Small extracellular vesicles (sEVs) are membrane-bound vesicles with a size of less than 200 nm, released by cells. Due to their relatively small molecular weight and ability to participate in intercellular communication, sEVs can serve not only as carriers of biomarkers for disease diagnosis but also as effective drug delivery agents. Furthermore, these vesicles are involved in regulating the onset and progression of various diseases, reflecting the physiological and functional states of cells. This paper introduces the classification of extracellular vesicles, with a focus on the extraction and identification of sEVs and their significant role in repair, diagnosis, and intercellular communication. Additionally, the paper addresses the engineering modification of sEVs to provide a reference for enhanced understanding and application.

Gastrointestinal (GI) cancers, which predominantly manifest in the stomach, colorectum, liver, esophagus, and pancreas, accounting for approximately 35% of global cancer-related mortality. The advent of liquid biopsy has introduced a pivotal diagnostic modality for the early identification of premalignant GI lesions and incipient cancers. This non-invasive technique not only facilitates prompt therapeutic intervention, but also serves as a critical adjunct in prognosticating the likelihood of tumor recurrence. The wealth of circulating exosomes present in body fluids is often enriched with proteins, lipids, microRNAs, and other RNAs derived from tumor cells. These specific cargo components are reflective of processes involved in GI tumorigenesis, tumor progression, and response to treatment. As such, they represent a group of promising biomarkers for aiding in the diagnosis of GI cancer. In this review, we delivered an exhaustive overview of the composition of exosomes and the pathways for cargo sorting within these vesicles. We laid out some of the clinical evidence that supported the utilization of exosomes as diagnostic biomarkers for GI cancers and discussed their potential for clinical application. Furthermore, we addressed the challenges encountered when harnessing exosomes as diagnostic and predictive instruments in the realm of GI cancers.

Exploring the mechanisms underlying sorafenib resistance that arises in hepatocellular carcinoma (HCC) may provide new treatment perspectives.

Drug-resistant and drug-sensitive HCC cell lines were constructed from existing HepG2 and Huh7 cell lines, and gene expression profiles were determined. Genes differentially expressed between the resistant and sensitive lines were identified and organized into modules based on weighted gene co-expression network analysis. Pathways and biological processes involving the module genes were explored and validated using gene set enrichment analysis. By analyzing the expression differences of Long non-coding ribonucleic acid (RNAs), microRNAs (miR), circular RNAs, and messenger RNAs between drug-resistant and sensitive cell lines, a gene regulatory network was constructed to reveal the mechanism of sorafenib resistance. In addition, we also analyzed the correlation between the candidate sorafenib resistance gene and the survival of patients with liver cancer.

Our analyses suggested that sorafenib resistance could arise when the circular RNA circ_SPECC1 regulated the microRNA hsa-let-7c-5p, which in turn regulated the cell cycle proteins cyclin-dependent kinase 1 and polo-like kinase 1, as well as interleukin 13 receptor, alpha 1 in the Janus kinase-signal transducer (JAK-STAT) and activator of transcription signaling pathway. Patient survival was associated with miR-18a-z and mitogen-activated protein kinase kinase 4 levels.

Sorafenib resistance in HCC may involve the circ_SPECC1, hsa-let-7c-5p, cell cycle, and JAK-STAT signaling pathways. These insights may guide future efforts to mitigate or prevent such resistance.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, often diagnosed at advanced stages due to insufficient early screening and monitoring. MicroRNAs (miRNAs) are key regulators of gene expression and potential biomarkers for cancer diagnosis. This study investigated the diagnostic potential of miRNAs in Extracellular Vesicles (EVs) from HCC. miRNA expression in EVs was analyzed using HCC cell lines, circulating EVs from a Diethylnitrosamine (DEN)-induced liver tumor rat model, and plasma samples from HCC patients. Receiver Operating Characteristics (ROCs) were applied to evaluate the diagnostic accuracy of circulating EV miRNAs in patients. Five miRNAs (miR-183-5p, miR-19a-3p, miR-148b-3p, miR-34a-5p, and miR-215-5p) were consistently up-regulated in EVs across in vitro and in vivo HCC models. These miRNAs showed statistically significant differences in HCC patients stratified by TNM staging and Edmondson-Steiner grading compared to healthy controls. They also differentiated HCC patients with various etiologies from the control group and distinguished HCC patients, with or without liver cirrhosis, from cirrhotic and healthy individuals. Individually and as a panel, they demonstrated high sensitivity, specificity, and accuracy in identifying HCC patients. Their consistent upregulation across models and clinical samples highlights their robustness as biomarkers for HCC diagnosis, offering the potential for early disease management and prognosis.

Prognosis in patients with HCC is largely determined by stage at diagnosis, highlighting the importance of effective early detection strategies. HCC surveillance is associated with increased early detection and reduced HCC-related mortality and is currently recommended in patients with cirrhosis or chronic HBV infection.

We performed a targeted literature review to identify limitations of current HCC surveillance practices and strategies for improvement.

Semi-annual ultrasound continues as the cornerstone modality for HCC surveillance but has limited sensitivity for detecting early-stage HCC, particularly in patients with obesity and non-viral etiologies. Although sensitivity for early-stage HCC can be improved by using ultrasound with alpha fetoprotein, this strategy misses over one-third of HCC at an early stage. Emerging imaging and biomarker-based surveillance strategies currently remain in varying stages of validation and are not yet ready for routine use in practice. The cost-effectiveness of surveillance in patients with non-cirrhotic liver disease related to hepatitis C or metabolic dysfunction-associated steatotic liver disease continues to be debated, although subgroups with advanced fibrosis may warrant surveillance. Finally, the effectiveness of surveillance is diminished by underuse in clinical practice, particularly in racial minority and low-income groups, highlighting a need for interventions to increase utilization.

Cancer is the second leading cause of human mortality worldwide. Extracellular vesicles (EVs) from liquid biopsy samples are used in early cancer detection, characterization, and surveillance. Exosomes are a subset of EVs produced by all cells and present in all body fluids. They play an important role in the development of cancer because they are active transporters capable of carrying the contents of any type of cell. The objective of this review was to provide a brief overview of the clinical implication of exosomes or exosomal components in cancer diagnosis and prognosis.

An extensive review of the current literature of exosomes and their components in cancer diagnosis and prognosis were carried out in the current study.

Tumor cells release exosomes that contribute to the formation of the pre-metastatic microenvironment, angiogenesis, invasion, and treatment resistance. On the contrary, tumor cells release more exosomes than normal cells, and these tumor-specific exosomes can carry the genomic and proteomic signature contents of the tumor cells, which can act as tools for the diagnosis and prognosis of patients with cancers.

This information may help clinicians to improve the management of cancer patients in clinical settings in the future.

Breast cancer (BC) is the prevailing malignant tumor, with its prevalence and death rate steadily rising over time. BC often does not show obvious symptoms in its early stages and is difficult to distinguish from benign breast disease. We aimed to find a distinct group of miRNAs utilizing serum as a non-invasive biomarker for early BC diagnosis.

Herein, we mainly include the screening stage, testing stage, and verification stage. In the screening stage, 8 miRNAs associated with BC were selected and analyzed via literature reading, and the expression of the above miRNAs in BC was further verified by bioinformatics and included in the research analysis. In the testing phase, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was deployed to select the five miRNAs with the most significant expression differences in 15 BC patients and 15 benign breast controls to proceed to the next stage. In a subsequent validation phase, the five miRNAs obtained from serum samples from an additional 75 BC patients and 50 benign control patients were evaluated using RT-qPCR. The diagnostic capacity, specificity, and sensitivity of candidate miRNAs were estimated with the receiver operating characteristic (ROC) curve and area under the curve (AUC). Finally, the optimal diagnostic combination model with high sensitivity and strong specificity was constructed by using the above 5 miRNAs.

The BC patients reported a significant decline in mir-10b-5p, mir-133a-3p, mir-195-5p, and mir-155-3p levels in serum levels contrasted with those in benign controls. Additionally, BC patients experienced elevated mir-195-3p levels than in benign controls. We implemented ROC analysis to evaluate its diagnostic capacity for BC. We demonstrated that all five miRNAs had robust diagnostic capability, with an AUC above 0.8. We developed a conclusive diagnostic combination model consisting of these 5 miRNAs in order to enhance the diagnosis accuracy. This model demonstrated a high diagnostic value, as shown by an AUC of 0.948.

The serum biomarker panels composed of five miRNAs identified in this study (mir-10b-5p, mir-133a-3p, mir-195-5p, mir-195-3p, and mir-155-3p) provide hope for early, non-invasive, and accurate diagnosis of BC.

Hepatocellular carcinoma (HCC) associated with Hepatitis B Virus (HBV) is one of the most severe malignancies in East Asia, where early diagnosis is crucial for improving patient prognosis. So we aim to identify effective early diagnostic model for HCC.

We enrolled 108 early-stage HCC patients and 102 non-HCC individuals underlying HBV infection, collecting plasma exosomal miRNAs (exo-miRNAs) from all participants. These patients were randomly assigned to sequencing, screening, training, and validation group. After preliminary screening of candidate exo-miRNAs by next-generation high-throughput sequencing, qPCR data from the screening group were utilized in conjunction with the random forest machine learning algorithm to identify candidate exo-miRNAs with diagnostic potential. Subsequently, logistic regression diagnostic model was constructed using the relative expression levels of candidate exo-miRNAs, alpha-fetoprotein (AFP) levels and clinical parameters of gender and the presence of cirrhosis from the training group. The diagnostic accuracy of diagnostic model was subsequently validated in the validation group.

Firstly, we identified miR-212-5p, miR-1248, and miR-1250-5p as candidate exo-miRNAs with potential diagnostic value. The exo-miRNAs panel, which consisted of miR-212-5p, miR-1248, miR-1250-5p, along with clinical parameters of gender and cirrhosis, achieved an AUC of 0.8634 (95% CI: 0.8027-0.9241), demonstrating diagnostic performance non-inferior to AFP in the independent dataset. Subsequently, by combining exo-miRNAs, AFP level and clinical parameter of gender, we enhanced the diagnostic panel, miRAGe, which exhibited an AUC of 0.9499 (95% CI: 0.9192-0.9806), sensitivity of 0.8900, and specificity of 0.9468.

Our study indicates that the miRAGe panel has low rate of both missed diagnosis and misdiagnosis rates, potentially serving as a useful diagnostic tool for HBV-related HCC in early stage, which may subsequently contribute to improve the prognosis.

Current research is focused on utilizing EVs as a biopsy tool to improve the diagnostic accuracy of HCC, reduce surgical risk, and explore their potential in modulating drug resistance and advancing immunotherapeutic strategies. Extracellular vesicles (EVs) have been increasingly recognized as important non-invasive biomarkers in hepatocellular carcinoma (HCC) due to the presence of a variety of biomolecules within them, such as proteins and RNAs, etc. EVs play a key role in the early detection, diagnosis, treatment, and prognostic monitoring of HCC. These vesicles influence the development of HCC and therapeutic response in a variety of ways, including influencing the tumor microenvironment, modulating drug resistance, and participating in immune regulatory mechanisms. In addition, specific molecules such as miRNAs and specific proteins in EVs are regarded as potential markers for monitoring treatment response and recurrence of HCC, which have certain research space and development prospects. In this paper, we summarize the aspects of EVs as HCC diagnostic and drug resistance markers, and also discuss the questions that may be faced in the development of EVs as markers.

Exosomes, which are extracellular vesicles with a diameter ranging from 40 to 160 nm, are abundantly present in various body fluids. Exosomal microRNA (ex-miR), due to its exceptional sensitivity and specificity, has garnered significant attention. Notably, ex-miR is consistently detected in almost all bodily fluids, highlighting its potential as a reliable biomarker. This attribute of ex-miR has piqued considerable interest in its application as a diagnostic tool for the early detection, continuous monitoring, and prognosis evaluation of cancer. Given the critical role of exosomes and their cargo in cancer biology, this review explores the intricate processes of exosome biogenesis and uptake, their multifaceted roles in cancer development and progression, and the potential of ex-miRs as biomarkers for tumor diagnosis and prognosis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally. Most patients present with late diagnosis, leading to poor prognosis. This narrative review explores novel biomarkers for early HCC detection. We conducted a comprehensive literature review analyzing protein, circulating nucleic acid, metabolite, and quantitative proteomics-based biomarkers, evaluating the advantages and limitations of each approach. While established markers like alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, and AFP-L3 remain relevant, promising candidates include circulating tumor DNA, microRNAs, long noncoding RNAs, extracellular vesicle, and metabolomic biomarkers. Multi-biomarker panels like the GALAD score, Oncoguard, and Helio liver test show promise for improved diagnostic accuracy. Non-invasive approaches like urine and gut microbiome analysis are also emerging possibilities. Integrating these novel biomarkers with current screening protocols holds significant potential for earlier HCC detection and improved patient outcomes. Future research should explore multi-biomarker panels, omics technologies, and artificial intelligence to further enhance early HCC diagnosis and management.

Cancer presents a significant challenge to global health, driving worldwide concerted efforts to advance early detection, predict therapeutic response, and identify novel targeted therapies. Liquid biopsies emerge as promising avenues for discerning cancer biomarkers, offering less invasive approaches compared to conventional methods. Utilizing increasingly robust technologies, diverse bodily fluids can unveil genetic variants, epigenetic modifications, transcriptional alterations, and metabolomic signatures associated with cancer, thereby furnishing valuable insights for clinical management. This chapter intends to review the sources of cancer-related biomarkers found in circulation, prevalent techniques utilized for their identification, and the potential implications of different biomarker types on the management of cancer. Certain biomarkers currently used in clinical practice will be addressed, as well as potential biomarkers still in the study phase, and the inherent challenges in their practical implementation.

This review comprehensively explores the complex interplay between extracellular vesicles (ECVs)/exosomes and circadian rhythms, with a focus on the role of this interaction in hepatocellular carcinoma (HCC). Exosomes are nanovesicles derived from cells that facilitate intercellular communication by transporting bioactive molecules such as proteins, lipids, and RNA/DNA species. ECVs are implicated in a range of diseases, where they play crucial roles in signaling between cells and their surrounding environment. In the setting of cancer, ECVs are known to influence cancer initiation and progression. The scope of this review extends to all cancer types, synthesizing existing knowledge on the various roles of ECVs. A unique aspect of this review is the emphasis on the circadian-controlled release and composition of exosomes, highlighting their potential as biomarkers for early cancer detection and monitoring metastasis. We also discuss how circadian rhythms affect multiple cancer-related pathways, proposing that disruptions in the circadian clock can alter tumor development and treatment response. Additionally, this review delves into the influence of circadian clock components on ECV biogenesis and their impact on reshaping the tumor microenvironment, a key component driving HCC progression. Finally, we address the potential clinical applications of ECVs, particularly their use as diagnostic tools and drug delivery vehicles, while considering the challenges associated with clinical implementation.

Exosomes, small membranous microvesicles released by cells, contain a range of bioactive molecules, including proteins and miRNAs, which play critical roles in intercellular communication and physiological and pathological processes. Current research suggests that exosomal miRNAs could serve as valuable biomarkers for prenatal diseases, offering a noninvasive method for early detection and monitoring. Studies linking exosomal miRNAs to various birth defects, including fetal growth restriction, urinary tract malformations, cardiovascular system malformations, and hereditary diseases like Down syndrome, were discussed. However, there are some conflicting study findings due to different exosome separation methods. Here, we also discussed exosome separation methods, emphasizing the importance of method selection based on specific purposes and sample types. Further studies are needed to standardize isolation techniques, understand the specific mechanisms underlying exosomal miRNA function, and develop reliable noninvasive prenatal diagnostic indicators. Overall, exosomal miRNAs show promise as potential biomarkers for prenatal diagnosis, but further research is necessary to validate their clinical utility.

As information messengers for cell-to-cell communication, exosomes, typically small membrane vesicles (30-150 nm), play an imperative role in the physiological and pathological processes of living systems. Accumulating studies have demonstrated that exosomes are potential biological candidates for theranostics, including liquid biopsy-based diagnosis and drug delivery. However, their clinical applications are hindered by several issues, especially their unspecific detection and insufficient targeting ability. How to upgrade the accuracy of exosome-based theranostics is being widely explored. Aptamers, benefitting from their admirable characteristics, are used as excellent molecular recognition elements to empower exosomes for precision theranostics. With high affinity against targets and easy site-specific modification, aptamers can be incorporated with platforms for the specific detection of exosomes, thus providing opportunities for advancing disease diagnostics. Furthermore, aptamers can be tailored and functionalized on exosomes to enable targeted therapeutics. Herein, this review emphasizes the empowering of exosomes by aptamers for precision theranostics. A brief introduction of exosomes and aptamers is provided, followed by a discussion of recent progress in aptamer-based exosome detection for disease diagnosis, and the emerging applications of aptamer-functionalized exosomes for targeted therapeutics. Finally, current challenges and opportunities in this research field are presented.

Gastrointestinal (GI) cancers account for one-fourth of the global cancer incidence and are incriminated to cause one-third of cancer-related deaths. GI cancer includes esophageal, gastric, liver, pancreatic, and colorectal cancers, mostly diagnosed at advanced stages due to a lack of accurate markers for early stages. The invasiveness of diagnostic methods like colonoscopy for solid biopsy reduces patient compliance as it cannot be frequently used to screen patients. Therefore, minimally invasive approaches like liquid biopsy may be explored for screening and early identification of gastrointestinal cancers. Liquid biopsy involves the qualitative and quantitative determination of certain cancer-specific biomarkers in body fluids such as blood, serum, saliva, and urine to predict disease progression, therapeutic tolerance, toxicities, and recurrence by evaluating minimal residual disease and its correlation with other clinical features. In this review, we deliberate upon various tumor-specific cellular and molecular entities such as circulating tumor cells (CTCs), tumor-educated platelets (TEPs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), exosomes, and exosome-derived biomolecules and cite recent advances pertaining to their use in predicting disease progression, therapy response, or risk of relapse. We also discuss the technical challenges associated with translating liquid biopsy into clinical settings for various clinical applications in gastrointestinal cancers.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, usually occurring in the background of chronic liver disease. HCC lethality rate is in the third highest place in the world. Patients with HCC have concealed early symptoms and possess a high-level of heterogeneity. Once diagnosed, most of the tumors are in advanced stages and have a poor prognosis. The sensitivity and specificity of existing detection modalities and protocols are suboptimal. HCC calls for more sophisticated and individualized therapeutic regimens. Liquid biopsy is non-invasive, repeatable, unaffected by location, and can be monitored dynamically. It has emerged as a useable aid in achieving precision malignant tumor treatment. Circulating tumor cells (CTCs), circulating nucleic acids, exosomes and tumor-educated platelets are the commonest components of a liquid biopsy. It possesses the theoretical ability to conquer the high heterogeneity and the difficulty of early detection for HCC patients. In this review, we summarize the common enrichment techniques and the clinical applications in HCC for different liquid biopsy components. Tumor recurrence after HCC-related liver transplantation is more insidious and difficult to treat. The clinical use of liquid biopsy in HCC-related liver transplantation is also summarized in this review.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. It is a major public health problem worldwide, and it is often diagnosed at advanced stages, when no effective treatment options are available. Extracellular vesicles (EVs) are nanosized double-layer lipid vesicles containing various biomolecule cargoes, such as lipids, proteins, and nucleic acids. EVs are released from nearly all types of cells and have been shown to play an important role in cell-to-cell communication. In recent years, many studies have investigated the role of EVs in cancer, including HCC. Emerging studies have shown that EVs play primary roles in the development and progression of cancer, modulating tumor growth and metastasis formation. Moreover, it has been observed that non-coding RNAs (ncRNAs) carried by tumor cell-derived EVs promote tumorigenesis, regulating the tumor microenvironment (TME) and playing critical roles in the progression, angiogenesis, metastasis, immune escape, and drug resistance of HCC. EV-related ncRNAs can provide information regarding disease status, thus encompassing a role as biomarkers. In this review, we discuss the main roles of ncRNAs present in HCC-derived EVs, including micro(mi) RNAs, long non-coding (lnc) RNAs, and circular (circ) RNAs, and their potential clinical value as biomarkers and therapeutic targets.

Hepatocellular carcinoma (HCC) is primary liver cancer, frequently diagnosed at advanced stages with limited therapeutic options. MicroRNAs (miRNAs) regulate target gene expression and through inhibitory competitive binding of miRNA influence cellular processes including carcinogenesis. Extensive evidence proved that certain miRNA's are specifically expressed in neoplastic tissues of HCC patients and are confirmed as important factors that can participate in the regulation of key signalling pathways in cancer cells. As such, miRNAs have a great potential in the clinical diagnosis and treatment of HCC and can improve the limitations of standard diagnosis and treatment. Long non-coding RNAs (lncRNAs) have a critical role in the development and progression of HCC. HCC-related lncRNAs have been demonstrated to exhibit abnormal expression and contribute to transformation process (such as proliferation, apoptosis, accelerated vascular formation, and gain of invasive potential) through their interaction with DNA, RNA, or proteins. LncRNAs can bind mRNAs to release their target mRNA and enable its translation. These lncRNA-miRNA networks regulate cancer cell expression and so its proliferation, apoptosis, invasion, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and autophagy. In this narrative review, we focus on miRNA and lncRNA in HCC tumor tissue and their interaction as current tools, and biomarkers and therapeutic targets unravelled in recent years.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, with high recurrence rates and notorious resistance to conventional chemotherapy. Cancer stemness refers to the stem-cell-like phenotype of cancer cells and has been recognized to play important roles in different aspects of hepatocarcinogenesis. Small extracellular vesicles (sEVs) are small membranous particles secreted by cells that can transfer bioactive molecules, such as nucleic acids, proteins, lipids, and metabolites, to neighboring or distant cells. Recent studies have highlighted the role of sEVs in modulating different aspects of the cancer stemness properties of HCC. Furthermore, sEVs derived from diverse cellular sources, such as cancer cells, stromal cells, and immune cells, contribute to the maintenance of the cancer stemness phenotype in HCC. Through cargo transfer, specific signaling pathways are activated within the recipient cells, thus promoting the stemness properties. Additionally, sEVs can govern the secretion of growth factors from non-cancer cells to further maintain their stemness features. Clinically, plasma sEVs may hold promise as potential biomarkers for HCC diagnosis and treatment prediction. Understanding the underlying mechanisms by which sEVs promote cancer stemness in HCC is crucial, as targeting sEV-mediated communication may offer novel strategies in treatment and improve patient outcome.

Ultrasound screening for hepatocellular carcinoma (HCC) in patients with liver cirrhosis has a poor sensitivity for small tumors. Circulating microRNAs (miRNAs) have been explored as HCC biomarkers, but results are diverging. Here, we evaluate if miRNAs up-regulated in HCC tissue can be detected in plasma and used as screening biomarkers for HCC. In this cross-sectional study, plasma, HCC tissue and surrounding non-tumorous liver tissue were collected from liver resections. Tissue miRNAs were identified and quantitated by RNA-sequencing analysis, and the fold-changes between HCC and surrounding liver tissue were calculated. The miRNAs up-regulated in HCCs were then re-analyzed in plasma from the same patients, and the miRNAs with the highest plasma levels were subsequently measured in plasma from an independent cohort of patients with cirrhosis or HCC. In tissues from 84 resected patients, RNA-sequencing detected 197 differentially expressed miRNAs, 40 of which had a raw count above 200 and were analyzed in plasma from the same cohort. Thirty-one miRNAs were selected for further analysis in 200 patients with HCC or cirrhosis. Of these, eleven miRNAs were significantly increased in HCC as compared to cirrhosis patients. Only miR-93-5p and miR-151a-3p were significantly associated with HCC, with an AUC of 0.662. In comparison, alpha-fetoprotein and des-gamma-carboxy prothrombin yielded an AUC of 0.816, which increased to 0.832 if miR-93-5p and miR-151a-3p were added. When including sex and age, the addition of miR-93-5p and miR-151a-3p did not further improve the AUC (from 0.910 to 0.911). In conclusion, micro-RNAs up-regulated in HCCs are detectable in plasma but have a poor performance as screening biomarkers of HCC.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, with poor prognosis owing to its high frequency of recurrence and metastasis. Moreover, most patients are diagnosed at an advanced stage owing to a lack of early detection markers. Exosomes, which are characterized by their cargos of stable intracellular messengers, such as DNA, RNA, proteins, and lipids, play a crucial role in regulating cell differentiation and HCC development. Recently, exosomal noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, have become increasingly important diagnostic, prognostic, and predictive markers of HCC. Herein, we discuss the clinical implications of exosomal ncRNAs, specifically those within the HCC regulatory network.

Gastrointestinal (GI) cancers, including colorectal, gastric, esophageal, pancreatic, and liver, are associated with high mortality and morbidity rates worldwide. One of the underlying reasons for the poor survival outcomes in patients with these malignancies is late disease detection, typically when the tumor has already advanced and potentially spread to distant organs. Increasing evidence indicates that earlier detection of these cancers is associated with improved survival outcomes and, in some cases, allows curative treatments. Consequently, there is a growing interest in the development of molecular biomarkers that offer promise for screening, diagnosis, treatment selection, response assessment, and predicting the prognosis of these cancers. Extracellular vesicles (EVs) are membranous vesicles released from cells containing a repertoire of biological molecules, including nucleic acids, proteins, lipids, and carbohydrates. MicroRNAs (miRNAs) are the most extensively studied non-coding RNAs, and the deregulation of miRNA levels is a feature of cancer cells. EVs miRNAs can serve as messengers for facilitating interactions between tumor cells and the cellular milieu, including immune cells, endothelial cells, and other tumor cells. Furthermore, recent years have witnessed considerable technological advances that have permitted in-depth sequence profiling of these small non-coding RNAs within EVs for their development as promising cancer biomarkers -particularly non-invasive, liquid biopsy markers in various cancers, including GI cancers. Herein, we summarize and discuss the roles of EV-associated miRNAs as they play a seminal role in GI cancer progression, as well as their promising translational and clinical potential as cancer biomarkers as we usher into the area of precision oncology.

Hepatocellular carcinoma (HCC) is one of the most common cancers and is responsible for the second cancer-related death globally. Many treatment regimens have been developed to cure the disease; however, life expectancy is still low. Therefore, there is an urgent need to explore new selective, specific, and robust diagnosis markers for efficient early recognition of the ailment. Along with the diagnosis, the treatment's effectiveness can be determined by prognostic markers, and miRNAs are excellent tools for the diagnosis and prognosis of HCC. In addition, the altered expression profile of a few miRNAs promotes HCC cell migration and invasion, and selective up- or downregulation of these responsible genes may help mitigate the disorder. On one hand, few of the miRNAs have been found to enhance angiogenesis, a crucial step of tumor growth; on the other hand, upregulation of specific miRNAs is reported to suppress angiogenesis and resulting tumor growth of HCC cells. Exosomal miRNAs have significant implications in promoting angiogenesis, increased endothelial cell permeability, tube formation, and metastasis to hepatic and pulmonary tissues. miRNA also attributes to drug resistance toward chemotherapy and the prevention of autophagy also. Identifying novel miRNA and determining their differential expression in HCC tissue may serve as a potential tool for diagnosis, prognosis, and therapy to enhance the life expectancy and quality of life of HCC patients. In the present review, we have summarized the recent advances in HCC-related research.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Due to the insidiousness of HCC onset and the lack of specific early-stage markers, the early diagnosis and treatment of HCC are still unsatisfactory, leading to a poor prognosis. Exosomes are a type of extracellular vesicle containing various components, which play an essential part in the development, progression, and metastasis of HCC. A large number of studies have demonstrated that exosomes could serve as novel biomarkers for the diagnosis of HCC. These diagnostic components mainly include proteins, microRNAs, long noncoding RNAs, and circular RNAs. The exosome biomarkers showed high sensitivity and high specificity in distinguishing HCC from health controls and other liver diseases, such as chronic HBV and liver cirrhosis. The expression of these biomarkers also exhibits correlations with various clinical factors such as tumor size, TMN stage, overall survival, and recurrence rate. In this review, we summarize the function of exosomes in the development of HCC and highlight their application as HCC biomarkers for diagnosis and prognosis prediction.

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. The objective of this review is to present a thorough overview of recent studies focusing on EVs in hepatocellular carcinoma (HCC), with an emphasis on their potential utility as diagnostic biomarkers as well as therapeutic agents. Initially, we explore the utility of EVs as diagnostic biomarkers for HCC, followed by a discussion of their potential as carriers of therapeutic payloads. Additionally, we delve into the emerging field of therapeutic EVs for modulating tumor immune responses. Through this review, our ultimate aim is to provide a comprehensive understanding of the opportunities and challenges in the clinical translation of EV research in the domain of HCC.

Extracellular vesicles (EVs) are emerging as a promising field of research in liver disease. EVs are small, membrane-bound vesicles that contain various bioactive molecules, such as proteins, lipids, and nucleic acids and are involved in intercellular communication. They have been implicated in numerous physiological and pathological processes, including immune modulation and tissue repair, which make their use appealing in liver transplantation (LT). This review summarizes the current state of knowledge regarding the role of EVs in LT, including their potential use as biomarkers and therapeutic agents and their role in graft rejection. By providing a comprehensive insight into this emerging topic, this research lays the groundwork for the potential application of EVs in LT.

Exosomes are cell-derived membranous structures primarily involved in the delivery of the payload to the recipient cells, and they play central roles in carcinogenesis and metastasis. Radiotherapy is a common cancer treatment that occasionally generates exosomal miRNA-associated modulation to regulate the therapeutic anticancer function and side effects. Combining radiotherapy and natural products may modulate the radioprotective and radiosensitizing responses of non-cancer and cancer cells, but there is a knowledge gap regarding the connection of this combined treatment with exosomal miRNAs and their downstream targets for radiation and exosome biogenesis. This review focuses on radioprotective natural products in terms of their impacts on exosomal miRNAs to target radiation-modulating and exosome biogenesis (secretion and assembly) genes. Several natural products have individually demonstrated radioprotective and miRNA-modulating effects. However, the impact of natural-product-modulated miRNAs on radiation response and exosome biogenesis remains unclear. In this review, by searching through PubMed/Google Scholar, available reports on potential functions that show radioprotection for non-cancer tissues and radiosensitization for cancer among these natural-product-modulated miRNAs were assessed. Next, by accessing the miRNA database (miRDB), the predicted targets of the radiation- and exosome biogenesis-modulating genes from the Gene Ontology database (MGI) were retrieved bioinformatically based on these miRNAs. Moreover, the target-centric analysis showed that several natural products share the same miRNAs and targets to regulate radiation response and exosome biogenesis. As a result, the miRNA-radiomodulation (radioprotection and radiosensitization)-exosome biogenesis axis in regard to natural-product-mediated radiotherapeutic effects is well organized. This review focuses on natural products and their regulating effects on miRNAs to assess the potential impacts of radiomodulation and exosome biogenesis for both the radiosensitization of cancer cells and the radioprotection of non-cancer cells.

Early and non-invasive detection of hepatocellular carcinoma (HCC), which is usually asymptomatic, can improve overall survival outcomes. The objective of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of serum-derived exosomes for diagnosing HCC.

PubMed, Web of Science, and Scopus databases were searched for relevant studies up to April 2023. The quality of included studies was assessed using the QUADAS-2 checklist, and data were extracted. Statistical analysis was performed on 18 studies from 3,993 records, and a diagnostic meta-analysis was conducted. Biomarkers were categorized into four groups based on their type (exosomal miRNAs, exosomal RNAs, alpha-fetoprotein (AFP), and exosomal RNAs+AFP panel), and a meta-analysis was conducted for each category separately.

The highest pooled sensitivity was 0.86 for exosomal miRNAs, and exosomal RNAs+AFP had the highest pooled specificity; (0.89). Furthermore, exosomal RNAs+AFP had the highest pooled positive likelihood ratio; (7.55), the highest pooled diagnostic odds ratio (35.96) and the highest pooled area under the curve (0.93). Exosomal miRNAs had the lowest pooled negative likelihood ratio; (0.17).

The diagnostic accuracy of exosomal biomarkers is superior to that of AFP, and combining the two in a panel yields the better results.

Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatocellular carcinoma (PHC). Early diagnosis of HCC remains the key to improve the prognosis. In recent years, with the promotion of the concept of precision medicine and more in-depth analysis of the biological mechanism underlying HCC, new diagnostic methods, including emerging serum markers, liquid biopsies, molecular diagnosis, and advances in imaging (novel contrast agents and radiomics), have emerged one after another. Herein, we reviewed and analyzed scientific advances in the early diagnosis of HCC and discussed their application and shortcomings. This review aimed to provide a reference for scientific research and clinical practice of HCC.

Hepatocellular carcinoma (HCC) has developed into one of the most lethal, aggressive, and malignant cancers worldwide. Although HCC treatment has improved in recent years, the incidence and lethality of HCC continue to increase yearly. Therefore, an in-depth study of the pathogenesis of HCC and the search for more reliable therapeutic targets are crucial to improving the survival quality of HCC patients. Currently, miRNAs have become one of the hotspots in life science research, which are widely present in living organisms and are non-coding RNAs involved in regulating gene expression. MiRNAs exert their biological roles by suppressing the expression of downstream genes and are engaged in various HCC-related processes, including proliferation, apoptosis, invasion, and metastasis. In addition, the expression status of miRNAs is related to the drug resistance mechanism of HCC, which has important implications for the systemic treatment of HCC. This paper reviews the regulatory role of miRNAs in the pathogenesis of HCC and the clinical applications of miRNAs in HCC in recent years.

Exosomes are extracellular vesicles that originate from endosomes and are released by all cells irrespective of their origin or type. They play an important role in cell communication and can act in an autocrine, endocrine, or paracrine fashion. They are 40-150 nm in diameter and have a similar composition to the cell of origin. An exosome released by a particular cell is unique since it carries information about the state of the cell in pathological conditions such as cancer. miRNAs carried by cancer-derived exosomes play a multifaceted role by taking part in cell proliferation, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis, apoptosis, and immune evasion. Depending on the type of miRNA that it carries as its cargo, it can render cells chemo- or radiosensitive or resistant and can also act as a tumor suppressor. Since the composition of exosomes is affected by the cellular state, stress, and changes in the environment, they can be used as diagnostic or prognostic biomarkers. Their unique ability to cross biological barriers makes them an excellent choice as vehicles for drug delivery. Because of their easy availability and stability, they can be used to replace cancer biopsies, which are invasive and expensive. Exosomes can also be used to follow the progression of diseases and monitor treatment strategies. A better understanding of the roles and functions of exosomal miRNA can be used to develop noninvasive, innovative, and novel treatments for cancer.

Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In addition, the molecular background of ULMS has not been fully elucidated due to its low incidence. Therefore, no effective treatment strategies have been established based on its molecular background. The present study aimed to investigate the roles of microRNAs (miRNAs/miRs) in the development of ULMS. Comprehensive miRNA sequencing was performed using six ULMS and three myoma samples, and revealed 53 and 11 significantly upregulated and downregulated miRNAs, respectively. One of the most abundant miRNAs in myoma samples was miR‑10b‑5p. The mean normalized read count of miR‑10b‑5p was 93,650 reads in myoma, but only 27,903 reads in ULMS. Subsequently, to investigate the roles of miR‑10b‑5p, gain‑of‑function analysis was performed using SK‑UT‑1 and SK‑LMS‑1 cell lines. The overexpression of miR‑10b‑5p suppressed cell proliferation and reduced the number of colonies. Moreover, miR‑10b‑5p increased the number of cells in the G1 phase. In conclusion, tumor‑suppressive miR‑10b‑5p was significantly downregulated in ULMS compared with in myoma; thus, miR‑10b‑5p may serve a specific role in sarcoma progression.

Liver cancer is one of the most common malignancies, with severe morbidity and mortality. While considerable progress has been made in liver cancer treatment, the 5-year overall survival (OS) of patients has not improved significantly. Reasons include the inadequate capability of early screening and diagnosis, a high incidence of recurrence and metastasis, a high degree of tumor heterogeneity, and an immunosuppressive tumor microenvironment. Therefore, the identification and validation of specific and robust liver cancer biomarkers are of major importance for early screening, timely diagnosis, accurate prognosis, and the prevention of tumor progression. In this review, we highlight some of the latest research progress and potential applications of liver cancer biomarkers, describing hotspots and prospective directions in biomarker discovery.

Exosomes are membrane-defined extracellular vesicles (EVs) approximately 40-160 ​nm in diameter that are found in all body fluids including blood, urine, and saliva. They act as important vehicles for intercellular communication between both local and distant cells and can serve as circulating biomarkers for disease diagnosis and prognosis. Exosomes play a key role in tumor metastasis, are abundant in biofluids, and stabilize biomarkers they carry, and thus can improve cancer detection, treatment monitoring, and cancer staging/prognosis. Despite their clinical potential, lack of sensitive/specific biomarkers and sensitive isolation/enrichment and analytical technologies has posed a barrier to clinical translation of exosomes. This review presents a critical overview of technologies now being used to detect tumor-derived exosome (TDE) biomarkers in clinical specimens that have potential for clinical translation.

Extracellular vesicle (EV) microRNAs have been documented in several studies to have significantly different expressions in hepatitis B virus (HBV)-related liver diseases, such as hepatocellular carcinoma (HCC). The current work aimed to observe the characteristics of EVs and EV miRNA expressions in patients with severe liver injury chronic hepatitis B (CHB) and patients with HBV-associated decompensated cirrhosis (DeCi).

The characterization of the EVs in the serum was carried out for three different groups, namely, patients with severe liver injury-CHB, patients with DeCi, and healthy controls. EV miRNAs were analyzed using miRNA-seq and RT-qPCR arrays. Additionally, we assessed the predictive and observational values of the miRNAs with significant differential expressions in serum EVs.

Patients with severe liver injury-CHB had the highest EV concentrations when compared to the normal controls (NCs) and patients with DeCi (p < 0.001). The miRNA-seq of the NC and severe liver injury-CHB groups identified 268 differentially expressed miRNAs (|FC| > 2, p < 0.05). In this case, 15 miRNAs were verified using RT-qPCR, and it was found that novel-miR-172-5p and miR-1285-5p in the severe liver injury-CHB group showed marked downregulation in comparison to the NC group (p < 0.001). Furthermore, compared with the NC group, three EV miRNAs (novel-miR-172-5p, miR-1285-5p, and miR-335-5p) in the DeCi group showed various degrees of downregulated expression. However, when comparing the DeCi group with the severe liver injury-CHB group, only the expression of miR-335-5p in the DeCi group decreased significantly (p < 0.05). For the severe liver injury-CHB and DeCi groups, the addition of miR-335-5p improved the predictive accuracy of the serological levels, while miR-335-5p was significantly correlated with ALT, AST, AST/ALT, GGT, and AFP. Conclusions: The patients with severe liver injury-CHB had the highest number of EVs. The combination of novel-miR-172-5p and miR-1285-5p in serum EVs helped in predicting the progression of the NCs to severe liver injury-CHB, while the addition of EV miR-335-5p improved the serological accuracy of predicting the progression of severe liver injury-CHB to DeCi.

Hepatocellular carcinoma (HCC) usually occurs on the basis of chronic liver inflammatory diseases and cirrhosis. The liver microenvironment plays a vital role in the tumor initiation and progression. Exosomes, which are nanometer-sized membrane vesicles are secreted by a number of cell types. Exosomes carry multiple proteins, DNAs and various forms of RNA, and are mediators of cell-cell communication and regulate the tumor microenvironment. In the recent decade, many studies have demonstrated that exosomes are involved in the communication between HCC cells and the stromal cells, including endothelial cells, macrophages, hepatic stellate cells and the immune cells, and serve as a regulator in the tumor proliferation and metastasis, immune evasion and immunotherapy. In addition, exosomes can also be used for the diagnosis and treatment HCC. They can potentially serve as specific biomarkers for early diagnosis and drug delivery vehicles of HCC. Chinese herbal medicine, which is widely used in the prevention and treatment of HCC in China, may regulate the release of exosomes and exosomes-mediated intercellular communication. In this review, we summarized the latest progresses on the role of the exosomes in the initiation, progression and treatment of HCC and the potential value of Traditional Chinese medicine in exosomes-mediated biological behaviors of HCC.

DNA methylation profiles are in dynamic equilibrium via the initiation of methylation, maintenance of methylation and demethylation, which control gene expression and chromosome stability. Changes in DNA methylation patterns play important roles in carcinogenesis and primarily manifests as hypomethylation of the entire genome and the hypermethylation of individual loci. These changes may be reflected in blood-based DNA, which provides a non-invasive means for cancer monitoring. Previous blood-based DNA detection objects primarily included circulating tumor DNA/cell-free DNA (ctDNA/cfDNA), circulating tumor cells (CTCs) and exosomes. Researchers gradually found that methylation changes in peripheral blood mononuclear cells (PBMCs) also reflected the presence of tumors. Blood-based DNA methylation is widely used in early diagnosis, prognosis prediction, dynamic monitoring after treatment and other fields of clinical research on cancer. The reversible methylation of genes also makes them important therapeutic targets. The present paper summarizes the changes in DNA methylation in cancer based on existing research and focuses on the characteristics of the detection objects of blood-based DNA, including ctDNA/cfDNA, CTCs, exosomes and PBMCs, and their application in clinical research.

Hepatocellular carcinoma (HCC) has different etiologies that contribute to its heterogeneity. In regards to the number of HCC patients, Egypt ranks third in Africa and fifteenth worldwide. Despite significant advancements in HCC diagnosis and treatment, the precise biology of the tumor is still not fully understood, which has a negative impact on patient outcomes.

Advances in next-generation sequencing (NGS) have increased our knowledge of the molecular complexity of HCC.

In this research, 16 HCC and 6 tumor adjacent tissues (control) of Child A Egyptian patients were successfully profiled for the expression profile of miRNAs by NGS. Forty-one differentially expressed miRNAs (DEMs) were found by differential expression analysis, with 31 being upregulated and 10 being downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was then conducted on these differentially expressed miRNAs revealing that Sensitivity and specificity analysis showed that hsa-miR-4488, hsa-miR-3178, and hsa-miR-3182 were unique miRNAs as they are expressed in HCC tissues only. These miRNAs were all highly involved in AMPK signaling pathways. However, hsa-miR-214-3p was expressed in control tissues about eight times higher than in cancer tissues and was most abundant in "pathways in cancer and PI3K-Akt signaling pathway" KEGG terms. As promising HCC diagnostic markers, we here suggest hsa-miR-4488, hsa-miR-3178, hsa-miR-3182, and hsa-miR-214-3p. We further urge future research to confirm these markers' diagnostic and prognostic potential as well as their roles in the pathophysiology of HCC.

A significant number of cancer-related deaths are recorded globally each year, despite attempts to cure this illness. Medical science is working to develop new medication therapies as well as to find ways to identify this illness as early as possible, even using noninvasive techniques. Early detection of cancer can greatly aid its treatment. Studies into cancer diagnosis and therapy have recently shifted their focus to exosome (EXO) biomarkers, which comprise numerous RNA and proteins. EXOs are minuscule goblet vesicles that have a width of 30 to 140 nm and are released by a variety of cells, including immune, stem, and tumor cells, as well as bodily fluids. According to a growing body of research, EXOs, and cancer appear to be related. EXOs from tumors play a role in the genetic information transfer between tumor and basal cells, which controls angiogenesis and fosters tumor development and spread. To identify malignant activities early on, microRNAs (miRNAs) from cancers can be extracted from circulatory system EXOs. Specific markers can be used to identify cancer-derived EXOs containing miRNAs, which may be more reliable and precise for early detection. Conventional solid biopsy has become increasingly limited as precision and personalized medicine has advanced, while liquid biopsy offers a viable platform for noninvasive diagnosis and prognosis. Therefore, the use of body fluids such as serum, plasma, urine, and salivary secretions can help find cancer biomarkers using technologies related to EXOs.

This study examined exosomal hepatitis B virus (HBV)-DNA levels in chronic HBV infection (CHB). Patients were grouped according to the European Association for the Study of the Liver classification (1: HBV-DNA-positive CHB, normal alanine aminotransferase [ALT]; 2: HBV-DNA-positive CHB, elevated ALT; 3: HBV-DNA-negative HBeAb-positive CHB, normal ALT; 4: HBV-DNA-positive HBeAg-negative HBeAb-positive CHB, elevated ALT; 5: HBV-DNA-negative, HBcAb-positive; 6: HBV-negative, normal ALT). Exosomes were isolated, comparative analysis of exosomes and serum HBV-DNA. The HBV-DNA content was lower in exosomes than in serum for groups 1, 2, and 4 (all P < 0.05). In the groups negative for serum HBV-DNA (groups 3 and 5), the exosomal HBV-DNA levels were higher than the serum HBV-DNA levels (all P < 0.05). The exosomal and serum HBV-DNA levels were correlated in groups 2 (R ² = 0.84) and 4 (R ² = 0.98). The exosomal HBV-DNA levels were correlated with total bilirubin (R ² = 0.94), direct bilirubin (R ² = 0.82), and indirect bilirubin (R ² = 0.81) in group 5 (all P < 0.05). In patients with CHB and negative for serum HBV-DNA, exosomal HBV-DNA was detectable and could be used to monitor the treatment effects. Exosomal HBV-DNA could be used in patients with a high suspicion of HBV infection but negative for serum HBV-DNA.