Pancreatic cancer is recognized as one of the most lethal types of cancer globally, characterized by a high mortality rate and a bleak prognosis, which greatly contributes to cancer-related deaths. Forecasts suggest that by 2030, pancreatic cancer will exceed other cancer types in prevalence. The disease presents considerable difficulties owing to the lack of prominent symptoms in its early stages, restricted options for early detection, rapid progression, and unfavorable outcomes. Presently, traditional methods for diagnosing pancreatic cancer primarily rely on imaging techniques. However, these methods often entail significant costs, require considerable time, and necessitate specialized skills for both operating the equipment and interpreting the resulting images. To overcome these obstacles, the use of biosensors has been proposed as a potentially valuable tool for the early detection of pancreatic cancer. MicroRNAs (miRs), a type of small non-coding RNA molecules, have emerged as highly sensitive molecular diagnostic tools that have the potential to function as precise indicators for a range of diseases, including cancer. Biosensors have been suggested as a potential solution for tackling these challenges, offering a promising approach for the early detection of pancreatic cancer. Small non-coding RNA molecules known as MicroRNAs (miRs) have become recognized as extremely sensitive molecular diagnostic tools and can act as precise biomarkers for different diseases, such as cancer. Moreover, this manuscript presents a thorough summary of the latest innovations in nano-biosensors that have been specifically developed for the identification of non-coding RNAs related to pancreatic cancer.

In the recent decade, extracellular vesicles (EVs) have been released from nearly all the kingdoms, modulating intercellular communication and maintaining the human body's homeostasis by regulating different cellular processes. Among EVs, exosomes are the emerging field in biopharmaceuticals. They have lipid bilayer ranging from 30 to 150 nm in size and encompass DNA, RNA, protein lipids, etc. Their sources are widespread, easy to acquire, and cost-effective in manufacturing. This review focuses on the detailed classification of exosomes existing in nature, knowledge and application of omics, therapeutic, diagnostic and theranostic application of exosomes. It covers diseases such as cancer, infectious diseases (viral, bacterial, fungal infections), neurodegenerative diseases, metabolic diseases, lifestyle diseases (diabetes, cardiovascular, gastric disorder (IBD)), autoimmune disorders and their biodistribution. This article unfolds the recent progress in the exosomes arena and covers all the regulatory considerations (FDA, EMA, and other nations) involved with it. Moreover, a detailed discussion about clinical trials and its manifestation with exosomes and challenges associated with their isolation procedures, reproducibility, and safety concerns.

Extracellular vesicles (EVs) represent a diverse class of nanoscale membrane vesicles actively released by cells. These EVs can be further subdivided into categories like exosomes and microvesicles, based on their origins, sizes, and physical attributes. Significantly, disease-derived EVs have been detected in virtually all types of body fluids, providing a comprehensive molecular profile of their cellular origins. As a result, EVs are emerging as a valuable addition to liquid biopsy techniques. In this collective statement, the authors share their current perspectives on EV-related research and product development, with a shared commitment to translating this newfound knowledge into clinical applications for cancer and other diseases, particularly as disease biomarkers. The consensus within this document revolves around the overarching recognition of the merits, unresolved questions, and existing challenges surrounding EVs. This consensus manuscript is a collaborative effort led by the Committee of Exosomes, Society of Tumor Markers, Chinese anti-Cancer Association, aimed at expediting the cultivation of robust scientific and clinically applicable breakthroughs and propelling the field forward with greater swiftness and efficacy.

Glypican-1 (GPC-1) protein-positive small extracellular vesicles (GPC-1+-sEV) have been proposed as potential biomarkers for early diagnosis of pancreatic cancer. In this study, we present an integrated real-time isolation and detection platform (IRTIDP) to capture and analyze GPC-1+-sEV directly from sera of pancreatic cancer patients. First, CD63 antibody-modified metal-organic framework (MOF) materials were utilized to enrich sEVs with a capture efficiency of 93.93 %. Second, a SERS probe was constructed by Raman reporter 4-MBA and GPC-1 antibody modified SERS active silver nanoparticles (AgNPs), which formed a sandwich complex structure of "MOFs@GPC-1+-sEV@AgNPs-4-MBA" with MOFs-enriched sEVs. The IRTSDP can complete the capture and detection process within 35 min, with a detection limit for 1 GPC-1+-sEV/μL, and linear range between 105∼109 GPC-1+-sEV/mL. Furthermore, this approach has been applied to quantify serum sEV GPC-1 in clinical pancreatic cancer patients. Based on the SERS intensity analysis, pancreatic cancer patients can be distinguished from pancreatic cystadenoma patients and healthy individuals effectively using this innovative platform that provides highly specific and sensitive means for early diagnosis of pancreatic cancer as well as other tumor types.

Extracellular vesicles (EVs) composed of various biologically active constituents, such as proteins, nucleic acids, lipids, and metabolites, have emerged as a noteworthy mode of intercellular communication. There are several categories of EVs, including exosomes, microvesicles, and apoptotic bodies, which largely differ in their mechanisms of formation and secretion. The amount of evidence indicated that changes in the EV quantity and composition play a role in multiple aspects of cancer development, such as the transfer of oncogenic signals, angiogenesis, metabolism remodeling, and immunosuppressive effects. As EV isolation technology and characteristics recognition improve, EVs are becoming more commonly used in the early diagnosis and evaluation of treatment effectiveness for cancers. Actually, EVs have sparked clinical interest in their potential use as delivery vehicles or vaccines for innovative antitumor techniques. This review will focus on the function of biological molecules contained in EVs linked to cancer progression and their participation in the intricate interrelationship within the tumor microenvironment. Furthermore, the potential efficacy of an EV-based liquid biopsy and delivery cargo for treatment will be explored. Finally, we explicitly delineate the limitations of EV-based anticancer therapies and provide an overview of the clinical trials aimed at improving EV development.

In recent years, several giant pandas have suffered from testicular tumor, which has seriously affected giant panda health. However, the pathogenesis of testicular tumor in giant panda is still unclear. Studies have shown that miRNAs are involved in the occurrence and development of a variety of cancers. However, the effect of miRNAs on giant panda testicular tumor has been little studied. Therefore, this study explored the pathogenesis of giant panda testicular tumor through miRNA and mRNA sequencing, and screened out diagnostic markers of testicular tumor.

Combined with phenotypic symptoms and pathological section results, three giant pandas were diagnosed with testicular tumor and divided into tumor group, and three other giant pandas were divided into normal group. A total of 29 differentially expressed miRNAs (DEmiRNAs) were screened by blood miRNA-seq, and 3149 target gene candidates were predicted. Functional enrichment analysis showed that the target genes were mainly involved in intermembrane lipid transfer and ATP-dependent chromatin remodeling. However, only 5 DEmiRNAs were screened by miRNA-seq of blood-derived exosomes and 364 target genes were predicted, which were mainly involved in antigen processing and presentation. In addition, 216 differentially expressed genes (DEGs) were screened by RNA-seq, and functional enrichment analysis showed that tumor-specific DEGs significantly enriched to protein phosphorylation. Spearman correlation analysis of miRNA-mRNA showed that the expressions of miR-331-3p and PKIG were significantly positively correlated (spearman = 0.943, p < 0.01), while the expressions of miR-331-3p and ENSAMEG00000013628 were significantly negatively correlated (spearman= -0.829, p < 0.05). RT-PCR showed that the expression of miR-331-3p was significantly decreased in giant panda with tumor (p < 0.01).

blood miRNAs and exosomal miRNAs exhibit distinct regulatory patterns concerning giant panda testicular tumor, potentially reflecting divergent biological processes in the disease's etiology. Meanwhile, miR-331-3p could be used as a potential diagnostic marker for giant panda testicular tumor. Our findings are conducive to the rapid clinical diagnosis of testicular tumor in giant pandas, and are also expected to provide scientific reference for further research on the pathogenesis of testicular tumor.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, with its incidence rising due to improved survival rates of these infants. BPD results from a combination of prenatal and postnatal factors, such as mechanical ventilation, oxygen toxicity, and infections, all of which significantly impact the prognosis and growth of affected infants. Current treatment options for BPD are largely supportive and do not address the underlying pathology. Exosomes are cell-derived bilayer-enclosed membrane structures enclosing proteins, lipids, RNAs, growth factors, cytokines and metabolites. They have become recognized as crucial regulators of intercellular communication in various physiological and pathological processes. Previous studies have revealed the therapeutic potential of human umbilical cord mesenchymal stem cells-derived exosomes (HUCMSCs-Exos) in promoting tissue repair and regeneration. Therefore, HUCMSCs-Exos maybe a promising and effective therapeutic modality for BPD. In this review, we firstly provide a comprehensive overview of BPD, including its etiology and the mechanisms of lung injury. Then we detail the isolation, characterization, and contents of HUCMSCs-Exos, and discuss their potential mechanisms of HUCMSCs-Exos in BPD treatment. Additionally, we summarize current clinical trials and discuss the challenges in translating these findings from bench to bedside. This review aims to lay the groundwork for future clinical applications of HUCMSCs-Exos in treating BPD.

Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers.

We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort.

The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%).

We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality and it is often diagnosed at advanced stages due to non-specific clinical presentation. Disease detection at localized disease stage followed by surgical resection remains the only potentially curative treatment. In this era of precision medicine, a multifaceted approach to early detection of PDAC includes targeted screening in high-risk populations, serum biomarkers and "liquid biopsies", and artificial intelligence augmented tumor detection from radiologic examinations. In this review, we will review these emerging techniques in the early detection of PDAC.

Pancreatic cancer remains one of the most lethal diseases worldwide. Cancer-derived exosomes, benefiting from the protective role of the lipid membrane, exhibit remarkable stability in the circulatory system. These exosomes, released by tumor microenvironment, contain various biomolecules such as proteins, RNAs, and lipids that plays a pivotal role in mediating distant communication between the local pancreatic tumor and other organs or tissues. They facilitate the transfer of oncogenic factors to distant sites, contributing to the compromised body immune system, distant metastasis, diabetes, cachexia, and promoting a microenvironment conducive to tumor growth and metastasis in pancreatic cancer patients. Beyond their intrinsic roles, circulating exosomes in peripheral blood can be detected to facilitate accurate liquid biopsy. This approach offers a novel and promising method for the diagnosis and management of pancreatic cancer. Consequently, circulating exosomes are not only crucial mediators of systemic cell-cell communication during pancreatic cancer progression but also hold great potential as precise tools for pancreatic cancer management and treatment. Exosome-based liquid biopsy and therapy represent promising advancements in the diagnosis and treatment of pancreatic cancer. Exosomes can serve as drug delivery vehicles, enhancing the targeting and efficacy of anticancer treatments, modulating the immune system, and facilitating gene editing to suppress tumor growth. Ongoing research focuses on biomarker identification, drug delivery systems, and clinical trials to validate the safety and efficacy of exosome-based therapies, offering new possibilities for early diagnosis and precision treatment in pancreatic cancer. Leveraging the therapeutic potential of exosomes, including their ability to deliver targeted drugs and modulate immune responses, opens new avenues for innovative treatment strategies.

Early cancer detection and accurate monitoring are crucial to ensure increased patient survival. Recent research has focused on developing non-invasive biomarkers to diagnose cancer early and monitor disease progression at low cost and risk. Extracellular vesicles (EVs), nanosized particles secreted into extracellular spaces by most cell types, are gaining immense popularity as novel biomarker candidates for liquid cancer biopsy, as they can transport bioactive cargo to distant sites and facilitate intercellular communications. A literature search was conducted to discuss the current approaches for EV isolation and the advances in using EV-associated proteins, miRNA, mRNA, DNA, and lipids as liquid biopsies. We discussed the advantages and challenges of using these vesicles in clinical applications. Moreover, recent advancements in machine learning as a novel tool for tumor marker discovery are also highlighted.

The main objective of this study was to investigate the antitumor effect of a mouse anti-human glypican-1 (GPC1) monoclonal antibody (mAb) on non-small cell lung carcinoma (NSCLC) and associated molecular mechanisms.

The anti-proliferative and anti-migratory activities of anti-GPC1 mAb were examined in A549 and H460 NSCLC cells and LL97A lung fibroblasts. The inhibitory effect of anti-GPC1 mAb on tumor growth was evaluated in an orthotopic lung tumor model.

The in vitro study showed that anti-GPC1 mAb profoundly inhibited the anchorage-independent growth of A549 and H460 NSCLC cells and exhibited relatively high cytotoxic activities towards LL97A lung fibroblasts, A549/LL97A and H460/LL97A coculture spheroids. Moreover, anti-GPC1 mAb significantly decreased the expression of phospho-Src (p-Src; Tyr416), p-Akt (Ser473) and β-catenin in the co-cultured LL97A lung fibroblasts, and the expression of phospho-mitogen-activated protein kinase kinase (p-MEK; Ser217/221) and phospho-90 kDa ribosomal s6 kinase (p-p90RSK; Ser380) in co-cultured A549 cells. When anti-GPC1 mAb was administered to tumor-bearing mice, the inhibitory effect of anti-GPC1 mAb on the orthotopic lung tumor growth was not statistically significant. Nonetheless, results of Western blot analysis showed significant decrease in the phosphorylation of fibroblast growth factor receptor 1 (FGFR1) at Tyr766, Src at Tyr416, extracellular signal-regulated kinase (ERK) at Thr202/Tyr204, 90 kDa ribosomal S6 kinase (RSK) at Ser380, glycogen synthase kinases 3α (GSK3α) at Ser21 and GSK3β at Ser9 in tumor tissues. These data implicate that anti-GPC1 mAb treatment impairs the interaction between tumor cells and tumor associated fibroblasts by attenuating the paracrine FGFR signal transduction.

The relatively potent cytotoxicity of anti-GPC1 mAb in lung fibroblasts and its potential inhibitory effect on the paracrine FGFR signal transduction warrant further studies on the combined use of this mAb with targeted therapeutics to improve therapeutic outcomes in lung cancer.

Pancreatic cancer is a prevalent lethal gastrointestinal cancer that generally does not show any symptoms until it reaches advanced stages, resulting in a high mortality rate. People at high risk, such as those with a family history or chronic pancreatitis, do not have a universally accepted screening protocol. Chemotherapy and radiotherapy demonstrate limited effectiveness in the management of pancreatic cancer, emphasizing the urgent need for innovative therapeutic strategies. Recent studies indicated that the complex interaction among pancreatic cancer cells within the dynamic microenvironment, comprising the extracellular matrix, cancer-associated cells, and diverse immune cells, intricately regulates the biological characteristics of the disease. Additionally, mounting evidence suggests that EVs play a crucial role as mediators in intercellular communication by the transportation of different biomolecules, such as miRNA, proteins, DNA, mRNA, and lipids, between heterogeneous cell subpopulations. This communication mediated by EVs significantly impacts multiple aspects of pancreatic cancer pathogenesis, including proliferation, angiogenesis, metastasis, and resistance to therapy. In this review, we delve into the pivotal role of EV-associated miRNAs in the progression, metastasis, and development of drug resistance in pancreatic cancer as well as their therapeutic potential as biomarkers and drug-delivery mechanisms for the management of pancreatic cancer.

Pancreatic cancer is a highly lethal and metastatic malignancy, mainly because it often remains undetected until advanced stages due to the limitations of current diagnostic methods, rendering currently available therapies ineffective. Therefore, it is imperative to identify useful biomarkers for early diagnosis and new therapeutic targets for pancreatic cancer. Recently, extracellular vesicles have emerged as promising biomarkers for the diagnosis and prognosis of pancreatic cancer. Given their presence in various bodily fluids, extracellular vesicles offer a non-invasive approach through liquid biopsy to detect and monitor cancer progression. In this review, we comprehensively examine the multifaceted roles of extracellular vesicles in the progression of cancer, while also exploring their potential as diagnostic, prognostic, and therapeutic biomarkers in the context of pancreatic cancer.

This review aims to provide a quantitative and qualitative bibliometric analysis of literature from 2013 to 2023 on the role of exosomes in PC, with the goal of identifying current trends and predicting future hotspots.

We retrieved relevant publications concerning exosomes in PC, published between 2013 and 2023, from the Web of Science Core Collection. Bibliometric analyses were conducted using VOSviewer(1.6.19), CiteSpace(6.2.R4), and Microsoft Excel (2019).

A total of 624 papers were analyzed, authored by 4017 researchers from 55 countries/regions and 855 institutions, published in 258 academic journals. China (n=285, 34.42%) and the United States (n=183, 24.87%) were the most frequent contributors and collaborated closely. However, publications from China had a relatively low average number of citations (41.45 times per paper). The output of Shanghai Jiao Tong University ranked first, with 28 papers (accounting for 4.5% of the total publications). Cancers (n=31, 4.9%); published the most papers in this field. Researcher Margot Zoeller published the most papers (n=12) on this topic. Research hotspots mainly focused on the mechanisms of exosomes in PC onset and progression, the role of exosomes in PC early diagnosis and prognosis, exosomes promote the development of PC chemoresistance, and potential applications of exosomes as drug carriers for PC therapies. We observed a shift in research trends, from mechanistic studies toward clinical trials, suggesting that clinical applications will be the focus of future attention. Emerging topics were pancreatic stellate cells, diagnostic biomarkers, mesenchymal stem cells, extracellular vesicles.

Our scientometric and visual analysis provides a comprehensive overview of the literature on the role of exosomes in PC published during 2013-2023. This review identifies the frontiers and future directions in this area over the past decade, and is expected to provide a useful reference for researchers in this field.

Pancreatic cancer is the most fatal malignancy worldwide. Once diagnosed, most patients are already at an advanced stage because of their highly heterogeneous, drug-resistant, and metastatic nature and the lack of effective diagnostic markers. Recently, the study of proliferation, metastasis, and drug resistance mechanisms in pancreatic cancer and the search for useful diagnostic markers have posed significant challenges to the scientific community. Exosomes carry various biomolecules (DNA, non-coding RNAs (ncRNAs), proteins, and lipids) that mediate communication between tumors and other cells. ncRNAs can be transported through exosomes to numerous relevant receptor cells and regulate local epithelial-mesenchymal transition (EMT) in tumor tissue, proliferation, drug resistance, and the establishment of pre-metastatic ecological niches in distant organs. In summary, exosomal ncRNAs promote tumor cell proliferation, invasion, and metastasis through multiple EMT, immunosuppression, angiogenesis, and extracellular matrix remodeling pathways. Moreover, we discuss the significant therapeutic significance of exosomal ncRNAs as PC biomarkers.

Pancreatic cancer remains a formidable malignancy characterized by high mortality rates, primarily attributable to late-stage diagnosis and a dearth of effective therapeutic interventions. The identification of reliable biomarkers holds paramount importance in enhancing early detection, prognostic evaluation, and targeted treatment modalities. Small non-coding RNAs, particularly microRNAs, have emerged as promising candidates for pancreatic cancer biomarkers in recent years. In this review, we delve into the evolving role of cellular and circulating miRNAs, including exosomal miRNAs, in the diagnosis, prognosis, and therapeutic targeting of pancreatic cancer. Drawing upon the latest research advancements in omics data-driven biomarker discovery, we also perform a case study using public datasets and address commonly identified research discrepancies, challenges, and limitations. Lastly, we discuss analytical approaches that integrate multimodal analyses incorporating clinical and molecular features, presenting new insights into identifying robust miRNA-centric biomarkers.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, while it persists as the fourth most prevalent cause of cancer-related death in the United States of America. Although there are several novel therapeutic strategies for the approach of this intensely aggressive tumor, it remains a clinical challenge, as it is hard to identify in early stages, due to its asymptomatic course. A diagnosis is usually established when the disease is already in its late stages, while its chemoresistance constitutes an obstacle to the optimal management of this malignancy. The discovery of novel diagnostic and therapeutic tools is considered a necessity for this tumor, due to its low survival rates and treatment failures. One of the most extensively investigated potential diagnostic and therapeutic modalities is extracellular vesicles (EVs). These vesicles constitute nanosized double-lipid membraned particles that are characterized by a high heterogeneity that emerges from their distinct biogenesis route, their multi-variable sizes, and the particular cargoes that are embedded into these particles. Their pivotal role in cell-to-cell communication via their cargo and their implication in the pathophysiology of several diseases, including pancreatic cancer, opens new horizons in the management of this malignancy. Meanwhile, the interplay between pancreatic carcinogenesis and short non-coding RNA molecules (micro-RNAs or miRs) is in the spotlight of current studies, as they can have either a role as tumor suppressors or promoters. The deregulation of both of the aforementioned molecules leads to several aberrations in the function of pancreatic cells, leading to carcinogenesis. In this review, we will explore the role of extracellular vesicles and miRNAs in pancreatic cancer, as well as their potent utilization as diagnostic and therapeutic tools.

Liquid biopsy can detect circulating cancer cells or tumor cell-derived DNA at various stages of cancer. The fluid from these biopsies contains extracellular vesicles (EVs), such as apoptotic bodies, microvesicles, exomeres, and exosomes. Exosomes contain proteins and nucleic acids (DNA/RNA) that can modify the microenvironment and promote cancer progression, playing significant roles in cancer pathology. Clinically, the proteins and nucleic acids within the exosomes from liquid biopsies can be biomarkers for the detection and prognosis of cancer. We review EVs protein and miRNA biomarkers identified for select cancers, specifically melanoma, glioma, breast, pancreatic, hepatic, cervical, prostate colon, and some hematological malignancies. Overall, this review demonstrates that EV biomolecules have great potential to expand the diagnostic and prognostic biomarkers used in Oncology; ultimately, EVs could lead to earlier detection and novel therapeutic targets. Clinical implicationsEVs represent a new paradigm in cancer diagnostics and therapeutics. The potential use of exosomal contents as biomarkers for diagnostic and prognostic indicators may facilitate cancer management. Non-invasive liquid biopsy is helpful, especially when the tumor is difficult to reach, such as in pancreatic adenocarcinoma. Moreover, another advantage of using minimally invasive liquid biopsy is that monitoring becomes more manageable. Identifying tumor-derived exosomal proteins and microRNAs would allow a more personalized approach to detecting cancer and improving treatment.

Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late-stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes-rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles-rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early-stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late-stage PDAC patients undergoing chemotherapy, lower GPC1 tMV-mProtein and Exo-mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis.

Malignant tumours of the digestive system cover a wide range of diseases that affect the health of people to a large extent. Angiogenesis is indispensable in the development, and metastasis of tumours, mainly in two ways: occupation or formation. Vessels can provide nutrients, oxygen, and growth factors for tumours to encourage growth and metastasis, so cancer progression depends on simultaneous angiogenesis. Recently, exosomes have been proven to participate in the angiogenesis of tumours. They influence angiogenesis by binding to tyrosine kinase receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 with different affinities, regulating Yap-VEGF pathway, Akt pathway or other signaling pathway. Additionally, exosomes are potential therapeutic vectors that can deliver many types of cargoes to different cells. In this review, we summarize the roles of exosomes in the angiogenesis of digestive system tumours and highlight the clinical application prospects, directly used as targers or delivery vehicles, in antiangiogenic therapy.

Small extracellular vesicles (sEVs) contain lipids, proteins and nucleic acids, which often resemble their cells of origin. Therefore, plasma sEVs are considered valuable resources for cancer biomarker development. However, previous efforts have been largely focused on the level of proteins and miRNAs in plasma sEVs, and the post-translational modifications of sEV proteins, such as arginine methylation, have not been explored. Protein arginine methylation, a relatively stable post-translational modification, is a newly described molecular feature of PDAC. The present study examined arginine methylation patterns in plasma sEVs derived from patients with early-stage PDAC (n = 23) and matched controls. By utilizing the arginine methylation-specific antibodies for western blotting, we found that protein arginine methylation patterns in plasma sEVs are altered in patients with early-stage PDAC. Specifically, we observed a reduction in the level of symmetric dimethyl arginine (SDMA) in plasma sEV proteins derived from patients with early- and late-stage PDAC. Importantly, immunoprecipitation followed by proteomics analysis identified a number of arginine-methylated proteins exclusively present in plasma sEVs derived from patients with early-stage PDAC. These results indicate that arginine methylation patterns in plasma sEVs are potential indicators of PDAC, a new concept meriting further investigation.

Identifying biomarkers may lead to easier detection and a better understanding of pathogenesis of pancreatic ductal adenocarcinoma (PDAC).

Plasma small extracellular vesicles (sEV) from 106 participants, including 20 healthy controls (HC), 12 chronic pancreatitis (CP) patients, 12 benign pancreatic tumour (BPT) patients, and 58 PDAC patients, were profiled for microRNA (miRNA) sequencing. Three machine learning methods were applied to establish and evaluate the diagnostic model.

The plasma sEV miRNA diagnostic signature (d-signature) selected using the three machine learning methods could distinguish PDAC patients from non-PDAC individuals, HC, and benign pancreatic disease (BPD, CP plus BPT) both in training and validation cohort. Combining the d-signature with carbohydrate antigen 19-9 (CA19-9) performed better than with each model alone. Plasma sEV miR-664a-3p was selected by all methods and used to predict PDAC diagnosis with high accuracy combined with CA19-9. Plasma sEV miR-664a-3p was significantly positively associated with the presence of vascular invasion, lower surgery ratio, and poor differentiation. MiR-664a-3p was mainly distributed in the PDAC cancer stroma, including fibers and vessels, and was accompanied by VEGFA expression. Overexpression of miR-664a-3p could promote the epithelial-mesenchymal transition (EMT) and angiogenesis.

In conclusion, our study demonstrated the potential utility of the sEV-miRNA d-signature in the diagnosis of PDAC via machine learning methods. A novel sEV biomarker, miR-664a-3p, was identified for the diagnosis of PDAC. It can also potentially promote angiogenesis and metastasis, provide insight into PDAC pathogenesis, and reveal novel regulators of this disease.

The extent of both scientific articles and reviews on extracellular vesicles (EVs) has grown impressively over the last few decades [...].

Substantial research has been devoted to elucidating the role of extracellular vesicles (EVs) in the different hallmarks of cancer. Consequently, EVs are increasingly explored as a source of cancer biomarkers in body fluids. However, the heterogeneity in EVs, the complexity of body fluids, and the diversity in methods available for EV analysis, challenge the development and translation of EV-based biomarker assays.

Essential steps in EV-associated biomarker development are emphasized covering biobanking, biomarker discovery, verification and validation, and clinical implementation. A meticulous study design is essential and ideally results from close interactions between clinicians and EV researchers. A plethora of different EV preparation protocols exists which warrants quality control and transparency to ensure reproducibility and thus enable verification of EV-associated biomarker candidates identified in the discovery phase in subsequent independent cohorts. The development of an EV-associated biomarker assay requires thorough analytical and clinical validation. Finally, regulatory affairs must be considered for clinical implementation of EV-based biomarker assays.

In this review, the current challenges that prevent us from exploiting the full potential of EV-based biomarker assays are identified. Guidelines and tools to overcome these hurdles are highlighted and are crucial to advance EV-based biomarker assays into clinical use.

One of the biggest challenges in the fight against cancer is early detection. Early diagnosis is vital, but there are some barriers such as economic, cultural, and personal factors. Considering the disadvantages of radiological imaging techniques or serological analysis methods used in cancer diagnosis, such as being expensive, requiring expertise, and being time-consuming, there is a need to develop faster, more reliable, and cost-effective diagnostic methods for use in cancer diagnosis. Exosomes, which are responsible for intercellular communication with sizes ranging from 30-120 nm, are naturally produced biological nanoparticles. Thanks to the cargo contents they carry, they are a potential biomarker to be used in the diagnosis of cancer. Exosomes, defined as extracellular vesicles of endosomal origin, are effective in cancer growth, progression, metastasis, and drug resistance, and changes in microenvironmental conditions during tumor development change exosome secretion. Due to their high cellular activity, tumor cells produce much higher exosomes than healthy cells. Therefore, it is known that the number of exosomes in body fluids is significantly rich compared to other cells and can act as a stand-alone diagnostic biomarker. Cancer- derived exosomes have received great attention in recent years for the early detection of cancer and the evaluation of therapeutic response. In this article, the content, properties, and differences of exosomes detected in common types of cancer (lung, liver, pancreas, ovaries, breast, colorectal), which are the leading causes of cancer-related deaths, are reviewed. We also discuss the potential utility of exosome contents as a biomarker for early detection, which is known to be important in targeted cancer therapy.

Pancreatic ductal adenocarcinoma is one of the most lethal malignant diseases, with a mortality rate being close to incidence. Due to its heterogeneity and plasticity, as well as the lack of distinct symptoms in the early phases, it is very often diagnosed at an advanced stage, resulting in poor prognosis. Traditional tissue biopsies remain the gold standard for making a diagnosis, but have an obvious disadvantage in their inapplicability for frequent sampling. Blood-based biopsies represent a non-invasive method which potentially offers easy and repeated sampling, leading to the early detection and real-time monitoring of the disease and hopefully an accurate prognosis. Given the urgent need for a reliable biomarker that can estimate a patient's condition and response to an assigned treatment, blood-based biopsies are emerging as a potential new tool for improving patients' survival and surveillance. In this article, we discuss the current advances and challenges in using liquid biopsies for pancreatic cancer, focusing on circulating tumour DNA (ctDNA), extracellular vesicles (EVs), and circulating tumour cells (CTCs), and compare the performance and reliability of different biomarkers and combinations of biomarkers.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely deadly form of cancer, with limited progress in 5-year survival rates despite significant research efforts. The main challenges in treating PDAC include difficulties in early detection, and resistance to current therapeutic approaches due to aggressive molecular and microenvironment features. These challenges emphasize the importance of identifying clinically validated biomarkers for early detection and clinical management. Extracellular vesicles (EVs), particularly exosomes, have emerged as crucial mediators of intercellular communication by transporting molecular cargo. Recent research has unveiled their role in initiation, metastasis, and chemoresistance of PDAC. Consequently, utilizing EVs in liquid biopsies holds promise for the identification of biomarkers for early detection, prognosis, and monitoring of drug efficacy. However, numerous limitations, including challenges in isolation and characterization of homogeneous EVs populations, as well as the absence of standardized protocols, can affect the reliability of studies involving EVs as biomarkers, underscoring the necessity for a prudent approach. EVs have also garnered considerable attention as a promising drug delivery system and novel therapy for tumors. The loading of biomolecules or chemical drugs into exosomes and their subsequent delivery to target cells can effectively impede tumor progression. Nevertheless, there are obstacles that must be overcome to ensure the accuracy and efficacy of therapies relying on EVs for the treatment of tumors. In this review, we examine both recent advancements and remaining obstacles, exploring the potential of utilizing EVs in biomarker discovery as well as for the development of drug delivery vehicles.

Liquid biopsies have emerged as groundbreaking tools for minimally invasive monitoring of cancer, encompassing the analysis of Cell-Free DNA (cfDNA), circulating tumor DNA (ctDNA) and exosomes. This paradigm shift offers an emerging approach for understanding tumor dynamics, treatment responses, and disease progression. Leveraging advancements in molecular biology and technology, liquid biopsies enable clinicians to gain intricate insights from peripheral blood, thereby transforming the landscape of cancer care. This review describes the clinical impact, technological innovations, and recent evidence surrounding the integration of ctDNA and exosome analysis in cancer monitoring. Through early detection, real-time treatment response assessment, and the tracking of minimal residual disease, liquid biopsies have redefined the standards of precision oncology. Key advancements in ctDNA analysis, such as high-throughput sequencing and digital PCR, empower the detection of actionable mutations with high sensitivity. Concurrently, the characterization of exosomal cargo, facilitated by next-generation sequencing and mass spectrometry, unveils the molecular nuances of tumors. Recent studies underscore the utility of these approaches, demonstrating their efficacy in predicting relapse, guiding therapeutic decisions, and ultimately improving patient outcomes. As the field continues to evolve, liquid biopsies hold promise not only as diagnostic tools but also as agents of personalized medicine, enabling precise navigation of the intricate landscape of cancer with minimally invasiveness.

Extracellular vesicles (EV) carry their cargo in a membrane protected form, however, their value in early diagnostics is not well known. Although pancreatic cysts are heterogeneous, they can be clustered into the larger groups of pseudocysts (PC), and serous and mucinous pancreatic cystic neoplasms (S-PCN and M-PCN, respectively). In contrast to PCs and S-PCNs, M-PCNs may progress to malignant pancreatic cancers. Since current diagnostic tools do not meet the criteria of high sensitivity and specificity, novel methods are urgently needed to differentiate M-PCNs from other cysts. We show that cyst fluid is a rich source of EVs that are positive and negative for the EV markers CD63 and CD81, respectively. Whereas we found no difference in the EV number when comparing M-PCN with other pancreatic cysts, our EV-based biomarker identification showed that EVs from M-PCNs had a higher level of miR-200b. We also prove that not only EV-derived, but also total cyst fluid miR-200b discriminates patients with M-PCN from other pancreatic cysts with a higher sensitivity and specificity compared to other diagnostic methods, providing the possibility for clinical applications. Our results show that measuring miR-200b in cyst fluid-derived EVs or from cyst fluid may be clinically important in categorizing patients.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, primarily due to its propensity for metastasis. Patients diagnosed with localized primary cancer have higher survival rates than those with metastasis. Thus, it is imperative to discover biomarkers for the early detection of NSCLC and the timely prediction of tumor metastasis to improve patient outcomes.

Here, we utilized an integrated approach to isolate and characterize plasma exosomes from NSCLC patients as well as healthy individuals. We then conducted proteomics analysis and parallel reaction monitoring to identify and validate the top-ranked proteins of plasma exosomes.

Our study revealed that the proteome in exosomes from NSCLC patients with metastasis was distinctly different from that from healthy individuals. The former had larger diameters and lower concentrations of exosomes than the latter. Furthermore, among the 1220 identified exosomal proteins, we identified two distinct panels of biomarkers. The first panel of biomarkers (FGB, FGG, and VWF) showed potential for early NSCLC diagnosis and demonstrated a direct correlation with the survival duration of NSCLC patients. The second panel of biomarkers (CFHR5, C9, and MBL2) emerged as potential biomarkers for assessing NSCLC metastasis, of which CFHR5 alone was significantly associated with the overall survival of NSCLC patients.

These findings underscore the potential of plasma exosomal biomarkers for early NSCLC diagnosis and metastasis prediction. Notably, CFHR5 stands out as a promising prognostic indicator for NSCLC patients. The clinical utility of exosomal biomarkers offers the potential to enhance the management of NSCLC.

Pancreatic cancer (PC) has the greatest mortality rate of all the main malignancies. Its advanced stage and poor prognosis place it at the bottom of all cancer sites. Hence, emerging biomarkers can enable precision medicine where PC therapy is tailored to each patient. This highlights the need for new, highly sensitive and specific biomarkers for early PC diagnosis. Prognostic indicators are also required to stratify PC patients. To avoid ineffective treatment, adverse events, and expenses, biomarkers are also required for patient monitoring and identifying responders to treatment. There is substantial evidence that microRNAs (miRs, miRNAs) play a critical role in regulating mRNA and, as a consequence, protein expression in normal and malignant tissues. Deregulated miRNA profiling in PC can help with diagnosis, treatment planning, and prognosis. Furthermore, knowledge of the primary effector genes and downstream pathways in PC can help pinpoint potential miRNAs for use in treatment. Different miRNA expression profiles may serve as diagnostic, prognostic markers, and therapeutic targets across the spectrum of malignant pancreatic illness. Dysregulation of miRNAs has been linked to the malignant pathophysiology of PC through affecting many cellular functions such as increasing invasive and proliferative prospect, supporting angiogenesis, cell cycle aberrance, apoptosis elusion, metastasis promotion, and low sensitivity to particular treatments. Accordingly, in the current review, we summarize the recent advances in the roles of oncogenic and tumor suppressor (TS) miRNAs in PC and discuss their potential as worthy diagnostic and prognostic biomarkers for PC, as well as their significance in PC pathogenesis and anticancer drug resistance.

Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer alarmingly expanding in our modern societies that is still proving to be very challenging to counteract. This disease constitutes a quintessential example of the multiple interactions existing between the tumour and its surrounding microenvironment. In particular, PDAC is characterized by a very immunosuppressive environment that favours cancer growth and makes this cancer type very resistant to immunotherapy. The primary tumour releases many factors that influence both the microenvironment and the immune landscape. Extracellular vesicles (EVs), recently identified as indispensable entities ensuring cell-to-cell communication in both physiological and pathological processes, seem to play a pivotal function in ensuring the delivery of these factors to the tumour-surrounding tissues. In this review, we summarize the present understanding on the crosstalk among tumour cells and the cellular immune microenvironment emphasizing the pro-malignant role played by extracellular vesicles. We also discuss how a greater knowledge of the roles of EVs in tumour immune escape could be translated into clinical applications.

Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.

Gastrointestinal cancer remains a significant global health burden. The pursuit of advancing the comprehension of tumorigenesis, along with the identification of reliable biomarkers and the development of precise therapeutic strategies, represents imperative objectives in this field. Exosomes, small membranous vesicles released by most cells, commonly carry functional biomolecules, including noncoding RNAs (ncRNAs), which are specifically sorted and encapsulated by exosomes. Exosome-mediated communication involves the release of exosomes from tumor or stromal cells and the uptake by nearby or remote recipient cells. The bioactive cargoes contained within these exosomes exert profound effects on the recipient cells, resulting in significant modifications in the tumor microenvironment (TME) and distinct alterations in gastrointestinal tumor behaviors. Due to the feasibility of isolating exosomes from various bodily fluids, exosomal ncRNAs have shown great potential as liquid biopsy-based indicators for different gastrointestinal cancers, using blood, ascites, saliva, or bile samples. Moreover, exosomes are increasingly recognized as natural delivery vehicles for ncRNA-based therapeutic interventions. In this review, we elucidate the processes of ncRNA-enriched exosome biogenesis and uptake, examine the regulatory and functional roles of exosomal ncRNA-mediated intercellular crosstalk in gastrointestinal TME and tumor behaviors, and explore their potential clinical utility in diagnostics, prognostics, and therapeutics.

Pancreatic cancer (PC) is one of the most lethal human cancers. Currently, most PC cases are diagnosed at an already advanced stage. Early detection of PC is critical to improving survival rates. Therefore, there is an urgent need to identify biomarkers for the early detection of PC. Recently, circulating miRNAs in whole blood and other body fluids have been reported as promising biomarkers for the early detection of various cancers, including PC. Furthermore, due to minimal invasiveness and technical availability, circulating miRNAs hold promise for further wide usage. As a potential novel molecular marker, circulating miRNAs not only represent promising noninvasive diagnostic and prognostic tools but could also improve the evaluation of tumor classification, metastasis, and curative effect. The purpose of this review is to outline the available information regarding circulating miRNAs as biomarkers for the early detection of PC.

The use of blood-based biomarkers for the assessment of pancreatic cystic lesions is a rapidly growing field with incredible potential. CA 19-9 remains the only blood-based marker in common use, while many novel biomarkers are in early stages of development and validation. We highlight current work in the fields of proteomics, metabolomics, cell-free DNA/circulating tumor DNA, extracellular vesicles, and microRNA among others, as well as barriers to development and future directions in the work of blood-based biomarkers for pancreatic cystic lesions.