Extracellular vesicles in Inter-Kingdom communication in gastrointestinal cancer

Abstract

The production and secretion of extracellular vesicles (EVs) are common features of cells (including various normal cells, neoplastic cell lines as well as bacteria) that span all domains of life. Tumor-derived exosomes are enriched with kinds of tumorigenesis mediators which are derived from the cytoplasm of cancer cells and fully reflect the tumor conditions. Indeed, the major topics and challenges on current oncological research are the identification of tumorigenic and metastatic molecules in tumor-cell-derived exosomes as well as elucidating the pathways that guarantee these components to be included in exosomes. The bacterial EVs have also been implicated in the pathogenesis of gastrointestinal (GI) tumors and chronic inflammatory diseases; however, the possible function of outer membrane vesicles (OMVs) in tumorigenesis remains largely underestimated. We suggest that EVs from both eukaryotic cells and different microbes in GI tract act as regulators of intracellular and cross-species communication, thus particularly facilitate tumor cell survival and multi-drug resistance. Therefore, our review introduces comprehensive knowledge on the promising role of EVs (mainly exosomes and OMVs) production of GI cancer development and gut microbiome, as well as its roles in developing novel therapeutic strategies.

Keywords: Extracellular vesicles; exosomes; gastrointestinal cancer; gut microbiome.

Figure 1

Composition, structure, biogenesis, and uptake of exosomes. A. Exosomes are heterogeneous in size and composition and are rich in protein complexes, DNA, RNA molecules, etc. B. Exosomes are produced in three ways (left): (a) After endocytosis, scattered endosomes develop into mature MVB, which then fuse with the cell membrane and release exosomes; (b) The plasma membrane secretes exosomes directly; (c) The intracellular-plasma-membrane connected compartments (IPMCs) bud out and subsequently release exosomes through the IPMC necks. After exosomes are released, they can interact with recipient cells through ligand/receptor signaling. Exosomes can enter recipient cells in different ways (right), such as endocytosis, direct membrane fusion, micropinocytosis, and even phagocytosis. HSP, heat shock protein; ICAM-1, intracellular, adhesion molecule-1; MfgE8, milk fat globule protein E8; Wnt proteins, wingless proteins.

Figure 2

Different routine of bacterial membrane vesicles. A. There are two main ways for G- bacteria to form vesicles: the blebbing and formation of OMVs, or explosive cell lysis, producing OIMVs or EOMVs. B. The bubbling of G+ bacteria leads to the formation of cytoplasmic CMVs. The OMVs of G- bacteria harbor an internal phospholipid lobule and an external LPS lobule, which activates immune cells through TLR-4. At present, our understanding of the composition, molecular structure, and function of OMVs mainly comes from bacteria cultured in the lab. OIMVs: outer-inner membrane vesicles; EOMVs: explosive outer-membrane vesicles; LPS: lipopolysaccharide. TLR-4: toll-like receptor 4.

Figure 3

Clinical applications of EVs. The structure and composition of EVs contributes to its clinical applications. Multiple proteins, PAMPs, lipids and other EV molecules make it promising vaccines, cancer immunotherapy agents, adjuvants, drug delivery tools and anti-bacteria agents and endow it broad prospects.