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.

Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives

“…Through autocrine and paracrine mechanisms, exosomes enable the interaction between tumor cells and TME, with immune-modulatory effects and the stimulation of the epithelial to mesenchymal transition that favors vascular invasion and metastatization [ 112 ]. Moreover, increasing evidence suggests that the interaction between tumor-derived exosomes, tumor cells, and TME may play a significant role in the development of drug resistance to TKIs in patients with HCC [ 113 , 114 , 115 , 116 , 117 , 118 ]. The exposure of PD-L1 on exosomes causes the direct inhibition of T cells’ function.…”

“…The exposure of PD-L1 on exosomes causes the direct inhibition of T cells’ function. Exosomes expressing PD-L1 compete with cancer cells and peritumoral cells in binding ICIs; as a result, lower levels of a drug can target tumor cells, resulting in a mechanism of resistance against therapy [ 116 ]. Similar to exosomes, MVs express specific markers on their surface derived from the type of cell that generates them and contain nucleic acids and proteins that could influence several biologic processes [ 117 ].…”

“…In particular, ctDNA and CTCs have important prognostic implications, as they could identify mutational signatures that reflect the genomic landscape of the primary tumor [ 103 , 104 , 105 , 106 ]. In addition, exosomes, being able to modulate cellular communication directly and indirectly through the release of their cargos, provide important information on tumors’ mutational burden, invasiveness, and resistance during therapy to a degree surpassed by no other previous biomarker [ 112 , 113 , 114 , 115 , 116 ]. Compared with traditional AFP, it has been shown that ctDNA [ 81 , 82 , 83 ] might be a better prognostic marker of responses in patients with unresectable HCC, but these findings have not been confirmed in other studies.…”

Role of Exosomes in Immunotherapy of Hepatocellular Carcinoma

“…In HCC TME, not only immune cells but also non-immune cells are involved in tumorigenic processes, including tumor proliferation, invasion, and metastasis [ 26 , 27 ]. Recent studies have highlighted the critical role of exosomes for cell-to-cell communication in the HCC TME, which are recognized as a key factor in tumor progress and may be closely associated with resistance to immunotherapy in HCC patients [ 28 , 29 ].…”

Importance and implications of exosomes in nephrology and urology

“…Tumor-derived exosomes, also known as oncosomes, have been extensively studied and promote tumor progression through activation of tumor-promoting pathways, the downregulation of tumor suppressor genes, next to other possibilities [ 41 , 104 ]. For example, Chen et al showed that melanoma-derived EVs exhibit programmed death ligand 1 (PD-L1) that interacts with PD-1 of T-cells [ 34 ] and inhibits anti-tumor immunity [ 14 ].…”