Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells

Lucero, Rocco; Zappulli, Valentina; Sammarco, Alessandro; Murillo, Óscar; Cheah, Pike See; Srinivasan, Srimeenakshi; Tai, Eric C.; Ting, David T.; Wei, Zhiyun; Roth, Matthew E.; Laurent, Louise C.; Krichevsky, Anna M.; Breakefield, Xandra O.; Milosavljevic, Aleksandar

doi:10.1016/j.celrep.2020.01.073

Cited by 122 publications

(90 citation statements)

References 73 publications

(86 reference statements)

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“…CAFs are the most abundant stromal cells in TME, producing an ECM that differs from normal ECM in terms of stiffness and alignment, which support tumor cells migration [9]. Hypoxia in TME causes tumor to secrete angiogenic factors to act on endothelial cells and promote angiogenesis [44,45]. The immune cells in TME show diversity, and they block the immune response.…”

Section: The Overview Of Microenvironment and Exosomes In Cancermentioning

confidence: 99%

See 1 more Smart Citation

Exosomal miRNAs in tumor microenvironment

Tan

Xia

et al. 2020

J Exp Clin Cancer Res

138

117

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Tumor microenvironment (TME) is the internal environment in which tumor cells survive, consisting of tumor cells, fibroblasts, endothelial cells, and immune cells, as well as non-cellular components, such as exosomes and cytokines. Exosomes are tiny extracellular vesicles (40-160nm) containing active substances, such as proteins, lipids and nucleic acids. Exosomes carry biologically active miRNAs to shuttle between tumor cells and TME, thereby affecting tumor development. Tumor-derived exosomal miRNAs induce matrix reprogramming in TME, creating a microenvironment that is conducive to tumor growth, metastasis, immune escape and chemotherapy resistance. In this review, we updated the role of exosomal miRNAs in the process of TME reshaping.

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Section: The Overview Of Microenvironment and Exosomes In Cancermentioning

confidence: 99%

“…During tumor progression, EVs derived from different cells (tumor cells, stromal cells, immune cells, etc.) play an important role and participate in the formation of TME [44,[52][53][54].…”

Section: The Biosynthesis and Function Of Extracellular Vesicles And mentioning

confidence: 99%

Exosomal miRNAs in tumor microenvironment

Tan

Xia

et al. 2020

J Exp Clin Cancer Res

138

117

View full text Add to dashboard Cite

show abstract

“…Examples of miRs playing an important role in promoting angiogenesis in brain tumors are miR-19b and miR-9-5p [ 121 , 122 ]. The former has been found in glioblastoma-derived microvessels which also contain VEGF and PDGF.…”

Section: Levels Of Ec–tumor Cell Interactionmentioning

confidence: 99%

“…miR-19b further supports the pro-angiogenic role of the growth factors by repressing the expression of antiangiogenic proteins such as thrombospondin-1 [ 121 ]. The latter miR-9-5p has been very recently found in glioblastoma-derived EVs where it suppresses in vitro and in vivo the expression of genes like SOX7 and RGS5 which are responsible for maintaining physiological levels of angiogenesis and inhibiting EC growth, respectively [ 122 ].…”

Section: Levels Of Ec–tumor Cell Interactionmentioning

confidence: 99%

Endothelial-Tumor Cell Interaction in Brain and CNS Malignancies

Peleli

Moustakas

Papapetropoulos

2020

IJMS

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Glioblastoma and other brain or CNS malignancies (like neuroblastoma and medulloblastoma) are difficult to treat and are characterized by excessive vascularization that favors further tumor growth. Since the mean overall survival of these types of diseases is low, the finding of new therapeutic approaches is imperative. In this review, we discuss the importance of the interaction between the endothelium and the tumor cells in brain and CNS malignancies. The different mechanisms of formation of new vessels that supply the tumor with nutrients are discussed. We also describe how the tumor cells (TC) alter the endothelial cell (EC) physiology in a way that favors tumorigenesis. In particular, mechanisms of EC–TC interaction are described such as (a) communication using secreted growth factors (i.e., VEGF, TGF-β), (b) intercellular communication through gap junctions (i.e., Cx43), and (c) indirect interaction via intermediate cell types (pericytes, astrocytes, neurons, and immune cells). At the signaling level, we outline the role of important mediators, like the gasotransmitter nitric oxide and different types of reactive oxygen species and the systems producing them. Finally, we briefly discuss the current antiangiogenic therapies used against brain and CNS tumors and the potential of new pharmacological interventions that target the EC–TC interaction.

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“…In fact, EVs released from GSCs contain mRNAs, microRNAs (miRNAs), non-coding RNAs (ncRNAs), as well as genomic DNA and cDNAs. All these nuclei acid can be transferred to ECs [34,98,103,[110][111][112][113][114]. Remarkably, miRNAs derived from hypoxic CD133+ U87 glioblastoma cells emerged as powerful inducers of tumor vasculature and glioma cells proliferation in vitro [115].…”

Section: Mtor-dependent Gsc-derived Evs Promote Gbm Angiogenesismentioning

confidence: 99%

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme

Ryskalin

Biagioni

Lenzi

et al. 2020

Cancers

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Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications.

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Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells

Cited by 122 publications

References 73 publications

Exosomal miRNAs in tumor microenvironment

Exosomal miRNAs in tumor microenvironment

Endothelial-Tumor Cell Interaction in Brain and CNS Malignancies

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme

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