Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer

Hongbo Wang, Zaiming Lu, Xiangxuan Zhao, Hongbo Wang, Zaiming Lu, Xiangxuan Zhao

Abstract

Hepatocellular carcinoma (HCC, also called primary liver cancer) is one of the most fatal cancers in the world. Due to the insidiousness of the onset of HCC and the lack of effective treatment methods, the prognosis of HCC is extremely poor, and the 5-year average survival rate is less than 10%. Exosomes are nano-sized microvesicle and contain various components such as nucleic acids, proteins, and lipids. Exosomes are important carriers for signal transmission or transportation of material from cell to cell or between cells and tissues. In recent years, exosomes have been considered as potential therapeutic targets of HCC. A large number of reports indicate that exosomes play a key role in the establishment of an HCC microenvironment, as well as the development, progression, invasion, metastasis, and even the diagnosis, treatment, and prognosis of HCC. However, the exact molecular mechanisms and roles of exosomes in these processes remain unclear. We believe that elucidation of the regulatory mechanism of HCC-related exosomes and its signaling pathway and analysis of its clinical applications in the diagnosis and treatment of HCC can provide useful clues for future treatment regimens for HCC. This article discusses and summarizes the research progress of HCC-related exosomes and their potential clinical applications.

Keywords: Exosomes; Hepatocellular carcinoma; Signal transduction; Targeted therapy; Tumor markers.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic diagram of the main production and uptake mechanism of exosomes. a. The formation of exosomes. Endocytosis encapsulates the substances to form an early endosome that continue to mature into MVBs containing ILVs. (I) ESCRT-dependent pathway: (1) Ubiquitinated cargo activates nearby ECSRT0 to recruit more cargos to the vicinity. (2) Activated ESCRT0 further activates downstream ESCRTI and ESCRTII to form a large polymeric complex that further closes the lipid membrane invagination. (3) ESCRTII then induces the activation and polymerization CHMP4 subunit of ESCRTIII, which can lead to the formation of ILV. (4) The formation of ILV activates the nearby Vps-4 complex to dissociate CHMP4 from the lipid membrane into recycling. (II) ESCRT-independent pathway: (1) Cargo located close to the endosome lipid membrane enters the lipid membrane microdomains enriched in ceramide. (2) Cargo is enveloped in the invaginated pocket with the assistance of various tetraspanins, transmembrane proteins and lipids and (3) eventually forms ILV. MVB containing ILVs is transported to the vicinity of lysosome for degradation. MVB can also be delivered to the vicinity of specific plasma membrane, and anchor and fuse to the plasma membrane to secret the ILVs to form exosomes. b. Association and uptake of exosomes. (I) Exosomes can recognize and bind to the recipient cells and transmit specific signals. (II) Exosomes enter target cells by clathrin-dependent endocytosis. (III) Exosomes enter target cells by clathrin-independent macropinocytosis or phagocytosis pathway. (IV) Exosomes enter cells by lipid rafts, such as caveolae, mediated endocytosis. Depending on the needs of the cells, the exosomal contents are released into the cytosol, the exosomes are transported to the lysosome for degradation and digestion, or the exosomes fuse with cell membrane again and are released to accomplish the transcellular transport
Fig. 2
Fig. 2
Hepatocellular carcinoma (HCC) cells can affect biological behavior changes of many types of cells by releasing exosomes. a Exosomes secreted by HCC cells can regulate EMT in adjacent microenvironment and the transformation of inflammatory microenvironment, coordinate with nearby tumor cells to increase invasiveness, and induce the conversion of adjacent fibroblasts and macrophages to CAFs and TAMs. Moreover, HCC-related exosomes can regulate the functions of immune cells and endothelial cells, to induce immune escape and angiogenesis. b HCC cell exosomes mediate signaling pathways and regulatory factors of intercellular interactions or interactions between cells and tissues

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