Extracellular vesicles and oncogenic signaling

Abstract

In recent years, extracellular vesicles (EVs) emerged as potential diagnostic and prognostic markers for cancer therapy. While the field of EV research is rapidly developing and their application as vehicles for therapeutic cargo is being tested, little is still known about the exact mechanisms of signaling specificity and cargo transfer by EVs, especially in vivo. Several signaling cascades have been found to use EVs for signaling in the tumor-stroma interaction. These include potentially oncogenic, verbatim transforming, signaling cascades such as Wnt and TGF-β signaling, and other signaling cascades that have been tightly associated with tumor progression and metastasis, such as PD-L1 and VEGF signaling. Multiple mechanisms of how these signaling cascades and EVs interplay to mediate these complex processes have been described, such as direct signal activation through pathway components on or in EVs or indirectly by influencing vesicle biogenesis, cargo sorting, or uptake dynamics. In this review, we summarize the current knowledge of EVs, their biogenesis, and our understanding of EV interactions with recipient cells with a focus on selected oncogenic and cancer-associated signaling pathways. After an in-depth look at how EVs mediate and influence signaling, we discuss potentially translatable EV functions and existing knowledge gaps.

Keywords: exosomes; extracellular vesicles; metastasis; microvesicles; signaling; tumor progression.

Fig. 1

EV nomenclature. Size and cellular origin of different EV subpopulations with regard to commonly used terminology are schematized. Since EVs are heterogeneous and current isolation techniques depend on EV size, density, or insufficiently characterized surface markers, EV fractions obtained during the different isolation procedures are most likely impure mixtures of various EV fractions, for example, Exos and MVs. Therefore, current recommendations of the ISEV in the MISEV consensus are aiming to consolidate common classification standards for EV research in the future (see pink box as published in [2]). MISEV, Minimum Information for the Study of Extracellular Vesicles.

Fig. 2

Overview of oncogenic signaling cascades discussed in this review. (A) β‐catenin‐dependent and β‐catenin‐independent Wnt signaling cascades. (B) TGF‐β signaling. (C) ErbB signaling. (D) VEGF signaling. (E) PD‐L1 signaling. Simplified representations.

Fig. 3

EV–cell interaction. General mechanisms of EV–cell interaction, such as EV binding, uptake, processing, cargo sorting, and EV release, are depicted in pink. Specific mechanisms and effects of EV–cell interaction described in the context of oncogenic signaling cascades are highlighted in blue. Components of oncogenic and cancer‐associated signaling cascades have been described as EV cargo, inducing intracellular signaling through various mechanisms, influencing tumor progression through transcription‐dependent and transcription‐independent events, altering EV cargo and modulating EV release.

Fig. 4

Multifaceted effects of EVs in oncogenic and cancer‐associated signaling. Illustrative summary of how EVs from different origins use the indicated signaling pathways to drive cancer initiation, progression, and metastasis. As examples, tumor cell EVs influence neovascularization and angiogenesis through activation of Wnt signaling; radiotherapy‐induced EVs are able to inhibit immune cell function via PD1–PD‐L1.