bims-exocan 2022-09-25 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022–09–25
24 papers selected by
Muhammad Rizwan, COMSATS University

The updated role of exosomal proteins in the diagnosis, prognosis, and treatment of cancer.
Emerging innovations on exosome-based onco-therapeutics.
Small Extracellular Vesicles and Their Involvement in Cancer Resistance: An Up-to-Date Review.
An Optimized Procedure for Proteomic Analysis of Extracellular Vesicles Using In-Stage Tip Digestion and DIA LC-MS/MS: Application to Liquid Biopsy in Cancer.
Current perspectives on clinical use of exosomes as novel biomarkers for cancer diagnosis.
The distinct roles of exosomes in innate immune responses and therapeutic applications in cancer.
Exosome-delivered circSATB2 targets the miR-330-5p/PEAK1 axis to regulate proliferation, migration and invasion of lung cancer cells.
Integrated microfluidic-SERS for exosome biomarker profiling and osteosarcoma diagnosis.
A review on exosomes application in clinical trials: perspective, questions, and challenges.
Feasibility of Leukemia-Derived Exosome Enrichment and Co-isolated dsDNA Sequencing in Acute Myeloid Leukemia Patients: A Proof of Concept for New Leukemia Biomarkers Detection.
miRNAs in prostate cancer: Intercellular and extracellular communications.
Artificial Intelligent Label-Free SERS Profiling of Serum Exosomes for Breast Cancer Diagnosis and Postoperative Assessment.
Isolation and analysis of tumor‑derived extracellular vesicles from head and neck squamous cell carcinoma plasma by galectin‑based glycan recognition particles.
Urinary exosomal long non-coding RNAs as noninvasive biomarkers for diagnosis of bladder cancer by RNA sequencing.
Harnessing the Therapeutic Potential of Exosomes: A Novel Strategy for Anticancer and Antiviral Therapy.
Salivary Exosomal miRNA-1307-5p Predicts Disease Aggressiveness and Poor Prognosis in Oral Squamous Cell Carcinoma Patients.
Exosomal microRNA-1 and MYO15A as a target for therapy and diagnosis in renal cell carcinoma.
Ceramide Metabolism Regulated by Sphingomyelin Synthase 2 Is Associated with Acquisition of Chemoresistance via Exosomes in Human Leukemia Cells.
Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment.
Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway.
Exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) enhances the docetaxel resistance of prostate cancer via the microRNA-136-5p/tribbles homolog 1 pathway.
Targeted inhibition of tumor-derived exosomes as a novel therapeutic option for cancer.
Composition, Biogenesis, and Role of Exosomes in Tumor Development.
Exosomal microRNA-506 inhibits biological activity of lung adenocarcinoma cells and increases sensitivity to cisplatin-based hyperthermia.

Exp Mol Med. 2022 Sep 22.

The updated role of exosomal proteins in the diagnosis, prognosis, and treatment of cancer.

Xinyi Wang, Jing Huang, Wenjie Chen, Genpeng Li, Zhihui Li, Jianyong Lei.

Exosomes are vesicles encompassed by a lipid bilayer that are released by various living cells. Exosomal proteins are encapsulated within the membrane or embedded on the surface. As an important type of exosome cargo, exosomal proteins can reflect the physiological status of the parent cell and play an essential role in cell-cell communication. Exosomal proteins can regulate tumor development, including tumor-related immune regulation, microenvironment reconstruction, angiogenesis, epithelial-mesenchymal transition, metastasis, etc. The features of exosomal proteins can provide insight into exosome generation, targeting, and biological function and are potential sources of markers for cancer diagnosis, prognosis, and treatment. Here, we summarize the effects of exosomal proteins on cancer biology, the latest progress in the application of exosomal proteins in cancer diagnosis and prognosis, and the potential contribution of exosomal proteins in cancer therapeutics and vaccines.

DOI: https://doi.org/10.1038/s12276-022-00855-4
Front Immunol. 2022 ;13 865245

Emerging innovations on exosome-based onco-therapeutics.

Xiaofeng Dai, Yongju Ye, Fule He.

  Exosomes, nano-sized extracellular vesicles for intercellular communications, are gaining rapid momentum as a novel strategy for the diagnosis and therapeutics of a spectrum of diseases including cancers. Secreted by various cell sources, exosomes pertain numerous functionalities from their parental cells and have enhanced stability that enable them with many features favorable for clinical use and commercialization. This paper focuses on the possible roles of exosomes in cancer therapeutics and reviews current exosome-based innovations toward enhanced cancer management and challenges that limit their clinical translation. Importantly, this paper casts insights on how cold atmospheric plasma, an emerging anticancer strategy, may aid in innovations on exosome-based onco-therapeutics toward improved control over cancers.

Keywords:  cancer; cold atmospheric plasma; exosome; immunotherapy; therapeutics

DOI:  https://doi.org/10.3389/fimmu.2022.865245
Cells. 2022 Sep 17. pii: 2913. [Epub ahead of print]11(18):

Small Extracellular Vesicles and Their Involvement in Cancer Resistance: An Up-to-Date Review.

Artur Słomka, Miroslaw Kornek, William C Cho.

  In recent years, tremendous progress has been made in understanding the roles of extracellular vesicles (EVs) in cancer. Thanks to advancements in molecular biology, it has been found that the fraction of EVs called exosomes or small EVs (sEVs) modulates the sensitivity of cancer cells to chemotherapeutic agents by delivering molecularly active non-coding RNAs (ncRNAs). An in-depth analysis shows that two main molecular mechanisms are involved in exosomal modified chemoresistance: (1) translational repression of anti-oncogenes by exosomal microRNAs (miRs) and (2) lack of translational repression of oncogenes by sponging of miRs through long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). At the cellular level, these processes increase the proliferation and survival of cancer cells and improve their ability to metastasize and resist apoptosis. In addition, studies in animal models have shown enhancing tumor size under the influence of exosomal ncRNAs. Ultimately, exosomal ncRNAs are responsible for clinically significant chemotherapy failures in patients with different types of cancer. Preliminary data have also revealed that exosomal ncRNAs can overcome chemotherapeutic agent resistance, but the results are thoroughly fragmented. This review presents how exosomes modulate the response of cancer cells to chemotherapeutic agents. Understanding how exosomes interfere with chemoresistance may become a milestone in developing new therapeutic options, but more data are still required.

Keywords:  chemoresistance; circular RNAs; exosomes; non-coding RNAs; small extracellular vesicles

DOI:  https://doi.org/10.3390/cells11182913
Methods Mol Biol. 2022 ;2546 401-409

An Optimized Procedure for Proteomic Analysis of Extracellular Vesicles Using In-Stage Tip Digestion and DIA LC-MS/MS: Application to Liquid Biopsy in Cancer.

Rajesh Kumar Soni, Lyssa Dimapanat, Manpreet S Katari, Alex J Rai.

  Utilizing biofluids to identify cancer biomarkers has received considerable attention in the past decade. In this regard, serum and urine are convenient biofluids to noninvasively recapitulate information usually indicated by traditional tissue biopsies. In particular, we are interested in exploring the extracellular vesicle (ECV)-containing compartment of these fluids as a targeted source for cancer biomarker discovery. ECVs are membrane-enclosed particles, comprising of various fractions including exosomes, microvesicles, and apoptotic bodies. In both physiological and pathological states such as cancer, ECVs carry a rich load of molecular and protein cargoes, which aid in mediating intercellular communication between cells from various tissue types. Here we successfully enriched ECVs using a simple, low-cost, optimized method that we have developed; it is generalizable for the analysis of ECVs from multiple sample types. Such procedures are necessary as ECVs are nanoparticles that contain a treasure trove of large numbers of biomarkers each present at very low levels. Sample processing procedures can enrich for these vesicles and allow for the enhanced detection of proteins in downstream applications such as comprehensive proteomics methods using data-independent acquisition (DIA) and LC-MS/MS.

Keywords:  Cancer; Data-independent acquisition; Exosomes; Extracellular vesicles; Liquid biopsy; Proteomics

DOI:  https://doi.org/10.1007/978-1-0716-2565-1_35
Front Oncol. 2022 ;12 966981

Current perspectives on clinical use of exosomes as novel biomarkers for cancer diagnosis.

Xiaomei Yi, Jie Chen, Defa Huang, Shuo Feng, Tong Yang, Zhengzhe Li, Xiaoxing Wang, Minghong Zhao, Jiyang Wu, Tianyu Zhong.

  Exosomes are a heterogeneous subset of extracellular vesicles (EVs) that biogenesis from endosomes. Besides, exosomes contain a variety of molecular cargoes including proteins, lipids and nucleic acids, which play a key role in the mechanism of exosome formation. Meanwhile, exosomes are involved with physiological and pathological conditions. The molecular profile of exosomes reflects the type and pathophysiological status of the originating cells so could potentially be exploited for diagnostic of cancer. This review aims to describe important molecular cargoes involved in exosome biogenesis. In addition, we highlight exogenous factors, especially autophagy, hypoxia and pharmacology, that regulate the release of exosomes and their corresponding cargoes. Particularly, we also emphasize exosome molecular cargoes as potential biomarkers in liquid biopsy for diagnosis of cancer.

Keywords:  biogenesis; biomarkers; diagnostics; exogenous factors; exosomes; extracellular vesicles (EVs); molecular cargoes; release

DOI:  https://doi.org/10.3389/fonc.2022.966981
Eur J Pharmacol. 2022 Sep 20. pii: S0014-2999(22)00553-2. [Epub ahead of print] 175292

The distinct roles of exosomes in innate immune responses and therapeutic applications in cancer.

Jafar Rezaie, Tahereh Etemadi, Maryam Feghhi.

  The innate immune system is one of the major constituents of the host's defense against invading pathogens and extracellular vesicles (EVs) are involved in regulating its responses. Exosomes, a subclass of EVs, released from eukaryotic cells, contribute to intracellular communication and drive various biological processes by transferring nuclei acids, proteins, lipids, and carbohydrates between cells, protecting cargo from enzymatic degradation and immune recognition and consequent elimination by the immune system. A growing body of evidence has revealed that exosomes produced from host cells, infected cells, tumor cells, and immune cells regulate innate immune signaling and responses and thus play a significant role in the propagation of pathogens. Immune cells can recognize exosomes-bearing components including DNA strands, viral RNAs, and even proteins by various mechanisms such as through Toll-like receptor/NF-κB signaling, inducing cytokine production and reprogramming the innate immune responses, immunosuppression or immunesupportive. There is persuasive preclinical and clinical evidence that exosomes are therapeutic strategies for immunotherapy, cancer vaccine, drug-delivery system, and diagnostic biomarker. However, further scrutiny is essential to validate these findings. In this review, we describe the current facts on the regulation of innate immune responses by exosomes. We also describe the translational application of exosomes as cancer-therapy agents and immunotherapy.

Keywords:  Exosomes; Extracellular vesicles; Immunotherapy; Innate immune system

DOI:  https://doi.org/10.1016/j.ejphar.2022.175292
Thorac Cancer. 2022 Sep 23.

Exosome-delivered circSATB2 targets the miR-330-5p/PEAK1 axis to regulate proliferation, migration and invasion of lung cancer cells.

Jun Zhu, Fudong Wang, Yuan Weng, Jun Zhao.

  Exosomes can carry various kinds of RNAs to mediate intercellular communication. Circular RNA (circRNA) special AT-rich sequence-binding protein 2 (circSATB2) was identified as an oncogene in lung cancer. This study was performed to explore the association of circSATB2 with exosomes and the regulatory mechanism of circSATB2. Exosomes could transmit circSATB2 into lung cancer cells. Exosomes enhanced cell proliferation, invasion, and migration by carrying circSATB2. Exosomal circSATB2 abrogated the inhibitory effect of short hairpin (sh)-circSATB2 on lung cancer progression. Moreover, circSATB2 promoted tumor growth in vivo via exosomes. CircSATB2 interacted with microRNA-330-5p (miR-330-5p) and miR-330-5p targeted pseudopodium enriched atypical kinase 1 (PEAK1). In addition, circSATB2 affected the PEAK1 level via sponging miR-330-5p in lung cancer cells. All results suggested that exosomal transfer of circSATB2 contributed to the malignant development of lung cancer by acting as a sponge of miR-330-5p to upregulate PEAK1.

Keywords:  PEAK1; circSATB2; exosomes; lung cancer; miR-330-5p

DOI:  https://doi.org/10.1111/1759-7714.14652
Biosens Bioelectron. 2022 Sep 11. pii: S0956-5663(22)00749-7. [Epub ahead of print]217 114709

Integrated microfluidic-SERS for exosome biomarker profiling and osteosarcoma diagnosis.

Zhenzhen Han, Xinyan Peng, Yi Yang, Jia Yi, Dan Zhao, Qiyuan Bao, Shuping Long, Sai-Xi Yu, Xin-Xin Xu, Baohong Liu, Yan-Jun Liu, Yuhui Shen, Liang Qiao.

  Osteosarcoma is one of the most frequent primary sarcoma of bone among adolescents. Early diagnosis of osteosarcoma is the key factor to achieve high survival rate of patients. Nevertheless, traditional histological biopsy is highly invasive and associated with the risk of arousing tumor spread. Herein, we develop a method integrating microfluidics and surface-enhanced Raman spectroscopy (SERS) to isolate plasma-derived exosomes and profile multiple exosomal biomarkers for the diagnosis of osteosarcoma. The method showed highly efficient isolation of exosomes directly from human plasma and can profile exosomes based on protein biomarkers, with the detection limit down to 2 exosomes per μL. The whole assay can be performed in 5 h and only consumed 50 μL of plasma for one analysis. With the method, we analyzed the level of three protein biomarkers, i.e., CD63, vimentin (VIM) and epithelial cell adhesion molecule (EpCAM), on plasma-derived exosomes from 20 osteosarcoma patients and 20 heathy controls. Significantly higher levels of CD63, VIM and EpCAM were observed on plasma exosomes from the osteosarcoma patients compared to the healthy controls. Based on the level of the exosomal biomarkers, a classification model was built for the rapid diagnosis of osteosarcoma, with the sensitivity, specificity and accuracy of 100%, 90% and 95%, respectively. The proposed method does not require complex operations nor expensive equipment, and has great promise in clinical diagnosis of cancer as a liquid biopsy technique.

Keywords:  Cancer diagnosis; Exosome; Microfluidic chip; Protein biomarkers; SERS

DOI:  https://doi.org/10.1016/j.bios.2022.114709
Cell Commun Signal. 2022 Sep 19. 20(1): 145

A review on exosomes application in clinical trials: perspective, questions, and challenges.

Jafar Rezaie, Maryam Feghhi, Tahereh Etemadi.

   BACKGROUND: Exosomes are progressively known as significant mediators of cell-to-cell communication. They convey active biomolecules to target cells and have vital functions in several physiological and pathological processes, and show substantial promise as novel treatment strategies for diseases.
METHODS: In this review study, we studied numerous articles over the past two decades published on application of exosomes in different diseases as well as on perspective and challenges in this field.
RESULTS: The main clinical application of exosomes are using them as a biomarker, cell-free therapeutic agents, drug delivery carriers, basic analysis for exosome kinetics, and cancer vaccine. Different exosomes from human or plant sources are utilized in various clinical trials. Most researchers used exosomes from the circulatory system for biomarker experiments. Mesenchymal stem cells (MSCs) and dendritic cells (DCs) are two widely held cell sources for exosome use. MSCs-derived exosomes are commonly used for inflammation treatment and drug delivery, while DCs-exosomes are used to induce inflammation response in cancer patients. However, the clinical application of exosomes faces various questions and challenges. In addition, translation of exosome-based clinical trials is required to conform to specific good manufacturing practices (GMP). In this review, we summarize exosomes in the clinical trials according to the type of application and disease. We also address the main questions and challenges regarding exosome kinetics and clinical applications.
CONCLUSIONS: Exosomes are promising platforms for treatment of many diseases in clinical trials. This exciting field is developing hastily, understanding of the underlying mechanisms that direct the various observed roles of exosomes remains far from complete and needs further multidisciplinary research in working with these small vesicles. Video Abstract.

Keywords:  Clinical trials; Exosome therapy; Exosomes; Extracellular vesicles

DOI:  https://doi.org/10.1186/s12964-022-00959-4
Cancers (Basel). 2022 Sep 16. pii: 4504. [Epub ahead of print]14(18):

Feasibility of Leukemia-Derived Exosome Enrichment and Co-isolated dsDNA Sequencing in Acute Myeloid Leukemia Patients: A Proof of Concept for New Leukemia Biomarkers Detection.

Simona Bernardi, Mirko Farina, Katia Bosio, Anna Di Lucanardo, Alessandro Leoni, Federica Re, Nicola Polverelli, Alessandro Turra, Enrico Morello, Eugenia Accorsi Buttini, Tatiana Zollner, Cristian Bonvicini, Michele Malagola, Domenico Russo.

  Exosomes are extracellular vesicles playing a pivotal role in the intercellular communication. They shuttle different cargoes, including nucleic acids from their cell of origin. For this reason, they have been studied as carriers of tumor markers in different liquid biopsy approaches, in particular for solid tumors. Few data are available concerning exosomes as markers of myeloid neoplasia. To better understand their real potential and the best approach to investigate leukemic exosomes, we present the results of a pilot feasibility study evaluating the application of next-generation sequencing analysis of dsDNA derived from exosomes isolated in 14 adult patients affected by acute myeloid leukemias. In particular, leukemia-derived exosome fractions have been analyzed. The concentration of dsDNA co-extracted with exosomes and the number and types of mutations detected were considered and compared with ones identified in the Bone Marrow (BM) and Peripheral Blood (PB) cells. Exosomal DNA concentration, both considering the cargo and the DNA surrounding the lipid membrane resulted in a linear correlation with leukemic burden. Moreover, exosomal DNA mutation status presented 86.5% of homology with BM and 75% with PB. The results of this pilot study confirmed the feasibility of a leukemia-derived exosome enrichment approach followed by exosomal dsDNA NGS analysis for AML biomarker detection. These data point to the use of liquid biopsy in myeloid neoplasia for the detection of active leukemic cells resident in the BM via a painless procedure.

Keywords:  acute myeloid leukemia; cell of origin enrichment; exosomal DNA; exosomes; extracellular vesicles; liquid biopsy; next-generation sequencing

DOI:  https://doi.org/10.3390/cancers14184504
Int J Urol. 2022 Sep 19.

miRNAs in prostate cancer: Intercellular and extracellular communications.

Fumihiko Urabe, Yusuke Yamamoto, Takahiro Kimura.

  Prostate cancer is the most prevalent male cancer in Western Europe and North America. Although new drugs were recently approved, clinical challenges such as accurately predicting and screening drug-resistant prostate cancer remain. microRNAs are short noncoding RNA molecules that participate in gene regulation at the post-transcriptional level by targeting messenger RNAs. There is accumulating evidence that intracellular microRNAs play important roles as promoters or inhibitors of prostate cancer progression. Additionally, recent studies showed that microRNAs are encapsulated in extracellular vesicles and shuttled into the extracellular space. Transfer of extracellular microRNAs contributes to intercellular communication between prostate cancer cells and components of the tumor microenvironment, which can promote prostate cancer progression. Furthermore, due to their encapsulation in extracellular vesicles, extracellular microRNAs can be stably present in body fluids which contain high levels of RNase. Thus, circulating microRNAs have great potential as noninvasive diagnostic and prognostic biomarkers for prostate cancer. Here, we summarize the roles of intracellular and extracellular microRNAs in prostate cancer progression and discuss the potential of microRNA-based therapeutics as a novel treatment strategy for prostate cancer.

Keywords:  cancer biology; circulating miRNAs; extracellular vesicles; miRNA; prostate cancer

DOI:  https://doi.org/10.1111/iju.15043
Nano Lett. 2022 Sep 23.

Artificial Intelligent Label-Free SERS Profiling of Serum Exosomes for Breast Cancer Diagnosis and Postoperative Assessment.

Yangcenzi Xie, Xiaoming Su, Yu Wen, Chao Zheng, Ming Li.

  Breast cancer subtypes have important implications of treatment responses and clinical outcomes. Exosomes have been considered as promising biomarkers for liquid biopsies, but the utility of exosomes for accurate diagnosis of distinct breast cancer subtypes is a grand challenge due to the difficulty in uncovering the subtle compositional difference in complex clinical settings. Herein, we report an artificial intelligent surface-enhanced Raman spectroscopy (SERS) strategy for label-free spectroscopic analysis of serum exosomes, allowing for accurate diagnosis of breast cancer and assessment of surgical outcomes. Our deep learning algorithm trained with SERS spectra of cancer cell-derived exosomes is demonstrated with a 100% prediction accuracy for human patients with different breast cancer subtypes who do not undergo surgery using SERS spectra of serum exosomes. Furthermore, when combined with similarity analysis by principal component analysis, our approach is able to evaluate the surgical outcomes of breast cancer of distinct molecular subtypes.

Keywords:  artificial intelligence; breast cancer subtypes; exosomes; liquid biopsy; surface-enhanced Raman spectroscopy

DOI:  https://doi.org/10.1021/acs.nanolett.2c02928
Int J Oncol. 2022 Nov;pii: 133. [Epub ahead of print]61(5):

Isolation and analysis of tumor‑derived extracellular vesicles from head and neck squamous cell carcinoma plasma by galectin‑based glycan recognition particles.

Laura Benecke, Dapi Menglin Chiang, Eliane Ebnoether, Michael W Pfaffl, Laurent Muller.

  Extracellular vesicles (EVs) have recently come into the spotlight as potential cancer biomarkers. Isolation of pure EVs is complex, so wider use requires reliable and time‑efficient isolation methods. In the present study, galectin‑based magnetic glycan recognition particles, EXÖBead® were investigated for their practicality as a novel EV isolation technique, exemplified here for squamous cell carcinoma of the head and neck. Analysis of the isolation method showed a high concentration of pure EVs with detection of specific EV markers such as CD9, CD63, CD81 and TSG101. No apolipoprotein A1 was shown in the isolates, indicating low contamination of this isolation technique compared with size exclusion chromatography. In addition, common leukocyte antigen (CD45), three HNSCC [epithelial cell adhesion molecule (EpCAM), pan‑cytokeratin and programmed death‑ligand 1 (PD‑L1)] and PanEV markers (premixed CD9, CD63 and CD81 antibodies) were measured by bead‑based flow cytometry (BFC). BFC revealed that CD45Neg PanEV+, EpCAM+ PanEV+ and PD‑L1+ PanEV+ were significantly higher in tumor patients compared with healthy control plasma. CD45Neg PanEV+ and CD45+ PanEV+ carrying two or three HNSCC biomarkers were also significantly higher in tumor patients compared with healthy controls (BFC). Comparison of the functional immunosuppression effect of eluted tumor patient plasma EVs from EXÖBead® and commercial polyethylene glycol isolation showed a significant tumor‑dependent increase in concentration of EVs. A peripheral blood mononuclear cell activation assay also showed that the T‑cell functionality of tumor patient plasma EVs isolated with EXÖBead® was preserved in vitro. In conclusion, isolation using galectin‑based magnetic glycan recognition particles is a novel method for isolating plasma EVs with low lipoprotein contamination. Bead‑based flow cytometry provided an easy way to understand EV subpopulations. EXÖBead® therefore showed great potential as a new isolation tool with high throughput capacity that could potentially be used in a clinical setting.

Keywords:  beads‑based flow cytometry; biomarker; exosomes; extracellular vesicles; galectin‑based glycan recognition particles; head and neck squamous cell carcinoma; novel isolation technique; tumor‑derived extracellular vesicles

DOI:  https://doi.org/10.3892/ijo.2022.5423
Front Oncol. 2022 ;12 976329

Urinary exosomal long non-coding RNAs as noninvasive biomarkers for diagnosis of bladder cancer by RNA sequencing.

Bingxian Bian, Li Li, Xing Ke, Hui Chen, Yi Liu, Naisheng Zheng, Yingxia Zheng, Yanhui Ma, Yunlan Zhou, Junyao Yang, Lanshu Xiao, Lisong Shen.

   Introduction: Cystoscopy is the standard methodology for diagnosis of bladder cancer (BC), but it is invasive and relatively expensive. Previous studies have found that urinary exosomal long non-coding RNAs (lncRNAs) may act as potential noninvasive biomarkers for diagnosis. Here we identified urinary exosomal lncRNAs that are differentially expressed between BC and controls, and established a panel for diagnosis of BC.
Methods: We performed RNA sequencing in urinary exosomes of 7 controls and 7 patients, subsequently the differentially expressed lncRNAs were detected in training cohort (50 controls and 50 patients) and validation cohort (43 controls and 43 patients). The diagnostic power of lncRNAs for BC was calculated by the area under curve (AUC). The panel for diagnosis of BC was calculated by logistic regression.
Results: The results of RNA sequencing in urinary exosomes showed that 240 upregulated lncRNAs and 275 downregulated lncRNAs were differentially expressed. The levels of MKLN1-AS, TALAM1, TTN-AS1 and UCA1 in BC patients were higher than that in controls in the training and validation cohort by real-time PCR. Using logistic regression, with the combination of these four lncRNAs and NMP22, we identified a panel of five parameters capable of classifying BC patients versus controls on the basis of the training cohort (AUC=0.850). Moreover, the performance of the panel exhibited better performance than either single parameter in the validation cohort.
Conclusion: Collectively, this study confirmed the diagnostic value of lncRNAs for BC by high-throughout urinary exosomal RNA sequencing.

Keywords:  RNA sequencing; bladder cancer; diagnosis; long non-coding RNAs; urinary exosomes

DOI:  https://doi.org/10.3389/fonc.2022.976329
Biomed Res Int. 2022 ;2022 3356467

Harnessing the Therapeutic Potential of Exosomes: A Novel Strategy for Anticancer and Antiviral Therapy.

Njinju Asaba Clinton, Nkembi-Leke Joshua Ageboh, Baie Decler Nkache, Ebamu Sylvia Mencha, Asonganyi Aminkeng, Ewalu Justa Ndobegang, Esembieng Mencha Ivo, Simaa Rene Vigha, Cyril Jabea Ekabe.

Exosomes are extracellular membrane bound vesicles released from almost all cell types and can be retrieved from all body fluids. The molecular constituents of these extracellular bodies vary depending on their cell of origin, from which they can transport molecules such as DNA, RNA, proteins lipids, and several metabolites. They have been shown to execute several functions such as in cell growth, migration, differentiation, neuronal signaling, immune cell modulation, and some diseases such as cancer through intercellular communication and signaling. They are also described to act as key players in viral persistence and dissemination. Due to their ability to elicit potent cellular responses, high level of tolerance in host cells, and high efficiency in penetrating other cells, they are proposed to be potential therapeutics as well as vehicles for drug delivery. In recent years, several studies have been conducted in quest for the development of an effective anticancer therapy or antiviral therapy against highly persistent viruses. However, most of these studies become halted due to failure to achieve desired therapeutic outcomes. Nevertheless, the in vitro/in vivo application of exosomes in tumor and infectious disease diagnosis and therapy is prospective. This review discusses the role of exosomes as predictive markers for immune activation and potential targets for anticancer/antiviral therapies.

DOI: https://doi.org/10.1155/2022/3356467
Int J Mol Sci. 2022 Sep 13. pii: 10639. [Epub ahead of print]23(18):

Salivary Exosomal miRNA-1307-5p Predicts Disease Aggressiveness and Poor Prognosis in Oral Squamous Cell Carcinoma Patients.

Aditi Patel, Shanaya Patel, Parina Patel, Dushyant Mandlik, Kaustubh Patel, Vivek Tanavde.

  Background: Salivary exosomal miRNAs as biomarkers facilitate repeated sampling, real-time disease monitoring and assessment of therapeutic response. This study identifies a single salivary exosomal miRNA prognosticator that will aid in improved patient outcome using a liquid biopsy approach. Method: Small RNA and transcriptome sequencing profiles of tumour tissues (n = 12) and salivary exosomes (n = 8) from oral cancer patients were compared to their non-cancerous counterparts. We validated these results using The Cancer Genome Atlas database and performing Real-time PCR on a large patient cohort (n = 19 tissue samples; n = 12 salivary exosomes). Potential target genes and the miRNA-mRNA networks and enriched biological pathways regulated by this microRNA were identified using computational tools. Results: Salivary exosomes (size: 30-50 nm) demonstrated a strong expression of CD47 and detectable expression of tetraspanins CD63, CD81 and CD9 by flow cytometry. miR-1307-5p was exclusively overexpressed in tissues and salivary exosomes of oral cancer patients compared to their non-cancerous counterparts. Enhanced expression of miR-1307-5p clinically correlated with poor patient survival, disease progression, aggressiveness and chemo-resistance. Transcriptome analysis suggested that miRNA-1307-5p could promote oral cancer progression by suppressing THOP1, EHF, RNF4, GET4 and RNF114. Conclusions: Salivary exosomal miRNA-1307-5p is a potential prognosticator for predicting poor survival and poor patient outcome in oral cancers.

Keywords:  chemoresistance; exosomes; microRNAs; oral cancer; prognosis; saliva

DOI:  https://doi.org/10.3390/ijms231810639
Biochem Biophys Res Commun. 2022 Sep 16. pii: S0006-291X(22)01311-0. [Epub ahead of print]630 71-76

Exosomal microRNA-1 and MYO15A as a target for therapy and diagnosis in renal cell carcinoma.

Hirofumi Yoshino, Shuichi Tatarano, Motoki Tamai, Masafumi Tsuruda, Sayaka Iizasa, Junya Arima, Issei Kawakami, Wataru Fukumoto, Ichiro Kawahara, Gang Li, Takashi Sakaguchi, Satoru Inoguchi, Yasutoshi Yamada, Hideki Enokida.

  Exosomes are 40-100 nm nano-sized extracellular vesicles and are receiving increasing attention as novel structures that participate in intracellular communication. We previously found that miRNA-1 (miR-1) functions as a tumor suppressor in renal cell carcinoma (RCC). In this study, we investigated the function of exosomal miR-1 and the possibility that the exosome constitutes a tumor maker in RCC. First, we established the method to collect exosomes from cell lysates and human serum by a spin column-based method. Next, we assessed exosomes using Nanosight nanoparticle tracking analysis and Western blot analysis with exosome marker CD63. We confirmed that exosomes labeled with PKH26 fused with recipient cells. Moreover, miR-1 expression was elevated in RCC cells treated with exosomes derived from miR-1-transfected cells. Functional analyses showed that exosomal miR-1 significantly inhibited cell proliferation, migration and invasion compared to control treatment. Our analyses with TCGA database of RCCs showed that miR-1 expression was significantly downregulated in clinical RCC samples compared to that in normal kidney samples, and patients with low miR-1 expression had poorer overall survival in comparison to patients with high expression. Furthermore, RNA sequence analyses showed that expression levels of several genes were altered by exposure to exosomal miR-1. The analyses with TCGA database indicated that high expression of MYO15A was associated with a poorer outcome in RCC. In addition, RT-qPCR analysis of exosomes from clinical patients' sera showed that MYO15A was significantly upregulated in RCC patients compared to that in healthy controls. This study showed that treatment with exosomal miR-1 might be an effective approach to treating RCCs. In addition, exosomal MYO15A could be a diagnostic tumor marker in RCCs.

Keywords:  Exosome; MYO15A; Renal cell carcinoma; miR-1

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.056
Int J Mol Sci. 2022 Sep 13. pii: 10648. [Epub ahead of print]23(18):

Ceramide Metabolism Regulated by Sphingomyelin Synthase 2 Is Associated with Acquisition of Chemoresistance via Exosomes in Human Leukemia Cells.

Makoto Taniguchi, Shingo Nagaya, Kohei Yuyama, Ai Kotani, Yasuyuki Igarashi, Toshiro Okazaki.

  Ceramide levels controlled by the sphingomyelin (SM) cycle have essential roles in cancer cell fate through the regulation of cell proliferation, death, metastasis, and drug resistance. Recent studies suggest that exosomes confer cancer malignancy. However, the relationship between ceramide metabolism and exosome-mediated cancer malignancy is unclear. In this study, we elucidated the role of ceramide metabolism via the SM cycle in exosomes and drug resistance in human leukemia HL-60 and adriamycin-resistant HL-60/ADR cells. HL-60/ADR cells showed significantly increased exosome production and release compared with parental chemosensitive HL-60 cells. In HL-60/ADR cells, increased SM synthase (SMS) activity reduced ceramide levels, although released exosomes exhibited a high ceramide ratio in both HL-60- and HL-60/ADR-derived exosomes. Overexpression of SMS2 but not SMS1 suppressed intracellular ceramide levels and accelerated exosome production and release in HL-60 cells. Notably, HL-60/ADR exosomes conferred cell proliferation and doxorubicin resistance properties to HL-60 cells. Finally, microRNA analysis in HL-60 and HL-60/ADR cells and exosomes showed that miR-484 elevation in HL-60/ADR cells and exosomes was associated with exosome-mediated cell proliferation. This suggests that intracellular ceramide metabolism by SMS2 regulates exosome production and release, leading to acquisition of drug resistance and enhanced cell proliferation in leukemia cells.

Keywords:  ceramide; doxorubicin; drug resistance; exosome; leukemia; miR-484; microRNA; sphingomyelin; sphingomyelin synthase

DOI:  https://doi.org/10.3390/ijms231810648
Cancers (Basel). 2022 Sep 11. pii: 4412. [Epub ahead of print]14(18):

Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment.

Luis O González, Noemi Eiro, Maria Fraile, Nana Beridze, Andres R Escaf, Safwan Escaf, Jesús M Fernández-Gómez, Francisco J Vizoso.

  Prostate cancer (PCa) is a common cancer among males globally, and its occurrence is growing worldwide. Clinical decisions about the combination of therapies are becoming highly relevant. However, this is a heterogeneous disease, ranging widely in prognosis. Therefore, new approaches are needed based on tumor biology, from which further prognostic assessments can be established and complementary strategies can be identified. The knowledge of both the morphological structure and functional biology of the PCa stroma compartment can provide new diagnostic, prognostic or therapeutic possibilities. In the present review, we analyzed the aspects related to the tumor stromal component (both acellular and cellular) in PCa, their influence on tumor behavior and the therapeutic response and their consideration as a new therapeutic target.

Keywords:  biochemical recurrence in prostate cancer; cancer-associated fibroblasts; exosomes; extracellular vesicles; mesenchymal stromal cells; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14184412
World J Emerg Med. 2022 ;13(5): 379-385

Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway.

Xiao-Hu Zhou, Hao Xu, Chang Xu, Ying-Cai Yan, Lin-Shi Zhang, Qiang Sun, Wei-Lin Wang, Yan-Jun Shi.

   BACKGROUND: Exosomes and exosomal microRNAs have been implicated in tumor occurrence and metastasis. Our previous study showed that microRNA-761 (miR-761) is overexpressed in hepatocellular carcinoma (HCC) tissues and that its inhibition affects mitochondrial function and inhibits HCC metastasis. The mechanism by which exosomal miR-761 modulates the tumor microenvironment has not been elucidated.
METHODS: Exosomal miR-761 was detected in six cell lines. Cell counting kit-8 (CCK-8) and transwell migration assays were performed to determine the function of exosomal miR-761 in HCC cells. The luciferase reporter assay was used to analyze miR-761 target genes in normal fibroblasts (NFs). The inhibitors AZD1480 and C188-9 were employed to determine the role of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the transformation of cancer-associated fibroblasts (CAFs).
RESULTS: In this study, we characterized the mechanism by which miR-761 reprogrammed the tumor microenvironment. We found that HCC-derived exosomal miR-761 was taken up by NFs. Moreover, HCC exosomes affected the tumor microenvironment by activating NFs via suppressor of cytokine signaling 2 (SOCS2) and the JAK2/STAT3 signaling pathway.
CONCLUSIONS: These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs. Our findings may inspire new strategies for HCC prevention and therapy.

Keywords:  Exosomes; Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway; Suppressor of cytokine signaling 2; Tumor microenvironment; microRNA-761

DOI:  https://doi.org/10.5847/wjem.j.1920-8642.2022.089
Anticancer Drugs. 2022 Oct 01. 33(9): 871-882

Exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) enhances the docetaxel resistance of prostate cancer via the microRNA-136-5p/tribbles homolog 1 pathway.

Xiaoliang Tan, Xiaosen Song, Bo Fan, Ming Li, Aili Zhang, Long Pei.

Exosomal circular RNA was found to mediate cancer chemoresistance. However, whether exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) was involved in the chemoresistance of prostate cancer (PCa) remains unclear. The docetaxel (DTX) resistance of PCa cells was analyzed by Cell Counting Kit 8 assay. Quantitative real-time PCR was used to measure circSFMBT2, microRNA (miR)-136-5p and tribbles homolog 1 (TRIB1) expression. Cell proliferation, apoptosis, migration and invasion were analyzed by 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, wound-healing assay and transwell assay. RNA interaction was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Protein expression was measured by western blot analysis. Exosomes-extracted from cells were identified by transmission electron microscope, nanoparticles tracking analysis and western blot. Xenograft mice models were constructed to analyze the effect of exosomal circSFMBT2 on the DTX sensitivity of PCa tumors in vivo. CircSFMBT2 was upregulated in DTX-resistant PCa cells, and its knockdown enhanced the DTX sensitivity of DTX-resistant PCa cells by suppressing cell proliferation, migration, invasion and enhancing apoptosis. CircSFMBT2 severed as miR-136-5p sponge to positively regulate TRIB1. The regulation of circSFMBT2 knockdown on the DTX sensitivity of DTX-resistant PCa cells could be reversed by miR-136-5p inhibitor or TRIB1 overexpression. Exosomal circSFMBT2 from DTX-resistant PCa could increase the DTX resistance of normal PCa cells. In addition, exosomal circSFMBT2 also enhanced the DTX resistance of PCa tumors in vivo, and it was highly expressed in the serum of DTX-resistance PCa patients. Exosomal circSFMBT2 enhanced the DTX resistance of PCa by miR-136-5p/TRIB1 axis, indicating that circSFMBT2 might be a potential target for the treatment of PCa chemoresistance.

DOI: https://doi.org/10.1097/CAD.0000000000001365
Exp Mol Med. 2022 Sep 18.

Targeted inhibition of tumor-derived exosomes as a novel therapeutic option for cancer.

Ye Li, Zhuo-Kun Chen, Xu Duan, He-Jing Zhang, Bo-Lin Xiao, Kui-Ming Wang, Gang Chen.

Mounting evidence indicates that tumor-derived exosomes (TDEs) play critical roles in tumor development and progression by regulating components in the tumor microenvironment (TME) in an autocrine or paracrine manner. Moreover, due to their delivery of critical molecules that react to chemotherapy and immunotherapy, TDEs also contribute to tumor drug resistance and impede the effective response of antitumor immunotherapy, thereby leading to poor clinical outcomes. There is a pressing need for the inhibition or removal of TDEs to facilitate the treatment and prognosis of cancer patients. Here, in the present review, we systematically overviewed the current strategies for TDE inhibition and clearance, providing novel insights for future tumor interventions in translational medicine. Moreover, existing challenges and potential prospects for TDE-targeted cancer therapy are also discussed to bridge the gaps between progress and promising applications.

DOI: https://doi.org/10.1038/s12276-022-00856-3
Stem Cells Int. 2022 ;2022 8392509

Composition, Biogenesis, and Role of Exosomes in Tumor Development.

Leila Moeinzadeh, Iman Razeghian-Jahromi, Zeinab Zarei-Behjani, Zohreh Bagheri, Mahboobeh Razmkhah.

The role of exosomes and their mechanism of action at the tumor site have received increasing attention. These microvesicles are produced by a wide range of cells including mesenchymal stem cells (MSCs) and immune cells. In particular, tumor cells release remarkable amounts of exosomes which spread to distant organs through the blood and enhance the possibility of tumor metastasis. In spite of results on tumor promoting properties, there are reports demonstrating the tumor inhibiting effects of exosomes depending on the type of the tumor and cell source. This review aims to have a comprehensive appraisal on the biogenesis, composition, and isolation of exosomes and then highlights the current knowledge of their role in cancer progression or inhibition by special focusing on MSC's exosomes (MSC-EXOs).

DOI: https://doi.org/10.1155/2022/8392509
Cell Signal. 2022 Sep 14. pii: S0898-6568(22)00231-5. [Epub ahead of print] 110469

Exosomal microRNA-506 inhibits biological activity of lung adenocarcinoma cells and increases sensitivity to cisplatin-based hyperthermia.

Kunming Zhang, Xiwen Sun, Weikai Sun, Meng Wang, Fushi Han.

  Exosomal microRNAs (miRNAs) play a vital role in the occurrence and development of lung adenocarcinoma (LUAD). Based on the bioinformatics analyses, the current study sought to explore the effects of exosomal miR-506 on LUAD cell biology and the efficacy of cisplatin (CDDP)-based hyperthermia (HT). After sample preparation, we identified decreased miR-506 and elevated ATAD2. LUAD cells were subsequently transfected with miR-506 mimic, oe-ATAD2 and PI3K/AKT signaling pathway inhibitor LY294002 to analyze effects of the miR-506/ATAD2/PI3K/AKT axis on cell biological processes and chemoresistance. Effects of exosomal miR-506 on sensitivity of LUAD cells to CDDP-based HT were further assessed in a co-culture system of BMSC-derived exosomes and LUAD cells, which was also validated in tumor-bearing nude mice. miR-506 down-regulated ATAD2 to inhibit the PI3K/AKT signaling pathway, thereby inhibiting the malignant phenotypes of LUAD cells and augmenting LUAD cell sensitivity to CDDP-based HT. Further, BMSCs-derived exosomes harboring miR-506 sensitized LUAD cells to DDP/HT both in vitro and in vivo. Collectively, our findings revealed that exosomal miR-506 sensitized LUAD cells to CDDP-based HT by inhibiting ATAD2/PI3K/AKT signaling pathway, offering a potential therapeutic target for LUAD treatment.

Keywords:  ATPase family AAA domain-containing protein 2; Cisplatin-based hyperthermia; Exosome; Lung adenocarcinoma; MicroRNA-506; Phosphatidylinositol 3-kinase/protein kinase B signaling pathway

DOI:  https://doi.org/10.1016/j.cellsig.2022.110469