The αvβ6 Integrin Is Transferred Intercellularly via Exosomes

Fedele, Carmine; Singh, Amrita; Zerlanko, Brad J.; Iozzo, Renato V.; Languino, Lucia R.

doi:10.1074/jbc.c114.617662

Cited by 154 publications

(157 citation statements)

References 42 publications

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“…Moreover, ITG␣ v ␤ 6 is actively packaged into exosomes isolated from prostate cancer cell lines. Apart from having a potential adhesion function, ␣ v ␤ 6 is also efficiently transferred via exosomes from a donor cell to an ␣ v ␤ 6 -negative recipient cell and localizes to the cell surface (75). Many adhesion molecules, such as ICAMs and integrins, are also inserted into so-called tetraspaninenriched microdomains (TEMs) (76,77).…”

Section: Virus Attachment Molecules Are Exposed On the Ev Surfacementioning

confidence: 99%

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Dongen

Masoumi

Witwer

et al. 2016

Microbiol Mol Biol Rev

232

193

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SUMMARYExtracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, being involved in a wide array of key biological processes. Eukaryotic cells, and also bacteria, actively release heterogeneous subtypes of EVs into the extracellular space, where their contents reflect their (sub)cellular origin and the physiologic state of the parent cell. Within the past 20 years, presumed subtypes of EVs have been given a rather confusing diversity of names, including exosomes, microvesicles, ectosomes, microparticles, virosomes, virus-like particles, and oncosomes, and these names are variously defined by biogenesis, physical characteristics, or function. The latter category, functions, in particular the transmission of biological signals between cellsin vivoand how EVs control biological processes, has garnered much interest. EVs have pathophysiological properties in cancer, neurodegenerative disorders, infectious disease, and cardiovascular disease, highlighting possibilities not only for minimally invasive diagnostic applications but also for therapeutic interventions, like macromolecular drug delivery. Yet, in order to pursue therapies involving EVs and delivering their cargo, a better grasp of EV targeting is needed. Here, we review recent progress in understanding the molecular mechanisms underpinning EV uptake by receptor-ligand interactions with recipient cells, highlighting once again the overlap of EVs and viruses. Despite their highly heterogeneous nature, EVs require common viral entry pathways, and an unanticipated specificity for cargo delivery is being revealed. We discuss the challenges ahead in delineating specific roles for EV-associated ligands and cellular receptors.

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Section: Virus Attachment Molecules Are Exposed On the Ev Surfacementioning

confidence: 99%

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Dongen

Masoumi

Witwer

et al. 2016

Microbiol Mol Biol Rev

232

193

View full text Add to dashboard Cite

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“…[12][13][14][15] A major function of exosomes appears to be promotion of cell motility. 6,10,[16][17][18] Thus, exosomes have been shown to promote cell protrusion formation, 16 adhesion, 6,19 and cell polarity. 20 In neutrophils, autocrine generation of bioactive lipids on exosomes enhances motility toward the chemoattractant N-formyL-MethionyL-LeucyL-Phenylalanine (fMLP).…”

Section: Introductionmentioning

confidence: 99%

Exosome secretion promotes chemotaxis of cancer cells

Sung

Weaver

2017

Cell Adhesion & Migration

105

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Migration of cells toward chemical cues, or chemotaxis, is important for many biologic processes such as immune defense, wound healing and cancer metastasis. Although chemotaxis is thought to occur in cancer cells, it is less well characterized than chemotaxis of professional immune cells such as neutrophils. Here, we show that cancer cell chemotaxis relies on secretion of exosome-type extracellular vesicles. Migration of fibrosarcoma cells toward a gradient of exosome-depleted serum was diminished by knockdown of the exosome secretion regulator Rab27a. Rescue experiments in which chemotaxis chambers were coated with purified extracellular vesicles demonstrate that exosomes but not microvesicles affect both speed and directionality of migrating cells. Chamber coating with purified fibronectin and fibronectin-depleted exosomes demonstrates that the exosome cargo fibronectin promotes cell speed but cannot account for the role of exosomes in promoting directionality of fibrosarcoma cell movement during chemotaxis. These experiments indicate that exosomes contain multiple motility-promoting cargoes that contribute to different aspects of cell motility.

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“…Fedele et al investigated whether αvβ6 can be transferred from prostate cancer cells, in which it is highly expressed, to the surrounding Bnormal^prostate tissue where it is not expressed [70]. Fedele et al showed that αvβ6 is packaged into exosomes that were isolated from the RWPE and PC3 prostate cancer cell lines, where it can be transferred from a donor cell to an αvβ6-deficient recipient, whereupon it localises to the plasma membrane [70]. This was confirmed to be a result of exosomemediated transfer rather than expression that was induced in the recipient cells as de novo αvβ6 expression as it did not result from altered mRNA expression [70].…”

Section: αVβintegrin Is Intercellularly Transported Via Exosomes Andmentioning

confidence: 98%

“…Another recent development in the β6 research field that may be relevant to CRC has been the discovery by Fedele et al that the αvβ6 heterodimer is transported between prostate cancer cells by cell-derived vesicles (exosomes), continuously released into the extracellular space [70]. Fedele et al investigated whether αvβ6 can be transferred from prostate cancer cells, in which it is highly expressed, to the surrounding Bnormal^prostate tissue where it is not expressed [70].…”

Section: αVβintegrin Is Intercellularly Transported Via Exosomes Andmentioning

confidence: 99%

“…Fedele et al showed that αvβ6 is packaged into exosomes that were isolated from the RWPE and PC3 prostate cancer cell lines, where it can be transferred from a donor cell to an αvβ6-deficient recipient, whereupon it localises to the plasma membrane [70]. This was confirmed to be a result of exosomemediated transfer rather than expression that was induced in the recipient cells as de novo αvβ6 expression as it did not result from altered mRNA expression [70]. An extremely interesting finding of this study was that when incubated with these exosomes, recipient prostate cells migrated using the αvβ6-specific ligand (TGF-β LAP) which did not occur when treated with exosomes in which αvβ6 has been repressed by either shRNA or siRNA [70].…”

Section: αVβintegrin Is Intercellularly Transported Via Exosomes Andmentioning

confidence: 99%

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Integrin αvβ6 sets the stage for colorectal cancer metastasis

Cantor

Cheruku

Nice

et al. 2015

Cancer Metastasis Rev

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The β6 subunit of the αvβ6 integrin heterodimer has long been an enigma in cancer biology though recent research has provided many new insights into its biology. Collectively, these findings include discovery of the transcriptional, translational and cell biological mechanisms by which β6 acts, the identification of the cellular influences β6 exerts upon the cell proteome, the characterisation of multiple β6-centric pro-metastatic signalling systems and the search for pharmacological therapies (industry and academia) targeted against β6. Once expressional restriction is overcome in early colorectal cancer (CRC), epithelial cell surface restricted αvβ6 can physically interact with, and activate, known oncoproteins, and has the potential to enable the cross-talk through non-canonical signal transduction pathways, resulting in the adoption of an invasive/metastatic phenotype. This recent research has identified numerous interconnections and potential feedback loops, highlighting the fact that the expression of the β6 subunit may initiate a cascade of downstream effects on the CRC cell rather than acting through a single mechanism. We here review these recent studies and postulate that the existence of a cell surface uPAR/αvβ6/TGFβ "metastasome" interactome in/on a proportion of colorectal cancer cells, where β6 expression sequesters and activates multiple systems at the invasive front of tumour lesions, promoting cancer metastasis and hence explaining why β6 has been correlated with reduced patient survival in CRC.

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The αvβ6 Integrin Is Transferred Intercellularly via Exosomes

Cited by 154 publications

References 42 publications

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Exosome secretion promotes chemotaxis of cancer cells

Integrin αvβ6 sets the stage for colorectal cancer metastasis

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