The Origin and Functions of Exosomes in Cancer

Abstract

Exosomes are nanovesicles having a maximum size of 150 nm and is a newly emerging focus in various fields of research. Its role in cargo trafficking along with its differential expression is associated with the disrupted homeostasis and provides an opportunity to defend against different diseases like cancer. Furthermore, exosomes are rich in cargos, which contain proteins and nucleic acids that directly reflect the metabolic state of the cells from which it originates. This review summarizes recent studies on tumor-derived exosomes with an overview about biogenesis, their functions and potential of using as diagnostic and prognostic markers. We also discussed the current challenges and microfluidic-based detection approaches that might improve the detection of exosomes in different settings. More intricate studies of the molecular mechanisms in angiogenesis, pre-metastatic niche formation, and metastasis can give more promising insights and novel strategies in oncotherapeutics.

Keywords: angiogenesis; cancer; exosomes; extracellular vesicles; metastasis.

Figure 1

Graphical representation of exosomes showing general exosomal cargos. Nucleic acids, proteins, and lipids are the major cargos found in exosomes. Nucleic acid includes DNA, RNA along with non-coding RNAs like miRNAs. Different categories of proteins are present abundantly in exosomes, namely membrane and cytoplasmic proteins. Tetraspanins are the major membrane proteins such as CD9, 63, 81, 82, etc. Various heat shock proteins, alix, TSG101, and clathrin are cytoplasmic in its distribution. Presence of MHCI and II as transmembrane proteins indicates its role in immune cell induction. Sphingolipids such as ceramide and cholesterol are the major lipid species found in exosomes.

Figure 2

Schematic representation of exosomal biogenesis. Biogenesis of exosome is mainly through two types of pathways: endosomal sorting complex required for transport (ESCRT) dependent and ESCRT independent. ESCRT-dependent pathway is characterized with a set of proteins including ESCRT 0, I, II, and III and various tetraspanins, namely, CD9, 63, 81, 82, etc. They participate in the formation of multivesicular bodies (MVBs) from the late endosomes. ESCRT-independent pathway is proceeded by lipids such as ceramides and cholesterol. Further docking of these MVBs with the main plasma membrane with the aid of different soluble SNARE (N-ethylmaleimide-sensitive factor attachment protein receptors) complexes leads to the release of 40–150-nm sized nanovesicles.

Figure 3

Role of exosomes in pre-metastatic niche formation. Exosomes will be released from the primary cancer cells into the extracellular sites. Distribution and specific organotropic integration of these vesicles with oncoproteins or nucleic acids as cargos lead to the development of pre-metastatic niche in the secondary site of cancer metastasis. Induction of different signaling pathways and activation of different immune cells in the secondary site helps in the maintenance of cancer favorable inflammatory microenvironment that promotes successful cancer cell metastasis.