Exosomes: Diagnostic and Therapeutic Implications in Cancer

Abstract

Exosomes are a subset of extracellular vesicles produced by all cells, and they are present in various body fluids. Exosomes play crucial roles in tumor initiation/progression, immune suppression, immune surveillance, metabolic reprogramming, angiogenesis, and the polarization of macrophages. In this work, we summarize the mechanisms of exosome biogenesis and secretion. Since exosomes may be increased in the cancer cells and body fluids of cancer patients, exosomes and exosomal contents can be used as cancer diagnostic and prognostic markers. Exosomes contain proteins, lipids, and nucleic acids. These exosomal contents can be transferred into recipient cells. Therefore, this work details the roles of exosomes and exosomal contents in intercellular communications. Since exosomes mediate cellular interactions, exosomes can be targeted for developing anticancer therapy. This review summarizes current studies on the effects of exosomal inhibitors on cancer initiation and progression. Since exosomal contents can be transferred, exosomes can be modified to deliver molecular cargo such as anticancer drugs, small interfering RNAs (siRNAs), and micro RNAs (miRNAs). Thus, we also summarize recent advances in developing exosomes as drug delivery platforms. Exosomes display low toxicity, biodegradability, and efficient tissue targeting, which make them reliable delivery vehicles. We discuss the applications and challenges of exosomes as delivery vehicles in tumors, along with the clinical values of exosomes. In this review, we aim to highlight the biogenesis, functions, and diagnostic and therapeutic implications of exosomes in cancer.

Keywords: cellular interactions; clinical trials; diagnostics; drug carriers; exosomes; miRNAs; prognostics; siRNAs; therapeutics.

Figure 1

Overview of the exosome biogenesis. MVBs are derived from endocytosis [20]. Inward budding of the plasma membrane induces the formation of early endosomes [28,29]. Early endosomes sort various cargoes into ILVs to form MVBs [28,29]. After maturation, MVBs interact with Golgi, fuse with lysosomes to be degraded, fuse with plasma membrane to release exosomes (ILVs), or fuse with autophagosome to form amphisome [32]. Amphisome can fuse with lysosome to be degraded or fuse plasma membrane for exosome release [32]. MVBs containing exosome cargo are transported to the plasma membrane via microtubule, fuse with the cell surface and the ILVs are then secreted as exosomes [32].

Figure 4

Exosomes as delivery vehicles. (A) Advantages and disadvantages of exosomes as delivery vehicles [123,124,125,126,127,128,129,130,131,132]. (B) Exogenous loading involves the loading of various cargoes, such as drugs, DNAs, ncRNAs, and proteins, into native exosomes. Methods for loading these cargoes include electroporation, sonication, co-incubation, and extrusion [136,137,138,139,140,141]. Endogenous loading involves the packaging of biomolecules via the modification of donor cells [133,134,142,143,144,145]. This modification of donor cells can be performed by means of the transfection of DNAs and various ncRNAs.

Figure 2

Roles of exosomes and exosomal proteins in life processes [17,46,61,63,64,65,66,67,68,69,70,71]. GPC, pre-glycoprotein polyprotein complex; ICAM, intercellular adhesion molecule; MHC, major histocompatibility complex; PD-L1, programmed death-ligand 1. ↓ denotes decreased expression/activity. ↑denotes increased expression/activity. → denotes direction of reaction.

Figure 3

Diverse roles of exosomal non-coding RNAs. Exosomal miRNAs play important roles in cancer progression/metastasis [74,75,76,77,78,79,80], immune suppression [76], and M2 macrophages polarization [78]. Hollow arrows denote the direction of the reaction. ↓ denotes decreased expression/activity. ↑ denotes increased expression/activity. CAF denotes cancer-associated fibroblasts.