TKI-Resistant Renal Cancer Secretes Low-Level Exosomal miR-549a to Induce Vascular Permeability and Angiogenesis to Promote Tumor Metastasis

Xuan, Zuodong; Chen, Chen; Tang, Wenqi; Ye, Shaopei; Zheng, Jianzhong; Zhao, Yue; Shi, Zhiyuan; Zhang, Lei; Sun, Huimin; Shao, Chen

doi:10.3389/fcell.2021.689947

Cited by 36 publications

(28 citation statements)

References 50 publications

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“…Previous studies have revealed that RCC-derived exosomes are associated with tumor proliferation and metastasis ( 13 ). To verify the mechanism of exosomes in RCC, we isolated cancer cell-derived exosomes from the supernatant of two RCC cell lines, 769-P and ACHN.…”

Section: Resultsmentioning

confidence: 99%

Exosomal Circsafb2 Reshaping Tumor Environment to Promote Renal Cell Carcinoma Progression by Mediating M2 Macrophage Polarization

et al. 2022

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BackgroundMacrophages are the most abundant infiltrating immune-related stromal cells present in and around tumors, showing different phenotypes and functions. M2 macrophages mainly exert immunosuppressive functions and promote tumor growth. Exosomes are emerging as important mediators of cross-talk between tumor cells and the microenvironment. CircRNAs are novel members of non-coding RNAs that regulate cancer proliferation and progression. However, the mechanism by which exosomal circRNA regulates macrophage polarization in renal cell carcinoma (RCC) is still largely unknown.MethodsRCC-derived exosomes were characterized using transmission electron microscopy and nanoparticle tracking analysis (NTA). CCK-8, wound healing, and Transwell assays were performed to assess whether exosomes would affect the proliferation, migration, and invasion of RCC. Furthermore, we performed a bioinformatics analysis to identify circRNAs in RCC serum-derived exosomes from the GEO database. The fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circSAFB2. Bioinformatics analyses (StarBase 2.0) were used to pool the miRNA targets of circSAFB2. Luciferase assays were performed to verify the direct interactions. Western blotting was used to detect markers of macrophage M2 polarization. Lastly, mouse xenograft and bioluminescence imaging were used to examine the clinical relevance of exosomal circSAFB2 in vivo.ResultsWe report the circRNA derived from SAFB2 and evaluate its biological function in promoting the immune escape of RCC. We found that circSAFB2 was highly expressed in RCC tissues and RCC-derived exosomes. Furthermore, we demonstrated that exosomal circSAFB2 mediates the polarization of M2 macrophages through the miR-620/JAK1/STAT3 axis to promote RCC metastasis.ConclusionsOur data first demonstrated that circSAFB2 leads to immune escape from RCC by mediating M2 macrophage polarization via the miR-620/JAK1/STAT3 axis. These findings indicate a novel molecular mechanism of exosomal circSAFB2 in the progression of RCC and implicate circSAFB2 as a target for exosome-mediated tumor immune evasion.

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Section: Resultsmentioning

confidence: 99%

Exosomal Circsafb2 Reshaping Tumor Environment to Promote Renal Cell Carcinoma Progression by Mediating M2 Macrophage Polarization

et al. 2022

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“…In addition, Fu et al found that multidrug-resistant HCC Bel/5-FU cells transported exosomal miR-32-5p to Bel7402-sensitive cells and activated the PI3K/AKT pathway, thereby regulating angiogenesis and EMT to further induce multidrug resistance [141]. Additionally, exosomal miR-549a promotes angiogenesis and enhances vascular permeability by regulating the expression of HIF-1α in vascular ECs, thereby promoting tumorigenesis and metastasis in TKI-resistant clear cell renal cell carcinoma [142]. Therefore, overcoming drug resistance during cancer treatment is key to achieving good results.…”

Section: Ev-derived Ncrnas As Potential Anti-angiogenic Therapeutic T...mentioning

confidence: 99%

Noncoding RNAs of Extracellular Vesicles in Tumor Angiogenesis: From Biological Functions to Clinical Significance

Liu

et al. 2022

Cells

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Extracellular vesicles (EVs) act as multifunctional regulators of intercellular communication and are involved in diverse tumor phenotypes, including tumor angiogenesis, which is a highly regulated multi-step process for the formation of new blood vessels that contribute to tumor proliferation. EVs induce malignant transformation of distinct cells by transferring DNAs, proteins, lipids, and RNAs, including noncoding RNAs (ncRNAs). However, the functional relevance of EV-derived ncRNAs in tumor angiogenesis remains to be elucidated. In this review, we summarized current research progress on the biological functions and underlying mechanisms of EV-derived ncRNAs in tumor angiogenesis in various cancers. In addition, we comprehensively discussed the potential applications of EV-derived ncRNAs as cancer biomarkers and novel therapeutic targets to tailor anti-angiogenic therapy.

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“…Interestingly, a proof-of-principle validation was carried out in three NSCLC patients that were administered osimertinib and from whom plasma was drawn, for exosome isolation, before and after the onset of osimertinib resistance. In renal cancer, miR-549a was found to be reduced and such lower levels were reflected in the derived exosomes that were taken up by endothelial cells and the reduced miR-549a levels resulted in de-repression of HIF-1α and VEGF ultimately leading to increased angiogenesis [ 78 ]. In support of an interplay between lncRNAs and the miRNAs, lncRNA LNC000093 was found to be downregulated while the miRNA it sponged, miR-675, is elevated in imatinib-resistant leukemia cells [ 79 ].…”

Section: Mechanisms Of Exosome-mediated Cancer Drug Resistancementioning

confidence: 99%

Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery

Khan

Alsayed

Choudhry

et al. 2022

IJMS

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Exosomes, the extracellular vesicles produced in the endosomal compartments, facilitate the transportation of proteins as well as nucleic acids. Epigenetic modifications are now considered important for fine-tuning the response of cancer cells to various therapies, and the acquired resistance against targeted therapies often involves dysregulated epigenetic modifications. Depending on the constitution of their cargo, exosomes can affect several epigenetic events, thus impacting post-transcriptional regulations. Thus, a role of exosomes as facilitators of epigenetic modifications has come under increased scrutiny in recent years. Exosomes can deliver methyltransferases to recipient cells and, more importantly, non-coding RNAs, particularly microRNAs (miRNAs), represent an important exosome cargo that can affect the expression of several oncogenes and tumor suppressors, with a resulting impact on cancer therapy resistance. Exosomes often harbor other non-coding RNAs, such as long non-coding RNAs and circular RNAs that support resistance. The exosome-mediated transfer of all this cargo between cancer cells and their surrounding cells, especially tumor-associated macrophages and cancer-associated fibroblasts, has a profound effect on the sensitivity of cancer cells to several chemotherapeutics. This review focuses on the exosome-induced modulation of epigenetic events with resulting impact on sensitivity of cancer cells to various therapies, such as, tamoxifen, cisplatin, gemcitabine and tyrosine kinase inhibitors. A better understanding of the mechanisms by which exosomes can modulate response to therapy in cancer cells is critical for the development of novel therapeutic strategies to target cancer drug resistance.

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TKI-Resistant Renal Cancer Secretes Low-Level Exosomal miR-549a to Induce Vascular Permeability and Angiogenesis to Promote Tumor Metastasis

Cited by 36 publications

References 50 publications

Exosomal Circsafb2 Reshaping Tumor Environment to Promote Renal Cell Carcinoma Progression by Mediating M2 Macrophage Polarization

Exosomal Circsafb2 Reshaping Tumor Environment to Promote Renal Cell Carcinoma Progression by Mediating M2 Macrophage Polarization

Noncoding RNAs of Extracellular Vesicles in Tumor Angiogenesis: From Biological Functions to Clinical Significance

Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery

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