Cancer-Associated Fibroblast-Derived Interleukin-8 Promotes Ovarian Cancer Cell Stemness and Malignancy Through the Notch3-Mediated Signaling

Ji, Zhaodong; Tian, Wei; Gao, Wen; Zang, Rongyu; Wang, Huaying; Yang, Gong

doi:10.3389/fcell.2021.684505

Cited by 37 publications

(62 citation statements)

References 39 publications

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“…Zhou et al reported that exosomes released from TAMs transfer miRNAs that induce a Treg/Th17 imbalance and generate an immune-suppressive microenvironment that facilitates OC progression and metastasis [ 55 ]. Ji et al showed that IL-8 secreted from CAFs could stimulate malignant growth and increased OC cisplatin resistance [ 56 ]. The above suppressive cells can cause dysfunction in effector T cells, causing a state called “T cell exhaustion.” It is characterized by progressive loss of function, changes in transcriptional profiles, and sustained expression of inhibitory receptors [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CAPG Is Associated with Poor Prognosis and Immunosuppressive Cell Infiltration in Ovarian Cancer

et al. 2022

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Historically, immunotherapies have only resulted in a partial response from patients with advanced ovarian cancer, resulting in poor clinical efficacy. A full understanding of immune-related gene expression and immunocyte infiltration in ovarian cancer would be instrumental for the improved implementation of immunotherapy. The Capping Actin Protein, Gelsolin-Like (CAPG) gene encodes an actin-regulatory protein, which plays important roles in tumor progression and immune regulation. This study is aimed at identifying the potential therapeutic and prognostic roles of CAPG in ovarian cancer. CAPG expression and clinical information were investigated in the data collected from TCGA, Oncomine, GEPIA, UALCAN, and Kaplan-Meier plotter. CAPG coexpression networks were evaluated by LinkedOmics, GeneMANIA, and NetworkAnalyst. The correlation of CAPG with immune infiltrates was analyzed via TIMER, ImmuCellAI, and GEPIA. Our result showed that patients with high tumoral CAPG expression had significantly shorter 5-year overall survival. Functional enrichment analysis indicated that CAPG-related phenotypes were largely involved in inflammatory response, chemokine and cytokine signaling, cell adhesion, and Toll-like receptor signaling pathways. CAPG expression was positively correlated with infiltrating levels of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and exhausted T cells (Texs) while being negatively correlated with infiltrating levels of natural killer T cells (NKTs) and neutrophils in ovarian cancer. Moreover, the expression of FOXP3, CD25, CD127, CCR8, and TGFβ in respect to Tregs; CCL2 and CD68 in respect to TAM; CD163, VSIG4, and MS4A4A in respect to M2 macrophages; CD33 and CD11b in respect to myeloid-derived suppressor cells (MDSCs); and PD1, CTLA4, LAG3, TIM3, GZMB, 2B4, and TIGIT in respect to Texs was significantly correlated with CAPG expression in ovarian cancer. These findings suggest that CAPG may contribute to the immunosuppressive tumor microenvironment in ovarian cancer, leading to an exhausted T cell phenotype and tumor progression. Therefore, CAPG can be used as a potential biomarker for determining prognosis and immunotherapy effectiveness in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Overexpression of CAPG Is Associated with Poor Prognosis and Immunosuppressive Cell Infiltration in Ovarian Cancer

et al. 2022

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“…IL-8 is another molecule that plays a critical role in tumor progression and metastasis in different cancers. In ovarian cancers, CAF-derived IL-8 promotes normal fibroblast proliferation and stemness of tumor cells, activating the Notch-3 signaling pathway [ 99 ]. In addition, in pancreatic cancer, a subtype of CAFs with senescent features secretes more IL-8 than non-senescent CAFs.…”

Section: Caf–tumor Communicationmentioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis

Asif

Longobardi

Hahne

et al. 2021

Cancers

127

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Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is crucial to understand the role of CAFs in this process. Colorectal cancer (CRC) is a heterogeneous disease and lethality is especially common in a subtype of CRC with high stromal infiltration. A key component of stroma is cancer-associated fibroblasts (CAFs). To provide new perspectives for research on CAFs and CAF-targeted therapeutics, especially in CRC, we discuss the mechanisms, crosstalk, and functions involved in CAF-mediated cancer invasion, metastasis, and protection. This summary can serve as a framework for future studies elucidating these roles of CAFs.

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“…CXCL8 can induce normal ovarian fibroblasts to CAFs and stimulate xenograft tumor growth in mice. The ovarian cancer cell stemness was promoted by the CXCL8 secreted from CAFs through the Notch3 signaling pathway [ 50 ]. Gastric cancer extracellular vesicles transfer various miRNAs and induce chemokines such as CXCL1 and CXCL8 expression in CAFs.…”

Section: Cxcl8-cxcr1/2 Signaling Pathwaymentioning

confidence: 99%

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Han

Yang

et al. 2021

Molecules

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In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

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Cancer-Associated Fibroblast-Derived Interleukin-8 Promotes Ovarian Cancer Cell Stemness and Malignancy Through the Notch3-Mediated Signaling

Cited by 37 publications

References 39 publications

Overexpression of CAPG Is Associated with Poor Prognosis and Immunosuppressive Cell Infiltration in Ovarian Cancer

Overexpression of CAPG Is Associated with Poor Prognosis and Immunosuppressive Cell Infiltration in Ovarian Cancer

The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

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