Going live with tumor exosomes and microvesicles

Abstract

Tumor extracellular vesicles (EVs), including exosomes, emerged as key drivers of the pro-tumorigenic dialog between the tumor mass and its microenvironment by mediating long and short distance communication. In vitro studies defined the capacity of tumor EVs to modify the phenotypes of stromal and tumor cells. These studies are now supported by a growing number of functional in vivo experiments. Remarkably, they allowed the identification of a new role for tumor EVs in priming the pre-metastatic niches (PMN). Several molecules transported in tumor EVs (RNAs and proteins) have recently been found to be essential for tumor progression and metastasis in vivo. In parallel, novel EV labeling and tracking strategies have very recently allowed the first descriptions of tumor EVs in vivo and pave the way for a better understanding of their function in realistic pathophysiological contexts. Here, we review the functional approaches and the recent progress in in vivo imaging of EVs, which have refined our understanding of the role played by tumor EVs. Finally, we emphasize the remaining challenges and open questions related to the biology of tumor EVs.

Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy

“…Exosomes are distinct from microvesicles, another type of EVs that are released by blebbing off the plasma membrane. These two types of EVs are different not only in size, function, and cargo, but also in the intrinsic signals leading to their secretion (for comprehensive reviews on EV formation and secretion, see (Desrochers, Antonyak, & Cerione, 2016; Edgar, 2016; Hyenne, Lefebvre, & Goetz, 2017; Kowal et al, 2014; Raposo & Stoorvogel, 2013; Stoorvogel, 2015; Tkach, Kowal, & Thery, 2018; Tkach & Thery, 2016; van Niel, D’Angelo, & Raposo, 2018)). Exosomes carry RNA (micro RNA (miRNA), long-noncoding RNA (lncRNA), messenger RNA (mRNA), mitochondrial DNA, signaling proteins, enzymes, metabolites, and lipids from the donor to a recipient cell (Choi, Kim, Kim, & Gho, 2013; Kai, Dittmar, & Sen, 2017; Kinoshita, Yip, Spence, & Liu, 2017; Record, Carayon, Poirot, & Silvente-Poirot, 2014; Salehi & Sharifi, 2018; H.…”

In vivo characterisation of endogenous cardiovascular extracellular vesicles in larval and adult zebrafish

“…The potential of EVs as biomarkers of disease and as novel therapeutic delivery vehicles has generated significant interest in recent years, including applications in tissue (predominantly bone) regeneration (Wiklander et al, 2019). However, the ability to reliably define the heterogeneous spectrum of EV subtypes, and further, to ascribe functional significance to that specific subtype in vivo, is still in its infancy (Beer and Wehman, 2017;Hyenne et al, 2017). The majority of EV characterization to date, by necessity, has been performed in vitro (van Niel et al, 2018).…”

Studying the fate of tumor extracellular vesicles at high spatio-temporal resolution using the zebrafish embryo

“…EVs are heterogeneous in content and origin, as they can either arise from plasma membrane budding (then called microvesicles) or originate from a late endosomal compartment, the multivesicular body (MVB) (then called exosomes) (Kowal et al, 2014;van Niel et al, 2018). EVs are known to be important in tumor progression and metastasis, where the complex tumoral microenvironment requires a permanent cross-communication between cells (Becker et al, 2016;Hyenne et al, 2017). EVs secreted by tumor cells are enriched in pro-tumoral and pro-metastatic factors (proteins, mRNAs, miRNAs and other non-coding RNAs) and can modify the phenotype of both tumor and stromal cells that have uptaken them, mostly to the benefit of tumor growth and metastasis formation (Becker et al, 2016;Hyenne et al, 2017).…”

“…EVs are known to be important in tumor progression and metastasis, where the complex tumoral microenvironment requires a permanent cross-communication between cells (Becker et al, 2016;Hyenne et al, 2017). EVs secreted by tumor cells are enriched in pro-tumoral and pro-metastatic factors (proteins, mRNAs, miRNAs and other non-coding RNAs) and can modify the phenotype of both tumor and stromal cells that have uptaken them, mostly to the benefit of tumor growth and metastasis formation (Becker et al, 2016;Hyenne et al, 2017). For instance, tumor EVs were shown to transfer oncogenic traits from more aggressive to less aggressive tumor cells (Al-Nedawi et al, 2008;Chen et al, 2014;Di Vizio et al, 2009).…”

“…For these reasons, the zebrafish embryo appears as an adequate model to study tumor EVs in vitro. In order to track EVs, different fluorescent labeling methods have been described and debated (Hyenne et al, 2017). Genetic encoding of fusion proteins between fluorophores and proteins/peptides enriched in EVs presents the advantage of being specific.…”