Current Perspectives on the Unique Roles of Exosomes in Drug Resistance of Hepatocellular Carcinoma

Abstract

As a common malignant tumor worldwide, the prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory, even though treatment methods have improved. Despite the developments in traditional chemotherapy and emerging targeted immunotherapy, the problem of recurrence and metastasis of HCC and adverse effects on survival and prognosis are still serious. Drug resistance is a daunting challenge that impedes HCC treatment. Exosomes, a class of extracellular vesicles ranging in size from 30 to 100 nm, have been the focus of recent studies. Exosomes can activate various signaling pathways and regulate the tumor microenvironment with their cargo, which includes functional lipids, proteins, and nucleic acids. Thus, they change the phenotype of recipient cells via exosome-mediated communication. Exosomes secreted by tumors or stromal cells can also transfer drug-resistant traits to other tumor cells. However, their effects on drug resistance in HCC are not completely understood. In this review, we summarize and discuss the underlying relationship between exosomes and drug resistance in HCC. In addition, we also show that exosomes may act as candidate biomarkers for predicting and monitoring drug responses and as potential targets or vectors to reverse the drug resistance of HCC.

Keywords: exosome; hepatocellular carcinoma; targeted therapy; tumor microenvironment.

Figure 1

Exosomes mediate multiple drug resistance mechanisms to confer cytochemical resistance in HCC cells.

Figure 2

The exosome-mediated chemoresistance between resistant and sensitive HCC cells. Exosomes transfer multi-drug resistance (MDR) transporters from drug-resistant cells to sensitive cells causing increased efflux of cytotoxic drugs via integrating MDR transporters on the cell membrane. Besides, exosomes induce increased anti-apoptotic signaling and DNA repair in the recipient cells.

Figure 3

Transfer of drug resistance via exosomes between TME and HCC cells. (A) Exosomes loaded with a high level of miR-210-3p lead to epithelial-mesenchymal transition; (B) Cancer cells release miRNA (miR-210) containing exosomes to stimulate CSC-like features; (C). Exosomes secreted by cancer cells can promote cancer-associated differentiation in adjacent fibroblasts polarization towards a tumor-supportive phenotype; (D) Exosomes derived from cancer cells, immune cells, and other stromal cells serve essential roles in remodeling the tumor immune microenvironment.