EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling

Sato, Shinya; Vasaikar, Suhas; Eskaros, Adel; Kim, Young; Lewis, James S.; Zhang, Bing; Zijlstra, Andries; Weaver, Alissa M.

doi:10.1172/jci.insight.132447

Cited by 103 publications

(85 citation statements)

References 115 publications

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“…It is well described that cancer-derived sEVs promote tumor development [ 53 , 54 , 55 ] by acting at different stages of cancer progression [ 56 ] through various mechanisms. Evidence is provided to indicate that cancer sEVs are involved in enhancing tumorigenesis of epithelial cells [ 53 , 57 ], sustaining tumor angiogenesis [ 58 , 59 ], promoting tumor growth [ 60 , 61 ], facilitating cancer cell invasion and metastasis [ 54 , 55 , 62 , 63 ], and contributing to chemo-resistance [ 64 , 65 ] and immunosuppression [ 66 , 67 ]. These important findings of the tumor-promoting effects of cancer sEVs lead to new cancer therapeutic opportunities that aim at targeting cancer exosomal signaling processes, as discussed below.…”

Section: Ev Cargos and Functionsmentioning

confidence: 99%

Extracellular Vesicles in the Development of Cancer Therapeutics

Sun

Burrola

et al. 2020

IJMS

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Extracellular vesicles (EVs) are small lipid bilayer-delimited nanoparticles released from all types of cells examined thus far. Several groups of EVs, including exosomes, microvesicles, and apoptotic bodies, have been identified according to their size and biogenesis. With extensive investigations on EVs over the last decade, it is now recognized that EVs play a pleiotropic role in various physiological processes as well as pathological conditions through mediating intercellular communication. Most notably, EVs have been shown to be involved in cancer initiation and progression and EV signaling in cancer are viewed as potential therapeutic targets. Furthermore, as membrane nanoparticles, EVs are natural products with some of them, such as tumor exosomes, possessing tumor homing propensity, thus leading to strategies utilizing EVs as drug carriers to effectively deliver cancer therapeutics. In this review, we summarize recent reports on exploring EVs signaling as potential therapeutic targets in cancer as well as on developing EVs as therapeutic delivery carriers for cancer therapy. Findings from preclinical studies are primarily discussed, with early phase clinical trials reviewed. We hope to provide readers updated information on the development of EVs as cancer therapeutic targets or therapeutic carriers.

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Section: Ev Cargos and Functionsmentioning

confidence: 99%

Extracellular Vesicles in the Development of Cancer Therapeutics

Sun

Burrola

et al. 2020

IJMS

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“…By contrast, several other EV integral membrane proteins can elicit signaling by interacting with proteins on the plasma membrane of endothelial cells. Sato and colleagues recently identified that the ephrin type B receptor 2 (EPHB2) is present on small EVs secreted by head and neck cancer cells, and that EV-associated EPHB2 stimulates tumor angiogenesis by activating the STAT3 signaling pathway via engagement of ephrin-B2 on the surface of endothelial cells [68]. Whereas the cell adhesion molecule E-cadherin is expressed as a full-length protein on the plasma membrane of ovarian cancer cells [69], Tang and colleagues identified that the surface of ovarian cancer cell-derived exosomes contain the soluble ectodomain of E-cadherin (sE-cad) [70].…”

Section: Angiogenic Pathways Mediated By Ev Integral Membrane Proteinsmentioning

confidence: 99%

Extracellular Vesicle Membrane-Associated Proteins: Emerging Roles in Tumor Angiogenesis and Anti-Angiogenesis Therapy Resistance

Naora

2020

IJMS

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The tumor vasculature is essential for tumor growth and metastasis, and is a prime target of several anti-cancer agents. Increasing evidence indicates that tumor angiogenesis is stimulated by extracellular vesicles (EVs) that are secreted or shed by cancer cells. These EVs encapsulate a variety of biomolecules with angiogenic properties, and have been largely thought to stimulate vessel formation by transferring this luminal cargo into endothelial cells. However, recent studies have revealed that EVs can also signal to recipient cells via proteins on the vesicular surface. This review discusses and integrates emerging insights into the diverse mechanisms by which proteins associate with the EV membrane, the biological functions of EV membrane-associated proteins in tumor angiogenesis, and the clinical significance of these proteins in anti-angiogenic therapy.

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“…On the other hand, EVs have been implicated in various aspects of vascular regulation and pathological angiogenesis. Their effects are often attributed to intercellular transfer or deregulation of canonical angiogenic mediators, such as vascular endothelial growth factor (VEGF) [53][54][55] , interaction with NOTCH 56 or EPHB2 pathways 57 , intercellular transfer of membrane receptors 58 , including bioactive oncogenes, such as EGFR and through other effects 19,20 . These processes may also involve EV-mediated delivery of coding 30 or non-coding RNA to stromal and vascular cell compartments [59][60][61] .…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles from genetically unstable, oncogene-driven cancer cells trigger micronuclei formation in endothelial cells

Chennakrishnaiah

Tsering

Gregory

et al. 2020

Sci Rep

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oncogenic transformation impacts cancer cell interactions with their stroma, including through formation of abnormal blood vessels. This influence is often attributed to angiogenic growth factors, either soluble, or associated with tumor cell-derived extracellular vesicles (eVs). Here we examine some of the cancer-specific components of EV-mediated tumor-vascular interactions, including the impact of genetic driver mutations and genetic instability. cancer cells expressing mutant HRAS oncogene exhibit aberrations of chromatin architecture, aneuploidy, cytoplasmic chromatin deposition and formation of micronuclei with a non-random chromosome content. eVs released from such HRAS-driven cells carry genomic DnA, including oncogenic sequences, and transfer this material to endothelial cells while inducing abnormal formation of micronuclei, along with cell migration and proliferation. Micronuclei were also triggered following treatment with eVs derived from glioma cells (and stem cells) expressing eGfRviii oncogene, and in both endothelial cells and astrocytes. eVs from HRAS and eGfRviii-driven cancer cells carry 19 common proteins while EVs from indolent control cells exhibit more divergent proteomes. Immortalized endothelial cell lines with disrupted TP53 pathway were refractory to EVmediated micronuclei induction. We suggest that oncogenic transformation and intercellular trafficking of cancer-derived eVs may contribute to pathological vascular responses in cancer due to intercellular transmission of genomic instability. Formation of the vascular tumor stroma defines crucial events in cancer progression, including invasive growth, metastasis, interactions with the immune system, paraneoplastic states (e.g, thrombosis) and responses to therapy 1. A wide range of endothelial cell responses associated with the malignant process are exemplified by (and often reduced to) the angiogenic vascular growth program involving a network of canonical effectors including vascular endothelial growth factor (VEGF-A) and its receptors, as well as several other pathways essential for physiological vascular growth 2,3. While targeting this circuitry was postulated to give rise to promising anticancer therapies 4 and led to derivation of effective VEGF pathway antagonists 1 , several vascular and metastatic tumors do not respond to this form of treatment 5 raising questions as to alternative forms of vascular supply 6 and alternative, cancer-specific vascular regulators. Oncogenic transformation profoundly changes the ability of affected cells to interact with their microenvironment, including blood vessels 7 , blood components 8 , stroma 9 and the immune system 10. While this is often attributed to deregulation of the respective soluble mediators, such as VEGF or interleukins 7,11 , activation of oncogenic RAS or EGFR also impacts the particulate (insoluble) secretome of cancer cells including the composition of extracellular vesicles (EVs) and particles (EPs) 12. EVs are heterogenous, mostly spherical, cellular

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EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling

Cited by 103 publications

References 115 publications

Extracellular Vesicles in the Development of Cancer Therapeutics

Extracellular Vesicles in the Development of Cancer Therapeutics

Extracellular Vesicle Membrane-Associated Proteins: Emerging Roles in Tumor Angiogenesis and Anti-Angiogenesis Therapy Resistance

Extracellular vesicles from genetically unstable, oncogene-driven cancer cells trigger micronuclei formation in endothelial cells

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