Molecular mechanisms of Thrombospondin-2 modulates tumor vasculogenic mimicry by PI3K/AKT/mTOR signaling pathway

Huang, Ju; Wang, Congcong; Hou, Yixuan; Tian, Yuanyuan; Li, Yanru; Zhang, Haiying; Zhang, Lihong; Li, Wei

doi:10.1016/j.biopha.2023.115455

Cited by 13 publications

(3 citation statements)

References 106 publications

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“…Both PI3K and PTK2 are involved in pathways integral to tumor initiation and progression ( Lee et al, 2015 ; Alqahtani et al, 2019 ). Previous studies have reported that mutations in PI3K can augment the formation and functionality of VM ( Huang et al, 2023 ). Meanwhile, correlation analysis between methylation levels and transcriptome expression levels reveals a negative correlation for most genes.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer dissection of vasculogenic mimicry characteristic to provide potential therapeutic targets

Tang,

Chen,

Liu

et al. 2024

Front. Pharmacol.

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Introduction:Vasculogenic mimicry (VM) represents a novel form of tumor angiogenesis that is associated with tumor invasiveness and drug resistance. However, the VM landscape across cancer types remains poorly understood. In this study, we elucidate the characterizations of VM across cancers based on multi-omics data and provide potential targeted therapeutic strategies.Methods:Multi-omics data from The Cancer Genome Atlas was used to conduct comprehensive analyses of the characteristics of VM related genes (VRGs) across cancer types. Pan-cancer vasculogenic mimicry score was established to provide a depiction of the VM landscape across cancer types. The correlation between VM and cancer phenotypes was conducted to explore potential regulatory mechanisms of VM. We further systematically examined the relationship between VM and both tumor immunity and tumor microenvironment (TME). In addition, cell communication analysis based on single-cell transcriptome data was used to investigate the interactions between VM cells and TME. Finally, transcriptional and drug response data from the Genomics of Drug Sensitivity in Cancer database were utilized to identify potential therapeutic targets and drugs. The impact of VM on immunotherapy was also further clarified.Results:Our study revealed that VRGs were dysregulated in tumor and regulated by multiple mechanisms. Then, VM level was found to be heterogeneous among different tumors and correlated with tumor invasiveness, metastatic potential, malignancy, and prognosis. VM was found to be strongly associated with epithelial-mesenchymal transition (EMT). Further analyses revealed cancer-associated fibroblasts can promote EMT and VM formation. Furthermore, the immune-suppressive state is associated with a microenvironment characterized by high levels of VM. VM score can be used as an indicator to predict the effect of immunotherapy. Finally, seven potential drugs targeting VM were identified.Conclusion:In conclusion, we elucidate the characteristics and key regulatory mechanisms of VM across various cancer types, underscoring the pivotal role of CAFs in VM. VM was further found to be associated with the immunosuppressive TME. We also provide clues for the research of drugs targeting VM. Our study provides an initial overview and reference point for future research on VM, opening up new avenues for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Pan-cancer dissection of vasculogenic mimicry characteristic to provide potential therapeutic targets

Tang,

Chen,

Liu

et al. 2024

Front. Pharmacol.

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“…[ 27 ] It serves as a central node in the cellular signaling pathway, particularly in pathways related to cell survival and insulin signaling. [ 28 ] Studies have shown that TAGLN2 is induced in the hypoxic microenvironment of glioblastoma PDX cell lines, and it enhances cellular resistance to standard treatments by binding and inhibiting PTEN, thus activating the PI3K/Akt pathway. [ 29 ] Danphenolic acid F inhibits the growth of KRAS-dependent lung cancer cells via the PI3K/AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Investigating the molecular mechanism of Mori Cortex against osteosarcoma by bioinformatics analysis and in vitro experimental

Wang,

Xie

et al. 2024

Medicine

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Objective: To explore the therapeutic mechanism of Mori Cortex against osteosarcoma (OS), we conducted bioinformatics prediction followed by in vitro experimental validation. Methods: Gene expression data from normal and OS tissues were obtained from the GEO database and underwent differential analysis. Active Mori Cortex components and target genes were extracted from the Traditional Chinese Medicine System Pharmacology database. By intersecting these targets with differentially expressed genes in OS, we identified potential drug action targets. Using the STRING database, a protein-protein interaction network was constructed. Subsequent analyses of these intersected genes, including Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, were performed using R software to elucidate biological processes, molecular functions, and cellular components, resulting in the simulation of signaling pathways. Molecular docking assessed the binding capacity of small molecules to signaling pathway targets. In vitro validations were conducted on U-2 OS cells. The CCK8 assay was used to determine drug-induced cytotoxicity in OS cells, and Western Blotting was employed to validate the expression of AKT, extracellular signal-regulated kinases (ERK), Survivin, and Cyclin D1 proteins. Results: Through differential gene expression analysis between normal and OS tissues, we identified 12,364 differentially expressed genes. From the TCSMP database, 39 active components and 185 therapeutic targets related to OS were derived. The protein-protein interaction network indicated that AKT1, IL-6, JUN, VEGFA, and CASP3 might be central targets of Mori Cortex for OS. Molecular docking revealed that the active compound Morusin in Mori Cortex exhibits strong binding affinity to AKT and ERK. The CCK8 assay showed that Morusin significantly inhibits the viability of U-2 OS cells. Western Blot demonstrated a reduction in the p-AKT/AKT ratio, the p-ERK/ERK ratio, Survivin, and Cyclin D1. Conclusion: Mori Cortex may exert its therapeutic effects on OS through multiple cellular signaling pathways. Morusin, the active component of Mori Cortex, can inhibit cell cycle regulation and promote cell death in OS cells by targeting AKT/ERK pathway.

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“…Although these four mechanisms of angiogenesis are known, various regulators and signalling pathways involved in the mechanisms are still being researched [ 65 – 67 ]. The classical factor is vascular endothelial growth factor A (VEGF-A).…”

Section: Introductionmentioning

confidence: 99%

Research progress of exosomes in the angiogenesis of digestive system tumour

Liu,

Wu,

Sang

et al. 2024

Discov Onc

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Malignant tumours of the digestive system cover a wide range of diseases that affect the health of people to a large extent. Angiogenesis is indispensable in the development, and metastasis of tumours, mainly in two ways: occupation or formation. Vessels can provide nutrients, oxygen, and growth factors for tumours to encourage growth and metastasis, so cancer progression depends on simultaneous angiogenesis. Recently, exosomes have been proven to participate in the angiogenesis of tumours. They influence angiogenesis by binding to tyrosine kinase receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 with different affinities, regulating Yap-VEGF pathway, Akt pathway or other signaling pathway. Additionally, exosomes are potential therapeutic vectors that can deliver many types of cargoes to different cells. In this review, we summarize the roles of exosomes in the angiogenesis of digestive system tumours and highlight the clinical application prospects, directly used as targers or delivery vehicles, in antiangiogenic therapy.

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Molecular mechanisms of Thrombospondin-2 modulates tumor vasculogenic mimicry by PI3K/AKT/mTOR signaling pathway

Cited by 13 publications

References 106 publications

Pan-cancer dissection of vasculogenic mimicry characteristic to provide potential therapeutic targets

Pan-cancer dissection of vasculogenic mimicry characteristic to provide potential therapeutic targets

Investigating the molecular mechanism of Mori Cortex against osteosarcoma by bioinformatics analysis and in vitro experimental

Research progress of exosomes in the angiogenesis of digestive system tumour

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