistant strains. Currently, extensive efforts are being put into the development of strategies capable of effectively circumventing the physical and biological barriers present in the peritoneal cavity of metastatic OC patients, representing a late stage of gastrointestinal and gynecological cancer with an extremely poor prognosis. Naturally occurring extracellular vesicles (EVs) have been shown to play a pivotal role in progression of OC and are now being harnessed as a delivery vehicle for cancer chemotherapeutics. However, there are limitations to their clinical application due to current challenges in their preparation techniques. Intriguingly, there is a recent drive towards the use of engineered synthetic EVs for the delivery of chemotherapeutics and RNA interference therapy (RNAi), as they show the promise of overcoming the obstacles in the treatment of OC patients. This review discusses the therapeutic application of EVs in OC and elucidates the potential use of engineered EV-mimetic nanoparticles as a delivery vehicle for RNAi therapy and other chemotherapeutics, which would potentially improve clinical outcomes of OC patients.

scholarly journals Integrated Weighted Gene Co-expression Network Analysis Reveals ALB Associated With Prognosis of High-grade Serous Ovarian Cancer

2021 ◽  
Author(s):  
Bo Wang ◽  
Shan Chao ◽  
Bo Guo
Keyword(s):  
Ovarian Cancer ◽  
Survival Analysis ◽  
Network Analysis ◽  
Single Gene ◽  
Enrichment Analysis ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Hub Genes ◽  
Hub Gene ◽  
Proteomic Data

Abstract Background: Ovarian cancer is the gynecologic tumor with the highest fatality rate, and high-grade serous ovarian cancer (HGSOC) is the most common and malignant type of ovarian cancer. One important reason for the poor prognosis of HGSOC is the lack of effective diagnostic and prognostic biomarkers. New biomarkers are necessary for improvement of treatment strategies and to ensure appropriate healthcare decisions.Methods: To construct the co-expression network of HGSOC samples, we applied weighted gene co-expression network analysis (WGCNA) to assess the proteomic data downloaded from Clinical Proteomic Tumor Analysis Consortium (CPTAC), and module-trait relationship was then analyzed and plotted in a heat map to choose key module associated with HGSOC. Enrichment analysis was performed on the genes in the key modules to explore the functional information in which these genes participate. Hub genes with high connectivity in key module were identified by Cytoscape software. Furthermore, the true hub gene was selected through survival analysis, followed by expression verification with transcriptome dataset from TCGA and GTEx. Finally, the potential biological functions of hub gene were analyzed via single-gene Gene Set Enrichment Analysis (GSEA).Results: After merging similar modules, a total of 9 modules were identified. Module-trait analysis revealed that the brown module (cor = 0.7) was significantly associated with HGSOC. The results of enrichment analysis of the genes in the brown module show that these genes were related to the functions of the extracellular matrix, the complement system and the blood system. Ten hub genes with the highest connectivity were selected by protein-protein interaction analysis. After survival analysis and expression verification of hub genes, only ALB was confirmed to be the true hub gene and positively correlated with HGSOC prognosis. Single gene GSEA revealed that ALB was associated with cell material degradation.Conclusion: We conducted the first gene co-expression analysis based on proteomic data from HGSOC samples, and found that ALB had prognostic value, which could be applied in the treatment of HGSOC in the future.

Ubiquitin–Proteasome Axis, Especially Ubiquitin-Specific Protease-17 (USP17) Gene Family, is a Potential Target for Epithelial–Mesenchymal Transition in High-Grade Serous Ovarian Cancer

2018 ◽  
Vol 26 (6) ◽  
pp. 794-805 ◽  
Author(s):  
Nuri Yildirim ◽  
Gizem Calibasi Kocal ◽  
Zerrin Isik ◽  
Bahadır Saatli ◽  
Ugur Saygili ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gene Family ◽  
Primary Tumor ◽  
Epithelial Mesenchymal Transition ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Malignant Cells ◽  
Mesenchymal Transition ◽  
Peritoneal Implant ◽  
Ubiquitin Proteasome

Objectives: To investigate gene expression differences and related functions between primary tumor, malignant cells in ascites, and metastatic peritoneal implant in high-grade serous ovarian cancer. Methods: Biopsies from primary tumor, peritoneal implant, and ascites were collected from 10 patients operated primarily for high-grade, advanced-staged serous ovarian cancer. Total RNA isolation was performed from collected tissue biopsy and fluid samples, and RNA expression profile was measured. Messenger RNA expression profiles of 3 different groups were compared. Functional analyses of candidate genes were carried out by gene ontology and pathway analysis. Results: There were significant differences in the expression of 5 genes between primary tumor and peritoneal implant, 979 genes between primary tumor and malignant cells in ascites, and 649 genes between peritoneal implant and malignant cells in ascites. Three commonly enriched gene ontology functions between “primary tumor and malignant cells in the ascites” and “peritoneal implant and malignant cells in the ascites” were protein deubiquitination, ubiquitin-dependent protein catabolism, and apoptotic processes. All genes related to these functions belonged to USP17 gene family. Conclusion: Gene expression difference between primary tumor and the peritoneal implant is not as much as the difference between primary tumor and free cells in the ascites. These results show that malignant cells in the ascites return into its genetic origin after they invade on the peritoneum. Significantly increased expression of DUB-enzyme genes, SNAR gene family, and ribosomal pathway genes in epithelial–mesenchymal transition suggests that this regulation is ubiquitin–proteasome dependent. Especially, this is the first study that offers USP17 as a potential target for epithelial–mesenchymal transition.

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