Extracellular vesicle-mediated transport of non-coding RNAs between stem cells and cancer cells: implications in tumor progression and therapeutic resistance

Nawaz, Muhammad

doi:10.21037/sci.2017.10.04

Cited by 31 publications

(26 citation statements)

References 107 publications

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“…In contrast, MSCs-exosomes' repressive role on HCC may be mediated by high miR148a and low Bcl2 mRNA and TGF β 1 mRNA and protein levels. Furthermore, MSCs-exosomes are highly enriched in antiangiogenic miR16 that suppresses VEGF expression thereby favoring the inhibition of angiogenesis in recipient breast cancer cells (reviewed by [ 62 ]). In a similar way, we found upregulation of miR16 and VEGF gene in livers of HCC rats receiving BM-MSCs.…”

Section: Discussionmentioning

confidence: 99%

Potential Effect of Exosomes Derived from Cancer Stem Cells and MSCs on Progression of DEN-Induced HCC in Rats

Alzahrani

El-Magd

Abdelfattah‐Hassan

et al. 2018

Stem Cells International

128

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Cross talk, mediated by exosomes, between normal stem cells and cancer stem cells (CSCs) in the tumor microenvironment has been given less attention so far. In addition, no publications are available in the literature that address the in vivo impact of exosomes derived from CSCs and mesenchymal stem cells (MSCs) on progression of long-term hepatocellular carcinoma (HCC). Herein, we hypothesized that transfer of exosomes among the cells in the HCC microenvironment could either induce or inhibit tumor growth and metastasis depending on their source. To check this hypothesis, we investigated the effect of exosomes coming from two different stem cell populations, hepatic CSCs and bone marrow (BM) MSCs, on progression of long-term DEN-induced HCC in rats and the involved underlying mechanisms. CSCs-exosomes induced a significant increase in liver relative weight and serum levels of cancer markers (AFP and GGT) and liver enzymes (ALT, AST, and ALP), intensive immunostaining for the HCC marker GST-P, and an increased number and area of tumor nodules as compared to HCC rats injected by PBS. CSCs-exosomes also decreased apoptosis (marked by downregulation of Bax and p53 and upregulation of Bcl2, and increased immunostaining of PCNA), increased angiogenetic activity (revealed by upregulation of VEGF), enhanced metastasis and invasiveness (indicated by upregulation of P13K and ERK proteins and their downstream target MMP9 and downregulation of TIMP1), and induced epithelial mesenchymal transition (marked by increased serum and hepatic level of TGFβ1 mRNA and protein). Notably, CSCs-exosomes also elevated HCC exosomal microRNA (miR) 21, exosomal long noncoding (lnc) RNA Tuc339, lncHEIH, and the HCC lncHOTAIR and decreased liver miR122 and HCC miRs (miR148a, miR16, and miR125b). All these cellular, functional, and molecular changes were reversed following injection of BM-MSCs-exosomes. However, both CSCs- and MSCs-exosomes failed to change the elevated oxidative stress or the inhibited antioxidant activities induced by HCC. Collectively, our results revealed a tumor stimulatory effect (induction of tumor growth, progression, and metastasis) for exosomes derived from CSCs and an inhibitory effect for exosomes derived from MSCs. These results provide valuable insight on the effect of CSCs- and MSCs-exosomes on HCC growth and progression in vivo, which may be helpful to understand the mechanism of HCC development.

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Section: Discussionmentioning

confidence: 99%

Potential Effect of Exosomes Derived from Cancer Stem Cells and MSCs on Progression of DEN-Induced HCC in Rats

Alzahrani

El-Magd

Abdelfattah‐Hassan

et al. 2018

Stem Cells International

128

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“…Exosomes are small, 30-to 150-nm membrane vesicles that play a vital role in intercellular communication. [4][5][6][7] Tumor exosomes induce the activation and expansion of MDSCs, 8 and a recent study found that exosomes deliver noncoding RNAs, particularly microRNAs (miRNAs), 10 to recipient cells. 9 Interestingly, miRNAs play important roles in the expansion of functional MDSCs.…”

Section: Introductionmentioning

confidence: 99%

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

Guo

Qiu

Wang

et al. 2019

Intl Journal of Cancer

123

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Myeloid‐derived suppressor cells (MDSCs) play a pivotal role in mediating the formation of an immunosuppressive environment and assisting tumors in evading the host immune response. However, the mechanism through which tumors manipulate the differentiation and function of MDSCs remains unclear. Here, we report that hypoxia‐induced glioma cells can stimulate the differentiation of functional MDSCs by transferring exosomal miR‐29a and miR‐92a to MDSCs. Our results showed that glioma‐derived exosomes (GEXs) can enhance the differentiation of functional MDSCs both in vitro and in vivo, and hypoxia‐induced GEXs (H‐GEXs) demonstrated a stronger MDSCs induction ability than did normoxia‐induced GEXs (N‐GEXs). A subsequent miRNA sequencing analysis of N‐GEXs and H‐GEXs revealed that hypoxia‐induced exosomal miR‐29a and miR‐92a expression induced the propagation of MDSCs. miR‐29a and miR‐92a activated the proliferation and function of MDSCs by targeting high‐mobility group box transcription factor 1 (Hbp1) and protein kinase cAMP‐dependent type I regulatory subunit alpha (Prkar1a), respectively. Altogether, the results of our study provide new insights into the role of glioma exosomal miRNAs in mediating the formation of immunosuppressive microenvironments in tumors and elucidate the underlying exosomal miR‐29a/miR‐92a‐based regulatory mechanism responsible for the modulation of functional MDSC induction.

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“…They act through binding to the three prime untranslated region (3′-UTR) of their target mRNAs. It has been reported that microRNAs participate in the carcinogenetic processes of many cancers, including regulating the development, differentiation and proliferation of cancer cells [ 1 – 4 ]. Recent studies have indicated that microRNAs could be used as potential biomarkers and prognostic tools in gastric cancer (GC) [ 5 – 9 ], but the biological functions and molecular mechanisms of many of the miRNAs that have been implicated in GC remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Vasodilator-stimulated phosphoprotein (VASP), a novel target of miR-4455, promotes gastric cancer cell proliferation, migration, and invasion, through activating the PI3K/AKT signaling pathway

et al. 2018

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BackgroundMicroRNAs (miRNAs) are small non-coding RNAs which play important roles in the carcinogenesis of gastric cancer (GC). Expression profiling of miRNAs in paired gastric cancer and adjacent normal gastric tissues has demonstrated that miR-4455 is down-regulated in gastric cancer tissues, but its functional role in the carcinogenesis of GC had not previously been investigated.AimsThe purpose of this study was to investigate the functional and biological mechanisms of miR-4455 in the progression of GC, in vitro.MethodsExpression of miR-4455 was compared in human GC tissue samples and paired adjacent normal tissue samples. The in vitro effects of miR-4455 expression in MGC-803 cells on their proliferation, invasion, and migration were assessed by MTT assays and 5-bromo-2′-deoxyuridine staining, matrigel-invasion analysis and wound healing assays. Bioinformatics analysis (using PicTar, target scan and miRBase target) was used to identify potential targets for miR-4455, and the luciferase reporter assay, qRT-PCR and Western-blotting analyses were used to confirm VASP as the target of miR-4455. In addition, the effects of downregulation of VASP on the activation of PI3K/AKT signaling pathway were measured using Western-blot analysis.ResultsThe expression of miR-4455 was markedly down-regulated in gastric cancer tissues vs. adjacent normal tissues, and miR-4455 expression inhibited the proliferation, invasion and migration of MGC-803 GC cells in vitro. Luciferase reporter assays revealed that miR-4455 inhibited VASP expression by targeting the 3′-UTR sequence of VASP. Furthermore, silencing of VASP markedly inhibited the activation of the PI3K/AKT signaling pathway.ConclusionOur results suggest that miR-4455 functions as a tumor suppressor in gastric cancer, by targeting VASP leading to activation of the PI3K/AKT signaling pathway and the inhibition of VASP mediated proliferation, migration and invasion of gastric cancer cells.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0573-4) contains supplementary material, which is available to authorized users.

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Extracellular vesicle-mediated transport of non-coding RNAs between stem cells and cancer cells: implications in tumor progression and therapeutic resistance

Cited by 31 publications

References 107 publications

Potential Effect of Exosomes Derived from Cancer Stem Cells and MSCs on Progression of DEN-Induced HCC in Rats

Potential Effect of Exosomes Derived from Cancer Stem Cells and MSCs on Progression of DEN-Induced HCC in Rats

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

Vasodilator-stimulated phosphoprotein (VASP), a novel target of miR-4455, promotes gastric cancer cell proliferation, migration, and invasion, through activating the PI3K/AKT signaling pathway

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