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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: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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