Role of Extracellular Vesicles in Hepatocellular Carcinoma

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Rong Yan	--	2261	2023-11-16 12:50:00	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	2261	2023-11-20 02:36:01	\|

This entry is adapted from the peer-reviewed paper 10.3390/medicina59091599

Extracellular vesicles (EVs) play critical roles in intercellular communication by transporting bioactive cargo to recipient cells. EVs have been implicated in a range of physiological and pathological processes, including tumor progression, metastasis, immune modulation, and drug resistance.

hepatocellular carcinoma extracellular vesicle diagnostic markers therapeutic carrier

1. Background

Extracellular vesicles (EVs) are a heterogenous group of membrane-bound particles that transport bioactive molecules, such as metabolites, lipids, proteins, and nucleic acids, to communicate with recipient cells ^[1]. The membranes of EVs protect their internal cargo and express specific surface ligands that enable efficient binding to recipient cells ^[2]. Through the transfer of their cargoes to recipient cells, EVs participate in various processes, including tumor initiation and formation ^[3], apoptosis ^[4], angiogenesis ^[5], metastasis ^[6], immune escape ^[7], and drug resistance ^[8].

EVs are broadly categorized as exosomes, microvesicles, and apoptotic bodies, based on their size and biogenesis ^[9]. Exosomes have a diameter ranging from 30 to 100 nm, and are believed to originate from intracellular multivesicular bodies before being secreted though the plasma membrane ^[10]. Microvesicles, also known as ectosomes, are sized from 100 to 1000 nm, and are derived from the plasma membrane through budding ^[11]. Apoptotic bodies have diameters ranging from 1 to 4 µm, and are released during late-stage programmed cell death ^[12]. Notably, however, the current methods for isolating and characterizing EVs pose challenges in terms of distinguishing among these three types ^[13].

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 90% of all cases ^[14]. The early detection of HCC is difficult because patients often have few or no symptoms ^[15]. The current diagnostic methodologies for HCC include serum biomarker alpha-fetoprotein (AFP), ultrasonography, and other forms of imaging. These diagnostic tests, however, have low sensitivity for early detection ^[16]. Moreover, the presence of chronic liver disease (CLD) can further affect the accuracy of diagnosis ^[16]. To address these limitations, researchers have investigated alternative liquid biopsy biomarkers for high-risk populations ^[17]. EVs are emerging as promising candidates since they are secreted in greater quantities by cancer cells compared to normal cells, contain abundant genetic materials that can be measured, and can be targeted with antibodies ^[18]. In addition to blood, EVs from different body fluids, such as urine and ascites, were used for tumor diagnosis, which may be important for non-invasive diagnostic and prognostic approaches.

EVs have a lipid bilayer structure that can effectively package hydrophobic and hydrophilic drugs. Another aspect relevant to therapeutics is the possibility of targeting EVs and their cargo. The surfaces of EVs express peptides, either from the cell of origin or engineered, that can specifically bind to receptors on target cells. As the liver is the most important organ involved in human metabolism, exogenous EVs tend to be spontaneously enriched in the liver. This enrichment pattern and the rapid clearance from the circulation by liver macrophages ^[19] make EVs appealing as drug delivery carriers to target liver diseases such as HCC ^[20]. On the other hand, HCC-derived EVs have well-established roles in facilitating tumor progression, metastasis, and unfavorable prognosis. They can also serve as molecular conduits to systemically disseminate oncogenic signals that drive key disease hallmarks like proliferation, invasion, metastasis, and therapeutic resistance.

2. The Role of EVs in the Diagnosis of HCC

Extracellular vesicles have emerged as promising biomarkers for cancer diagnosis. With some EV markers, such as ExoDxLung (ALK) ^[21] and ExoDxProstate IntelliScore, which have already been translated into successful clinical applications ^[22], there is growing interest in utilizing EVs as liquid biopsy tools. As sequencing technologies continue to advance, EV nucleic acid testing is expected to become one of the liquid biopsy technologies utilized for early diagnosis. It has the advantages of being minimally invasive, allowing for repeated sampling, and eliminating risks like bleeding, infection, and needle track seeding of cancer cells.

Several studies have demonstrated the potential of EV-carried miRNAs, specifically miR-21, as diagnostic biomarkers for HCC. The sensitivity of detecting miR-21 in EVs was found to be much higher than in serum alone ^[23]^[24]^[25]. For instance, Tomimaru et al. showed that while the total circulating expression of miR-21 was elevated in HCC patients, its abundance in EVs was much higher ^[25], indicating that EVs carrying miR-21 could be more sensitive diagnostic markers. Similarly, Jun et al. found that the miR-21 levels in EVs were significantly higher in the HCC patients than in those with chronic hepatitis B (2.12-fold) or the healthy individuals (5.57-fold) ^[26]. Another study found that miR-21 and miR-10b were significantly increased in EVs from HCC patients compared with healthy individuals or those with chronic hepatitis B, suggesting their potential as diagnostic biomarkers for early HCC ^[27].

MiR-122, an abundant EV cargo, has also shown promise as a diagnostic biomarker for HCC. Wang et al. found that the combination of serum EV miR-122, EV miR-148a, and AFP could distinguish early-stage HCC from cirrhosis with high accuracy, increasing the AUC to 0.931 (95% CI: 0.857–0.973) ^[28].

Other miRNAs carried by EVs, such as miR-92b ^[29], miR-10b ^[30], miR-125b ^[31], miR-103 ^[32], miR-146a ^[33], miR-150-3p ^[34], miR-1307-5p ^[35], miR-221 ^[36], miR-665 ^[37], and miR-210 ^[38], have also been suggested as potential early diagnostic biomarkers. However, the reliability of these candidates needs to be further validated, as the studies supporting these claims have been conducted on small sample sizes. Therefore, further studies with larger sample sizes are required in order to confirm the diagnostic potential of these EV-associated miRNAs.

Changes in circular RNA (circRNA) ^[39] and transfer RNA-derived small RNA (tsRNA) ^[40] expression have also been reported as potential diagnostic markers for HCC. Sun et al. ^[41] found that the expression levels of hsa_circ_0004001, hsa_circ_0004123, and hsa_circ_0075792 in the plasma EVs of HCC patients had higher diagnostic sensitivity and specificity and were positively correlated with TNM stage and tumor size.

Proteins have also been examined as another type of cargo in EVs in HCC patients. Certain proteins have been found to be elevated in EVs from patients with HCC, suggesting their potential as biomarkers for HCC diagnosis. For example, Arbelaiz A et al. ^[42] found elevated levels of RasGAP SH3 domain-binding protein (G3BP) and polymeric immunoglobulin receptor (PIGR) in the EVs of HCC patients, which had higher predictive efficacy for HCC than AFP.

3. EVs, the Next Generation of Carriers for Drug Delivery

Liposomal and polymeric nanoparticles (NPs) are being investigated intensely for their promise in delivering various types of drug molecules, for example, anticancer drugs, antifungal drugs, and analgesics. However, they have limitations, such as their inability to withstand changes in shear pressure, temperature, pH, or diluent concentration, as well as their relative inability to precisely deliver drugs to specific cell types in the body ^[43]. EVs offer a promising alternative to liposomal and polymeric drug delivery systems due to their long circulating half-life, biocompatibility, lack of intrinsic toxicity, and ability to target tissues ^[44]. Some clinical applications of EVs with drug-loaded capabilities have shown therapeutic efficacy in pancreatic cancer, such as mesenchymal stem cell (MSC)-derived EVs loaded with K-RAS G12D-specific siRNAs, which have extended the half-life and targeting of nucleic acid drugs and are now in clinical trials [NCT03608631] ^[45]. By engineering EVs to express specific surface proteins, glycans, peptides, or charges, researchers also aim to optimize the surface properties of EVs to improve the targeting efficiency. For instance, expressing αvβ3 integrins on EVs allows them to enhance the conduction ability of paclitaxel ^[46].

Drug loading into EVs can be achieved through two methods: pre-secretion and post-secretion. In the pre-secretion method, parental cells are co-incubated with the “drug” (usually with transfection reagents), and EVs are obtained from conditioned media in cultured cells or from biological tissues or fluids ^[47]. The drug is then sorted into EVs by active or passive means. Parent cells are modified by bioengineering to secrete large amounts of specific EVs. As one of the most readily available primary cells, mesenchymal stem cells (MSCs) are widely used as the parent cells for engineered EVs due to their high EV productivity, tropism, and homing effect ^[48]. As for ncRNAs, they are often chosen as candidates for the pre-secretion method ^[49]. However, the drug delivery efficiency of EVs in this method is relatively low ^[50]. To increase the delivery efficiency of EVs, specific components can be artificially loaded into the vesicles.

Other approaches transfected the target ncRNA directly into the parental cells. Lou et al. ^[51] constructed miR-199a-modified adipose tissue-derived MSCs (AMSC-199a) by means of miR-199a lentivirus infection and obtained engineered EVs, which were found to be effective in transferring miR-199a to HCC cells. Engineered EVs expressing miR-199a-significantly increased the sensitivity of HCC cells to adriamycin in vitro and also significantly enhanced the antitumor effect of adriamycin on HCC in vivo. Similarly, miR-122-releasing plasmids were transfected into AMSC to generate miR-122-enriched EVs. These EVs induced G0/G1 phase arrest and apoptosis, increasing the sensitivity of HCC cells to chemotherapy ^[52].

On the other hand, post-secretion drug delivery involves isolating and purifying EVs before loading drugs into them. This method is more frequently used for large-scale industrial production. The loading of hydrophobic small molecules, such as curcumin ^[53] and paclitaxel ^[54], can be accomplished by simple incubation. Various methods (e.g., electroporation, extrusion, and sonication) have also been used to load hydrophilic molecules and larger molecules ^[55]. While this method is relatively simple and efficient in terms of loading drugs, additional purification steps are required in order to remove unencapsulated drugs, which may compromise the integrity of EVs.

4. Therapeutic EVs for Immunomodulation in HCC

The tumor microenvironment (TME) plays a crucial role in cancer development and progression, and EVs have been found to mediate intercellular communication within the TME ^[56]. Dendritic cell-derived EVs (DEVs) are particularly promising as immunotherapeutic agents against cancer, as they contain functional MHC peptide complexes and other immunostimulatory components, and function as antigen-presenting entities. DEVs are suggested to promote an immune-cell-dependent tumor rejection response ^[57].

In addition, tumor-derived EVs also stimulate antitumor immune responses and act as antigen-presenting vesicles that deliver tumor-associated antigens (TAA) to dendritic cells. The TAA carried by the EV is readily taken up by dendritic cells, enabling efficient presentation of the antigens on MHC molecules to homologous T cells. Inspired by the concept of chimeric antigen receptor-T (CAR-T) cell therapy, researchers have stimulated dendritic cells with tumor antigens. MHC-antigen complexes can be presented by DEVs as CAR, which trigger T cell activation and effective anti-tumor immunity in vitro and in vivo ^[58].

EVs engineered as tumor immunomodulators constitute an attractive approach for developing anti-tumor therapeutics due to their ability to act as tumor immunomodulators. One example is exoASO-STAT6, a precision drug candidate that uses EVs to selectively deliver antisense oligonucleotides to disrupt STAT6 signaling in tumor-associated macrophages (TAM) and induce antitumor immune responses ^[59]. Preclinical data released by Codiak BioSciences Inc. demonstrates the potent antitumor activity of its product candidate, exoASO-STAT6. Currently, a clinical trial using exoASO-STAT6 (CDK-004) in patients with advanced HCC or liver metastases is underway (NCT05375604). Another study found that EVs from the sera of HCC patients contained significantly less HMGN1 (high-mobility group nucleosome binding protein 1) than EVs from healthy individuals. Therefore, the researchers loaded a functional short peptide of HMGN1-N1ND onto the surfaces of EVs and successfully transported the N1ND molecule into dendritic cells to enhance their activation and immunogenicity ^[60].

Moreover, EVs can increase and modulate the immune response, making them a potential strategy for designing new vaccine formulations. EVs have the potential to activate granulocytes or NK cells and interact with CD8, CD4, and B cells to demonstrate antigen-specific immune responses ^[61]. Jesus et al. ^[62] suggested that EVs could enhance protective immune responses in vaccine development when coexisting with antigens. As they presented, EVs were isolated from a lipopolysaccharide endotoxin-stimulated human monocyte line (THP-1) as potential vaccine adjuvants and combined with hepatitis B recombinant antigen (HBsAg) solutions or suspensions composed of HBsAg-loaded poly-ε-caprolactone-chitosan nanoparticles. The combined EVs induced a humoral immune response similar to that of HBsAg. Figure 1 depicts a diagrammatic representation of engineered extracellular vesicles and their role in modulating the immune microenvironment in HCC.

Figure 1. A schematic illustration of EVs engineered as tumor immunomodulators of HCC; HCC-derived EVs are known to incite immune cell activation by transporting related proteins (TAA), while engineered EVs also exert an effect on the immune microenvironment by conveying diverse signaling molecules. The cellular binding mediated by CAR-EV-induced T-cell activation upon recognition of HCC is highlighted in the dashed box on the lower right. In addition, the generative patterns of pre-secretory EVs and post-secretory EVs are demonstrated in the lower left dashed box. (HCC: hepatocellular carcinoma cell; DEV: dendritic cell-derived EVs; TAA: tumor-associated antigens; CAR-EV: chimeric antigen receptor-EV; TAM: tumor-associated macrophage; MHC: major histocompatibility complex). Translating EV Research to the Bedside: Challenges and Limitations.

In conclusion, both natural and engineered EVs show promise as immunotherapeutic agents against HCC and other types of cancer. However, further research is needed to develop safer and more effective anti-tumor therapies using these EVs.

5. Conclusions

The global market for EV products is anticipated to experience significant growth. However, the majority of EV-related studies are still in the laboratory research phase. To support the practical application of EVs in clinical diagnosis and disease treatment, it is crucial to conduct multi-center and large-sample clinical trials. Over the next 10 years, with the advancement of various technologies and the improvement of research standards, it is anticipated that there will be a significant acceleration in the translation of EVs from the laboratory to practical clinical applications. This golden era will be facilitated by basic research on the formation and mechanism of action of EVs, as well as continuous breakthroughs in the engineering modification, delivery, and mass production of EVs. Possible directions for further research include identifying subtle interactions between exosomes and the tumor microenvironment, investigating the possibility of cargo alterations in exosomes for targeted therapies, and investigating exosome-based immunotherapy approaches.

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Subjects: Cell & Tissue Engineering

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Rong Yan

Haiming Chen

Florin M. Selaru

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Update Date: 20 Nov 2023

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