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Signaling within the epithelial ovarian cancer tumor microenvironment: the challenge of tumor heterogeneity.

ABSTRACT: Epithelial ovarian cancer (EOC) is a leading cause of cancer death in women. Standard of care treatment has remained platinum-containing cytotoxic chemotherapy for over three decades. Among the central challenges in treating ovarian CA are disease recurrence and the development of chemoresistance. Survival is uniformly poor for patients with chemoresistant recurrent disease and effective therapeutic options are limited. As such, delineating the mechanisms of chemoresistance and developing targeted therapies to prevent chemoresistance from occurring are of vital importance to improving survival for patients with EOC. Attempts to characterize mechanisms of chemoresistance have implicated numerous cellular pathways, but a rift remains between pre-clinical findings and translation to improving patient survival. More recently, the interplay among different cell types within the tumor microenvironment has become central to understanding how chemoresistance may develop and may be sustained. An improved understanding of how tumor cell-intrinsic and -extrinsic pathways converge during the development of chemoresistance may improve the likelihood of successful clinical translation. This review focuses on the roles of the EOC tumor microenvironment and tumor cell heterogeneity in the development of chemoresistance. We review recent studies into mechanisms of chemoresistance as they relate to tumor microenvironment and development of novel therapeutic approaches that exploit these mechanisms to prevent or reverse chemoresistance. This review attempts to cast these latest discoveries in a clinical context by summarizing trends in ongoing clinical trials for patients with EOC.

SUBMITTER: Horowitz M

PROVIDER: S-EPMC7396799 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Signaling within the epithelial ovarian cancer tumor microenvironment: the challenge of tumor heterogeneity.

Horowitz Max M Esakov Emily E Rose Peter P Reizes Ofer O

Annals of translational medicine 20200701 14

Epithelial ovarian cancer (EOC) is a leading cause of cancer death in women. Standard of care treatment has remained platinum-containing cytotoxic chemotherapy for over three decades. Among the central challenges in treating ovarian CA are disease recurrence and the development of chemoresistance. Survival is uniformly poor for patients with chemoresistant recurrent disease and effective therapeutic options are limited. As such, delineating the mechanisms of chemoresistance and developing target ...[more]

PMID: 32793749

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Project description:BackgroundIt was reported that tumor heterogeneity and the surrounding tumor microenvironment (TME) in ovarian cancer affects immunotherapy efficacy and patient outcomes. And the TME of ovarian cancer is intrinsically heterogeneous. CD47 plays vital roles in cell functional behavior and immune homeostasis relating to cancer prognosis. But how it affects TME and its contribution to heterogeneity in ovarian cancer has not been fully illustrated. Therefore, we aimed to identify a prognostic biomarker which may help explain tumor immune microenvironment heterogeneity of ovarian cancer.MethodsCancer single-cell state atlas (CancerSEA) was used to evaluate functional role of CD47. Several bioinformatics database including Oncomine, Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Human Protein Atlas (HPA), Ualcan and Kaplan-Meier plotter (KM plotter) were applied to illustrate correlation of CD47 with ovarian cancer prognosis and immune infiltration. Tumor Immune Single-cell Hub (TISCH) single cell database was employed to evaluate correlation of CD47 with tumor microenvironment. GeneMANIA was implemented to identify regulation networks of CD47. Differentially expressed genes (DEGs) between CD47 high and low expression groups were analyzed with R package DESeq2. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were utilized to explore how CD47 affect the immune related cell signaling pathway.ResultsCD47 expression was upregulated and connected to worse OS and PFS in ovarian cancer. Close relation was found between CD47 expression level and immune infiltration in ovarian cancer, especially with Treg cells, Monocytes, Macrophages and T cell exhaustion (P<0.05). The CD47 expression level was relatively low in plasma cells, dendritic cells and Mono/Macro cells of OV_GSE115007, in myofibroblasts, fibroblasts and endothelial cells of OV_GSE118828, compared to malignant cells of OV_GSE118828 dataset. The cell components and distribution in primary and metastatic ovarian cancer are quite distinct, which may lead to TME heterogeneity of ovarian cancer.ConclusionOur results indicated that CD47 is closely correlated to ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity. Therefore, CD47 may be used as a candidate prognostic biomarker and provide us with new insights into potential immunotherapy in ovarian cancer patients.

Project description:BackgroundEpithelial ovarian cancer (EOC) is one of the deadliest gynecologic cancers. The etiology of EOC has still not been elucidated thoroughly. Tumor necrosis factor-α-induced protein 8-like2 (TNFAIP8L2, TIPE2), an important regulator of inflammation and immune homeostasis, plays a critical role in the progression of various cancers. This study aims to investigate the role of TIPE2 in EOC.MethodsExpression of TIPE2 protein and mRNA in EOC tissues and cell lines was examined using Western blot and quantitative real-time PCR (qRT-PCR). The functions of TIPE2 in EOC were investigated by cell proliferation assay, colony assay, transwell assay, and apoptosis analysis in vitro. To further investigate the regulatory mechanisms of TIPE2 in EOC, RNA-seq and western blot were performed. Finally, the CIBERSORT algorithm and databases including Tumor Immune Single-cell Hub (TISCH), Tumor Immune Estimation Resource (TIMER), Tumor-Immune System Interaction (TISIDB), and The Gene Expression Profiling Interactive Analysis (GEPIA) were used to elucidate its potential role in regulating tumor immune infiltration in the tumor microenvironment (TME).ResultsTIPE2 expression was shown to be considerably lower in both EOC samples and cell lines. Overexpression of TIPE2 suppressed EOC cell proliferation, colony formation, and motility in vitro. Mechanistically, TIPE2 suppressed EOC by blocking the PI3K/Akt signaling pathway, according to bioinformatics analysis and western blot in TIPE2 overexpression EOC cell lines, and the anti-oncogenic potentials of TIPE2 in EOC cells could be partially abrogated by the PI3K agonist, 740Y-P. Finally, TIPE2 expression was positively associated with various immune cells and possibly involved in the regulation of macrophage polarization in ovarian cancer.ConclusionsWe detail the regulatory mechanism of TIPE2 in EOC carcinogenesis, as well as how it correlates with immune infiltration, emphasizing its potential as a therapeutic target in ovarian cancer.

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Signaling within the epithelial ovarian cancer tumor microenvironment: the challenge of tumor heterogeneity.

Publications

Signaling within the epithelial ovarian cancer tumor microenvironment: the challenge of tumor heterogeneity.

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