Let-7 MicroRNA Family Is Selectively Secreted into the Extracellular Environment via Exosomes in a Metastatic Gastric Cancer Cell Line

Ohshima, Keiichi; Inoue, Kanako; Fujiwara, A; Hatakeyama, Keiichi; Kanto, Kaori; Watanabe, Yuko; Muramatsu, Koji; Fukuda, Yorikane; Ogura, Shun‐ichiro; Yamaguchi, Ken; Mochizuki, Tohru

doi:10.1371/journal.pone.0013247

Cited by 518 publications

(389 citation statements)

References 42 publications

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“…Exosome purification was performed as previously described (Ohshima et al, 2010). Briefly, adMSC culture medium was collected and centrifuged at 800 g for 5 min and then for an additional 10 min at 2000 g to remove lifted cells.…”

Section: Exosome Purificationmentioning

confidence: 99%

Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a

Liang

Zhang

Wang

et al. 2016

Journal of Cell Science

425

298

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Angiogenesis plays crucial roles in various physiological processes including wound healing and tissue repair. It requires a tight interaction between endothelial cells and their surrounding environment. Mesenchymal stem cells (MSCs), one of the non-endothelial cell types present in the perivascular environment, have been shown to secret exosomes to modulate intercellular communications between MSCs and their target cells. In this study, we initially isolated exosomes secreted by human adipose-derived MSCs (adMSC-Exo) and examined their roles in angiogenesis. We found that adMSC-Exo could be taken up by endothelial cells and significantly promote angiogenesis in vitro and in vivo. Further study showed that miR-125a was enriched in adMSC-Exo, and repressed the expression of the angiogenic inhibitor delta-like 4 (DLL4) by targeting its 3′ untranslated region. Additionally, adMSC-Exo and its exosomal transferred miR-125a could repress DLL4 expression and modulate endothelial cell angiogenesis through promoting formation of endothelial tip cells. In conclusion, our study indicates that adMSC-Exo can transfer miR-125a to endothelial cells and promote angiogenesis by repressing DLL4. adMSC-Exo, as a pro-angiogenic factor, might be a promising candidate for therapeutical tissue repair.

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Section: Exosome Purificationmentioning

confidence: 99%

Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a

Liang

Zhang

Wang

et al. 2016

Journal of Cell Science

425

298

View full text Add to dashboard Cite

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“…Additionally, exosomes from metastatic gastric cancer cells, but not non-metastatic ones, were enriched in the let-7 family of miRNAs. 20 The enrichment of the miRNAs might display their oncogenic properties, especially metastasis. Direct exchange of proteins, especially oncoproteins, is also investigated in depth.…”

Section: Overview Of Exosomes In Cancer Progressionmentioning

confidence: 99%

The exosomes in tumor immunity

2015

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Exosomes are a kind of nanometric membrane vesicles and can be released by almost all kinds of cells, including cancer cells. As the important mediators in intercellular communications, exosomes mediate exchange of protein and genetic material derived from parental cells. Emerging evidences show that exosomes secreted by either host cells or cancer cells are involved in tumor initiation, growth, invasion and metastasis. Moreover, communications between immune cells and cancer cells via exosomes play dual roles in modulating tumor immunity. In this review, we focus on exosome-mediated immunosuppression via inhibition of antitumor responses elicited by immune cells (DCs, NK cells, CD4 C and CD8 C T cells, etc.) and induction of immunosuppressive or regulatory cell populations (MDSCs, Tregs and Bregs). Transfer of cytokines, microRNAs (miRNAs) and functional mRNAs by tumor-derived exosomes (TEXs) is crucial in the immune escape. Furthermore, exosomes secreted from several kinds of immune cells (DCs, CD4 C and CD8 C Tregs) also participate in immunosuppression. On the other hand, we summarize the current application of DCderived and modified tumor-derived exosomes as tumor vaccines. The potential challenges about exosome-based vaccines for clinical application are also discussed.

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“…Recently there have been considerable studies on understanding the roles of exosomes on promoting cell survival and controlling the cross-talk between cancer cells and their surrounding stroma (15,16). Exosomes are cell-derived and membrane-bound vesicles that carry a range of functional molecules including proteins, mRNAs, and microRNAs (17).…”

mentioning

confidence: 99%

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

Song

Ding

Liu

et al. 2016

Journal of Biological Chemistry

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Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signalregulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.Clinical and experimental evidences suggest that a particular type of macrophage population is present within the tumor microenvironment (1). Tumor-associated macrophages (TAMs) 4 are derived from recruited monocytes or resident tissue macrophages (2), and play essential roles in tumor initiation, progression, and metastasis (3). Monocyte recruitment, survival, and differentiation are fundamental steps for continuous generation of TAMs. Previous studies are focused on understanding the complicated mechanisms of monocyte recruitment and differentiation within tumor tissues (2). However, investigations regarding how monocytes maintain survival before differentiation into sufficient TAMs have never been reported.As key components of the innate immune system, monocytes are continuously produced by bone marrow but normally undergo spontaneous apoptosis within 48 h in blood circulation (4, 5). Monocyte apoptosis can be prevented in vitro by serum at high concentrations (Ͼ20%), differentiation factors, and a wide range of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-␥ (IFN-␥), all of which reduce the activation of caspases and trigger the differentiation of monocytes into macrophages or dendritic cells (5-10). However, i...

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Let-7 MicroRNA Family Is Selectively Secreted into the Extracellular Environment via Exosomes in a Metastatic Gastric Cancer Cell Line

Cited by 518 publications

References 42 publications

Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a

Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a

The exosomes in tumor immunity

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

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