bims-exocan 2022-08-28 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022–08–28
37 papers selected by
Muhammad Rizwan, COMSATS University

Exosomes at the crossroad between therapeutic targets and therapy resistance in head and neck squamous cell carcinoma.
Liquid Biopsy and Circulating Biomarkers for the Diagnosis of Precancerous and Cancerous Oral Lesions.
Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma.
Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion.
Ultrasensitive Detection of GRP78 in Exosomes and Observation of Migration and Proliferation of Cancer Cells by Application of GRP78-Containing Exosomes.
Extruded small extracellular vesicles: splinters of circulating tumour cells may promote cancer metastasis?
Electrochemical nano biosensors for the detection of extracellular vesicles exosomes: From the benchtop to everywhere?
Role of Exosomes in Immunotherapy of Hepatocellular Carcinoma.
Exosome-based strategies for diagnosis and therapy of glioma cancer.
Introduction of Nanomaterials to Biosensors for Exosome Detection: Case Study for Cancer Analysis.
Exosomal mir-625-3p derived from hypoxic lung cancer cells facilitates metastasis by targeting SCAI.
The Immunomodulatory Role of Hypoxic Tumor-Derived Extracellular Vesicles.
Exosomes: Small Vesicles with Important Roles in the Development, Metastasis and Treatment of Breast Cancer.
Extracellular vesicle-packaged miR-181c-5p from epithelial ovarian cancer cells promotes M2 polarization of tumor-associated macrophages via the KAT2B/HOXA10 axis.
Recent developments in biosensing methods for extracellular vesicle protein characterization.
Exosomes in Breast Cancer: Involvement in Tumor Dissemination and Prospects for Liquid Biopsy.
Breast Cancer-Delivered Exosomal miRNA as Liquid Biopsy Biomarkers for Metastasis Prediction: A Focus on Translational Research with Clinical Applicability.
BMSC-derived exosomal lncRNA PTENP1 suppresses the malignant phenotypes of bladder cancer by upregulating SCARA5 expression.
Tumor-Derived Exosomal RNA From Fine-Needle Aspiration Supernatant as a Novel Liquid Biopsy for Molecular Diagnosis of Cancer.
Exosomal Non-Coding RNAs: New Insights into the Biology of Hepatocellular Carcinoma.
Cancer-derived exosomal circ_0038138 enhances glycolysis, growth, and metastasis of gastric adenocarcinoma via the miR-198/EZH2 axis.
Small extracellular vesicle DNA-mediated horizontal gene transfer as a driving force for tumor evolution: Facts and riddles.
Cancer-associated fibroblast-released extracellular vesicles carrying miR-199a-5p induces the progression of gastric cancer through regulation of FKBP5-mediated AKT1/mTORC1 signaling pathway.
Activation of Inflammation by MCF-7 Cells-Derived Small Extracellular Vesicles (sEV): Comparison of Three Different Isolation Methods of sEV.
Blockade of exosome release alters HER2 trafficking to the plasma membrane and gives a boost to Trastuzumab.
Identification of novel early pancreatic cancer biomarkers KIF5B and SFRP2 from "first contact" interactions in the tumor microenvironment.
ROS triggered local delivery of stealth exosomes to tumors for enhanced chemo/photodynamic therapy.
Landscape of Clinically Relevant Exosomal tRNA-Derived Non-coding RNAs.
miRNome and Proteome Profiling of Small Extracellular Vesicles Secreted by Human Glioblastoma Cell Lines and Primary Cancer Stem Cells.
Naturally Equipped Urinary Exosomes Coated Poly (2-ethyl-2-oxazoline)-Poly (D, L-lactide) Nanocarriers for the Pre-Clinical Translation of Breast Cancer.
αvβ3 integrin-specific exosomes engineered with cyclopeptide for targeted delivery of triptolide against malignant melanoma.
Exosomal microRNAs in breast cancer and their potential in diagnosis, prognosis and treatment prediction.
Plasma exosomal DOK3 reflects immunological states in lung tumor and predicts prognosis of gefitinib treatment.
Pirfenidone promotes the levels of exosomal miR-200 to down-regulate ZEB1 and represses the epithelial-mesenchymal transition of non-small cell lung cancer cells.
[Research Progress on the Application of Liquid Biopsy in the Diagnosis  and Treatment of Small Cell Lung Cancer].
Intercellular communication in the tumour microecosystem: Mediators and therapeutic approaches for hepatocellular carcinoma.
Combination Therapy Comprising Paclitaxel and 5-Fluorouracil by Using Folic Acid Functionalized Bovine Milk Exosomes Improves the Therapeutic Efficacy against Breast Cancer.

Biochim Biophys Acta Rev Cancer. 2022 Aug 23. pii: S0304-419X(22)00109-3. [Epub ahead of print] 188784

Exosomes at the crossroad between therapeutic targets and therapy resistance in head and neck squamous cell carcinoma.

Abolfazl Jangholi, Juliana Müller Bark, Lizbeth Kenny, Sarju Vasani, Sudha Rao, Riccardo Dolcetti, Chamindie Punyadeera.

  Head and neck squamous cell carcinomas (HNSCCs) are aggressive and clinically challenging tumours that require a multidisciplinary management approach. Despite significant therapy improvements, HNSCC patients have a poor prognosis with a 5-year survival rate of about 65%. As recently recognised key players in cancer, exosomes are extracellular vesicles (EVs) with a diameter of nearly 50-120 nm which transport information from one cell to another. Exosomes are actively involved in various aspects of tumour initiation, development, metastasis, immune regulation, therapy resistance, and therapeutic applications. However, current knowledge of the role of exosomes in the pathophysiological processes of HNSCC is still in its infancy, and additional studies are needed. In this review, we summarise and discuss the relevance of exosomes in mediating local immunosuppression and therapy resistance of HNSCC. We also review the most recent studies that have explored the therapeutic potential of exosomes as cancer vaccines, drug carriers or tools to reverse the drug resistance of HNSCC.

Keywords:  Drug delivery; Exosomes; HNSCC; Head and neck cancer; Immune modulation; Immunotherapy; Therapy resistance; Vaccines

DOI:  https://doi.org/10.1016/j.bbcan.2022.188784
Noncoding RNA. 2022 Aug 10. pii: 60. [Epub ahead of print]8(4):

Liquid Biopsy and Circulating Biomarkers for the Diagnosis of Precancerous and Cancerous Oral Lesions.

Giuseppe Gattuso, Salvatore Crimi, Alessandro Lavoro, Roberta Rizzo, Giorgia Musumarra, Simona Gallo, Flavia Facciponte, Sabrina Paratore, Angela Russo, Roberto Bordonaro, Gaetano Isola, Alberto Bianchi, Massimo Libra, Luca Falzone.

  Oral cancer is one of the most common malignancies worldwide, accounting for 2% of all cases annually and 1.8% of all cancer deaths. To date, tissue biopsy and histopathological analyses are the gold standard methods for the diagnosis of oral cancers. However, oral cancer is generally diagnosed at advanced stages with a consequent poor 5-year survival (~50%) due to limited screening programs and inefficient physical examination strategies. To address these limitations, liquid biopsy is recently emerging as a novel minimally invasive tool for the early identification of tumors as well as for the evaluation of tumor heterogeneity and prognosis of patients. Several studies have demonstrated that liquid biopsy in oral cancer could be useful for the detection of circulating biomarkers including circulating tumor DNA (ctDNA), microRNAs (miRNAs), proteins, and exosomes, thus improving diagnostic strategies and paving the way to personalized medicine. However, the application of liquid biopsy in oral cancer is still limited and further studies are needed to better clarify its clinical impact. The present manuscript aims to provide an updated overview of the potential use of liquid biopsy as an additional tool for the management of oral lesions by describing the available methodologies and the most promising biomarkers.

Keywords:  Exosomes; NGS; circulating biomarkers; ctDNA; ddPCR; epigenetics; liquid biopsy; miRNAs; oral cancer; qPCR

DOI:  https://doi.org/10.3390/ncrna8040060
J Nanobiotechnology. 2022 Aug 23. 20(1): 383

Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma.

Xu Guo, Rui Sui, Haozhe Piao.

  Small extracellular vesicles (SEVs) are extracellular vesicles containing DNA, RNA, and proteins and are involved in intercellular communication and function, playing an essential role in the growth and metastasis of tumors. SEVs are present in various body fluids and can be isolated and extracted from blood, urine, and cerebrospinal fluid. Under both physiological and pathological conditions, SEVs can be released by some cells, such as immune, stem, and tumor cells, in a cytosolic manner. SEVs secreted by tumor cells are called tumor-derived exosomes (TEXs) because of their origin in the corresponding parent cells. Glioma is the most common intracranial tumor, accounting for approximately half of the primary intracranial tumors, and is characterized by insidious onset, high morbidity, and high mortality rate. Complete removal of tumor tissues by surgery is difficult. Chemotherapy can improve the survival quality of patients to a certain extent; however, gliomas are prone to chemoresistance, which seriously affects the prognosis of patients. In recent years, TEXs have played a vital role in the occurrence, development, associated immune response, chemotherapy resistance, radiation therapy resistance, and metastasis of glioma. This article reviews the role of TEXs in glioma progression, drug resistance, and clinical diagnosis.

Keywords:  Glioma; Immunotherapies; Malignant progression; Tumor-derived SEVs

DOI:  https://doi.org/10.1186/s12951-022-01584-6
Cancers (Basel). 2022 Aug 20. pii: 4020. [Epub ahead of print]14(16):

Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion.

Tatiana Lopatina, Alessandro Sarcinella, Maria Felice Brizzi.

  Control of the immune response is crucial for tumour onset and progression. Tumour cells handle the immune reaction by means of secreted factors and extracellular vesicles (EV). Tumour-derived extracellular vesicles (TEV) play key roles in immune reprogramming by delivering their cargo to different immune cells. Tumour-surrounding tissues also contribute to tumour immune editing and evasion, tumour progression, and drug resistance via locally released TEV. Moreover, the increase in circulating TEV has suggested their underpinning role in tumour dissemination. This review brings together data referring to TEV-driven immune regulation and antitumour immune suppression. Attention was also dedicated to TEV-mediated drug resistance.

Keywords:  cell-to-cell communication; exosomes; extracellular vesicles; tumour antigens; tumour immune editing; tumour immune suppression

DOI:  https://doi.org/10.3390/cancers14164020
Cancers (Basel). 2022 Aug 11. pii: 3887. [Epub ahead of print]14(16):

Ultrasensitive Detection of GRP78 in Exosomes and Observation of Migration and Proliferation of Cancer Cells by Application of GRP78-Containing Exosomes.

Naoko Tsurusawa, Kanako Iha, Akane Sato, Hsin-Yi Tsai, Hikaru Sonoda, Satoshi Watabe, Teruki Yoshimura, Deng-Chyang Wu, Ming-Wei Lin, Etsuro Ito.

  Cancer cells communicate with each other via exosomes in the tumor microenvironment. However, measuring trace amounts of proteins in exosomes is difficult, and thus the cancer stemness-promoting mechanisms of exosomal proteins have not been elucidated. In the present study, we attempted to quantify trace amounts of 78-kDa glucose-regulated protein (GRP78), which is involved in cancer progression, in exosomes released from cultured gastric cancer cells using an ultrasensitive ELISA combined with thio-NAD cycling. We also evaluated the cancer stemness-promoting effects by the application of high-GRP78-containing exosomes to cultured gastric cancer cells. The ultrasensitive ELISA enabled the detection of GRP78 at a limit of detection of 0.16 pg/mL. The stemness of cancer cultured cells incubated with high-GRP78-containing exosomes obtained from GRP78-overexpressed cells was increased on the basis of both an MTT assay and a wound healing assay. Our results demonstrated that the ultrasensitive ELISA has strong potential to measure trace amounts of proteins in exosomes. Further, exosomes with a high concentration of GRP78 promote the cancer stemness of surrounding cells. The technique for quantifying proteins in exosomes described here will advance our understanding of cancer stemness progression via exosomes.

Keywords:  GRP78; cancer stemness; cultured gastric cancer cell; exosome; ultrasensitive ELISA

DOI:  https://doi.org/10.3390/cancers14163887
Br J Cancer. 2022 Aug 23.

Extruded small extracellular vesicles: splinters of circulating tumour cells may promote cancer metastasis?

Yuan Wan, Yi-Qiu Xia, Si-Yang Zheng.

We speculate ruptured circulating tumour cells (CTC) in capillaries could release a large number of small extracellular vesicle-like vesicles, namely mechanically extruded sEV (sEVme), which can encapsulate chromosomal DNA fragments. These sEVme have similar physicochemical properties compared to small extracellular vesicles spontaneously secreted by living cells (sEVss), and thus sEVme and sEVss cannot be effectively distinguished based on their size or membrane protein markers. Meanwhile, these sEVme derived from CTC inherit oncogenic payloads, deliver cargo through the bloodstream to recipient cells, and thus may promote cancer metastasis. The validation of this speculation could facilitate our understanding of EV biogenesis and cancer pathology. The potential finding will also provide a theoretical foundation for burgeoning liquid biopsy using DNA fragments derived from harvested sEV.

DOI: https://doi.org/10.1038/s41416-022-01934-z
Biosens Bioelectron. 2022 Aug 14. pii: S0956-5663(22)00675-3. [Epub ahead of print]216 114635

Electrochemical nano biosensors for the detection of extracellular vesicles exosomes: From the benchtop to everywhere?

Sima Singh, Numan Arshid, Stefano Cinti.

  Detection of extracellular vesicles (EVs) exosomes is a challenge to address the need for better diagnostic tests and to create a point-of-care (POC) platform that can detect, monitor and treat health conditions early to allow personalized therapies. A multidisciplinary approach is needed to address these health-related technical issues. Over the past decade, materials scientists and engineers have worked on the same platform to develop flexible, lightweight, miniaturized, and integrated POC devices for exosome detection. Therefore, exosome detection based on various nanomaterials is of particular interest. In this paper, we describe the current state of knowledge on 0D-3D nanostructured materials and present a POC-based technique for exosome detection. Finally, the challenges that need to be solved to expand their clinical application are discussed.

Keywords:  Cancer biomarkers; Electrochemical detection; Exosomes; Extracellular vesicle; Nanomaterials; On-site monitoring

DOI:  https://doi.org/10.1016/j.bios.2022.114635
Cancers (Basel). 2022 Aug 21. pii: 4036. [Epub ahead of print]14(16):

Role of Exosomes in Immunotherapy of Hepatocellular Carcinoma.

Bao-Wen Tian, Cheng-Long Han, Zhao-Ru Dong, Si-Yu Tan, Dong-Xu Wang, Tao Li.

  Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, having a significantly poor prognosis and no sufficiently efficient treatments. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided new therapeutic approaches for HCC patients. Nevertheless, most patients with HCC do not benefit from immunotherapy. Exosomes are biologically active lipid bilayer nano-sized vesicles ranging in size from 30 to 150 nm and can be secreted by almost any cell. In the HCC tumor microenvironment (TME), numerous cells are involved in tumor progression, and exosomes-derived from tumor cells and immune cells-exhibit unique composition profiles and act as intercellular communicators by transporting various substances. Showing the dual characteristics of tumor promotion and suppression, exosomes exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells, mediating immunotherapy resistance by affecting the PD-1/PD-L1 axis or the anti-tumor function of immune cells in the TME. Targeting exosomes or the application of exosomes as therapies is involved in many aspects of HCC immunotherapies (e.g., ICIs, tumor vaccines, and adoptive cell therapy) and may substantially enhance their efficacy. In this review, we discuss the impact of exosomes on the HCC TME and comprehensively summarize the role of exosomes in immunotherapy resistance and therapeutic application. We also discuss the potential of exosomes as biomarkers for predicting the efficacy of immunotherapy to help clinicians in identifying HCC patients who are amenable to immunotherapies.

Keywords:  adoptive cell therapy; efficacy; exosomes; hepatocellular carcinoma; immune checkpoint inhibitor; immunotherapy; predictive effect; resistance mechanism; tumor vaccine

DOI:  https://doi.org/10.3390/cancers14164036
Cancer Cell Int. 2022 Aug 21. 22(1): 262

Exosome-based strategies for diagnosis and therapy of glioma cancer.

Mohsen Karami Fath, Jalil Azami, Alireza Masoudi, Reza Mosaddeghi Heris, Elnaz Rahmani, Fatemeh Alavi, Armina Alagheband Bahrami, Zahra Payandeh, Bahman Khalesi, Masoomeh Dadkhah, Navid Pourzardosht, Vahideh Tarhriz.

  Glioblastoma belongs to the most aggressive type of cancer with a low survival rate that is characterized by the ability in forming a highly immunosuppressive tumor microenvironment. Intercellular communication are created via exosomes in the tumor microenvironment through the transport of various biomolecules. They are primarily involved in tumor growth, differentiation, metastasis, and chemotherapy or radiation resistance. Recently several studies have highlighted the critical role of tumor-derived exosomes against immune cells. According to the structural and functional properties, exosomes could be essential instruments to gain a better molecular mechanism for tumor understanding. Additionally, they are qualified as diagnostic/prognostic markers and therapeutic tools for specific targeting of invasive tumor cells such as glioblastomas. Due to the strong dependency of exosome features on the original cells and their developmental status, it is essential to review their critical modulating molecules, clinical relevance to glioma, and associated signaling pathways. This review is a non-clinical study, as the possible role of exosomes and exosomal microRNAs in glioma cancer are reported. In addition, their content to overcome cancer resistance and their potential as diagnostic biomarkers are analyzed.

Keywords:  Biomarkers; Exosome; Glioblastoma multiforme; Immunotherapy; MicroRNA

DOI:  https://doi.org/10.1186/s12935-022-02642-7
Biosensors (Basel). 2022 Aug 17. pii: 648. [Epub ahead of print]12(8):

Introduction of Nanomaterials to Biosensors for Exosome Detection: Case Study for Cancer Analysis.

Myoungro Lee, Jinmyeong Kim, Moonbong Jang, Chulhwan Park, Jin-Ho Lee, Taek Lee.

  Exosomes have been gaining attention for early cancer diagnosis owing to their biological functions in cells. Several studies have reported the relevance of exosomes in various diseases, including pancreatic cancer, retroperitoneal fibrosis, obesity, neurodegenerative diseases, and atherosclerosis. Particularly, exosomes are regarded as biomarkers for cancer diagnosis and can be detected in biofluids, such as saliva, urine, peritoneal fluid, and blood. Thus, exosomes are advantageous for cancer liquid biopsies as they overcome the current limitations of cancer tissue biopsies. Several studies have reported methods for exosome isolation, and analysis for cancer diagnosis. However, further clinical trials are still required to determine accurate exosome concentration quantification methods. Recently, various biosensors have been developed to detect exosomal biomarkers, including tumor-derived exosomes, nucleic acids, and proteins. Among these, the exact quantification of tumor-derived exosomes is a serious obstacle to the clinical use of liquid biopsies. Precise detection of exosome concentration is difficult because it requires clinical sample pretreatment. To solve this problem, the use of the nanobiohybrid material-based biosensor provides improved sensitivity and selectivity. The present review will discuss recent progress in exosome biosensors consisting of nanomaterials and biomaterial hybrids for electrochemical, electrical, and optical-based biosensors.

Keywords:  biosensors; cancer; exosomes; nanomaterials

DOI:  https://doi.org/10.3390/bios12080648
Mol Biol Rep. 2022 Aug 21.

Exosomal mir-625-3p derived from hypoxic lung cancer cells facilitates metastasis by targeting SCAI.

Yi Zhang, Kun Qian, Xingsheng Liu, Xin Zhao, Teng Zhao, Gaojun Lu.

   BACKGROUND: Tumor hypoxia is a feature of tumor micro-environment (TME), which provides a suitable environment for tumor cells migration and invasion. However, up to now, the function of exosomes derived from hypoxic tumor cells is still not fully understood. The present study is aimed to explore the underlying mechanisms of lung cancer-secreted exosomes-mediated tumor metastasis under hypoxia.
METHODS & RESULTS: Exosomes were isolated from normoxic or hypoxic NCI-H446 cells. Some characteristic proteins were detected by western blots. Levels of CD63, CD 9 and CD 81 proteins were up-regulated on the membrane of exosomes secreted by hypoxic NCI-H446 cells. Basing on the results from miRNA sequencing, qRT-PCR and wound healing assay, hsa-miR-625-3p was discovered to be accumulated inside hypoxic exosomes and responsible for the metastasis of lung cancer cell. Further experiments from luciferase reporter gene assay demonstrated hsa-miR-625-3p could directly inhibit SCAI expression through binding with its 3'UTR, which suggested the mechanisms by which exosomal hsa-miR-625-3p suppressed tumor cells migration.
CONCLUSIONS: Exosomal miR-625-3p derived from hypoxic small lung cancer cells accelerated tumor cells migration through inhibiting SCAI directly.

Keywords:  Exosomal miR-625-3p; Hypoxic exosome; Lung Cancer cells; Metastasis; SCAI

DOI:  https://doi.org/10.1007/s11033-022-07763-w
Cancers (Basel). 2022 Aug 18. pii: 4001. [Epub ahead of print]14(16):

The Immunomodulatory Role of Hypoxic Tumor-Derived Extracellular Vesicles.

Joel E J Beaumont, Nicky A Beelen, Lotte Wieten, Kasper M A Rouschop.

  Tumor-associated immune cells frequently display tumor-supportive phenotypes. These phenotypes, induced by the tumor microenvironment (TME), are described for both the adaptive and the innate arms of the immune system. Furthermore, they occur at all stages of immune cell development, up to effector function. One major factor that contributes to the immunosuppressive nature of the TME is hypoxia. In addition to directly inhibiting immune cell function, hypoxia affects intercellular crosstalk between tumor cells and immune cells. Extracellular vesicles (EVs) play an important role in this intercellular crosstalk, and changes in both the number and content of hypoxic cancer-cell-derived EVs are linked to the transfer of hypoxia tolerance. Here, we review the current knowledge about the role of these hypoxic cancer-cell-derived EVs in immunosuppression. In addition, we provide an overview of hypoxia-induced factors (i.e., miRNA and proteins) in tumor-derived EVs, and their role in immunomodulation.

Keywords:  cancer; extracellular vesicles; hypoxia; immunosuppression; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14164001
Membranes (Basel). 2022 Aug 12. pii: 775. [Epub ahead of print]12(8):

Exosomes: Small Vesicles with Important Roles in the Development, Metastasis and Treatment of Breast Cancer.

Ling'ao Meng, Kedong Song, Shenglong Li, Yue Kang.

  Breast cancer (BC) has now overtaken lung cancer as the most common cancer, while no biopredictive marker isolated from biological fluids has yet emerged clinically. After traditional chemotherapy, with the huge side effects brought by drugs, patients also suffer from the double affliction of drugs to the body while fighting cancer, and they often quickly develop drug resistance after the drug, leading to a poor prognosis. And the treatment of some breast cancer subtypes, such as triple negative breast cancer (TNBC), is even more difficult. Exosomes (Exos), which are naturally occurring extracellular vesicles (EVs) with nanoscale acellular structures ranging in diameter from 40 to 160 nm, can be isolated from various biological fluids and have been widely studied because they are derived from the cell membrane, have extremely small diameter, and are widely involved in various biological activities of the body. It can be used directly or modified to make derivatives or to make some analogs for the treatment of breast cancer. This review will focus on the involvement of exosomes in breast cancer initiation, progression, invasion as well as metastasis and the therapeutic role of exosomes in breast cancer.

Keywords:  breast cancer; cancer therapeutics; drug resistance; exosome; targeted delivery

DOI:  https://doi.org/10.3390/membranes12080775
J Gene Med. 2022 Aug 26. e3446

Extracellular vesicle-packaged miR-181c-5p from epithelial ovarian cancer cells promotes M2 polarization of tumor-associated macrophages via the KAT2B/HOXA10 axis.

Shuyan Yang, Honghui Zhao, Wei Xiao, Lei Shao, Chunyan Zhao, Pengcheng Sun.

   OBJECTIVES: The molecular mechanistic actions of tumor-derived extracellular vesicles (EVs) in modulating macrophage polarization in the tumor microenvironment of epithelial ovarian cancer (EOC) is largely unknown. The study was performed to clarify the effect and downstream mechanism of microRNA-181c-5p (miR-181c-5p)-containing EVs from EOC cells in the M2 polarization of tumor-associated macrophages (TAMs).
METHODS: EVs were isolated from normoxic and hypoxic human EOC cells SKOV3. Human mononuclear cells THP-1 was induced by PMA to differentiate into TAMs. Targeting relationship between miR-181c-5p and KAT2B was verified by dual luciferase reporter gene assay. The interaction between KAT2B and HOXA10 was detected by immunofluorescence, Co-IP and ChIP assays. EdU staining, scratch test, and Transwell assay were used to assess the resultant cell proliferation, migration, and invasion. Mouse xenograft model and pulmonary metastasis model were developed through intraperitoneal injection of SKOV3 cells and tail vein injection of THP-1 cells, respectively.
RESULTS: Hypoxic SKOV3 cell-derived EVs could be internalized by TAMs. SKOV3 cell-derived EVs induced by hypoxia (H-EVs) promoted M2 polarization of TAMs and facilitated proliferation, migration, and invasion of SKOV3 cells. miR-181c-5p was highly expressed in H-EVs and promoted M2 polarization of TAMs. Further, miR-181c-5p targeted KAT2B, upregulated HOXA10 and activated the JAK1/STAT3 pathway, thereby promoting M2 polarization of TAMs. In both mouse models, H-EVs-derived miR-181c-5p promoted growth and metastasis of EOC cells.
CONCLUSION: The miR-181c-5p-containing EVs from hypoxic EOC cells may upregulate HOXA10 by targeting KAT2B and activate the JAK1/STAT3 pathway to promote the M2 polarization of TAMs and ultimately promoting growth and metastasis of EOC cells in vitro and in vivo.

Keywords:  Epithelial ovarian cancer; Extracellular vesicles; HOXA10; Hypoxia; KAT2B; M2 polarization; Tumor-associated macrophages; miR-181c-5p

DOI:  https://doi.org/10.1002/jgm.3446
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Aug 23. e1839

Recent developments in biosensing methods for extracellular vesicle protein characterization.

Jugal Suthar, Marissa Taub, Randy P Carney, Gareth R Williams, Stefan Guldin.

  Research into extracellular vesicles (EVs) has grown significantly over the last few decades with EVs being widely regarded as a source of biomarkers for human health and disease with massive clinical potential. Secreted by every cell type in the body, EVs report on the internal cellular conditions across all tissue types. Their presence in readily accessible biofluids makes the potential of EV biosensing highly attractive as a noninvasive diagnostic platform via liquid biopsies. However, their small size (50-250 nm), inherent heterogeneity, and the complexity of the native biofluids introduce challenges for effective characterization, thus, limiting their clinical utility. This has led to a surge in the development of various novel EV biosensing techniques, with capabilities beyond those of conventional methods that have been directly transferred from cell biology. In this review, key detection principles used for EV biosensing are summarized, with a focus on some of the most recent and fundamental developments in the field over the last 5 years. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > In Vitro Nanoparticle-Based Sensing.

Keywords:  absorbance; acoustic resonators; biosensing; electrochemical; electrochemical quartz crystal microbalance with dissipation; exosomes; extracellular vesicles; fluorescence; interferometry; plasmon resonance; surface enhanced Raman spectroscopy

DOI:  https://doi.org/10.1002/wnan.1839
Int J Mol Sci. 2022 Aug 09. pii: 8845. [Epub ahead of print]23(16):

Exosomes in Breast Cancer: Involvement in Tumor Dissemination and Prospects for Liquid Biopsy.

Aleksei Shefer, Alena Yalovaya, Svetlana Tamkovich.

  In women, breast cancer (BC) is the most commonly diagnosed cancer (24.5%) and the leading cause of cancer death (15.5%). Understanding how this heterogeneous disease develops and the confirm mechanisms behind tumor progression is of utmost importance. Exosomes are long-range message vesicles that mediate communication between cells in physiological conditions but also in pathology, such as breast cancer. In recent years, there has been an exponential rise in the scientific studies reporting the change in morphology and cargo of tumor-derived exosomes. Due to the transfer of biologically active molecules, such as RNA (microRNA, long non-coding RNA, mRNA, etc.) and proteins (transcription factors, enzymes, etc.) into recipient cells, these lipid bilayer 30-150 nm vesicles activate numerous signaling pathways that promote tumor development. In this review, we attempt to shed light on exosomes' involvement in breast cancer pathogenesis (including epithelial-to-mesenchymal transition (EMT), tumor cell proliferation and motility, metastatic processes, angiogenesis stimulation, and immune system repression). Moreover, the potential use of exosomes as promising diagnostic biomarkers for liquid biopsy of breast cancer is also discussed.

Keywords:  breast cancer; exosomal cargo; exosomes; liquid biopsy; microRNA; proteins

DOI:  https://doi.org/10.3390/ijms23168845
Int J Mol Sci. 2022 Aug 19. pii: 9371. [Epub ahead of print]23(16):

Breast Cancer-Delivered Exosomal miRNA as Liquid Biopsy Biomarkers for Metastasis Prediction: A Focus on Translational Research with Clinical Applicability.

Oana Baldasici, Valentina Pileczki, Daniel Cruceriu, Laura Ioana Gavrilas, Oana Tudoran, Loredana Balacescu, Laurian Vlase, Ovidiu Balacescu.

  Metastasis represents the most important cause of breast cancer-associated mortality. Even for early diagnosed stages, the risk of metastasis is significantly high and predicts a grim outcome for the patient. Nowadays, efforts are made for identifying blood-based biomarkers that could reliably distinguish patients with highly metastatic cancers in order to ensure a closer follow-up and a more personalized therapeutic method. Exosomes are nano vesicles secreted by cancer cells that can transport miRNAs, proteins, and other molecules and deliver them to recipient cells all over the body. Through this transfer, cancer cells modulate their microenvironment and facilitate the formation of the pre-metastatic niche, leading to sustained progression. Exosomal miRNAs have been extensively studied due to their promising potential as prognosis biomarkers for metastatic breast cancer. In this review, we tried to depict an overview of the existing literature regarding exosomal miRNAs that are already validated as potential biomarkers, and which could be immediately available for the clinic. Moreover, in the last section, we highlighted several miRNAs that have proven their function in preclinical studies and could be considered for clinical validation. Considering the lack of standard methods for evaluating exosomal miRNA, we also discussed the challenges and the technical aspects underlying this issue.

Keywords:  biomarker; breast cancer; clinical applicability; exosomes; extracellular vesicles; metastasis; miRNA; translational research

DOI:  https://doi.org/10.3390/ijms23169371
Cancer Biol Ther. 2022 Dec 31. 23(1): 1-13

BMSC-derived exosomal lncRNA PTENP1 suppresses the malignant phenotypes of bladder cancer by upregulating SCARA5 expression.

Shu-Cheng Liu, You-Han Cao, Li-Bo Chen, Ran Kang, Zhong-Xin Huang, Xin-Sheng Lu.

  LncRNAs can be transported to tumor cells where they exert regulatory effects by bone marrow mesenchymal stem cells (BMSC)-derived exosomes. Here, we aimed to investigate the functional mechanism of BMSC-derived exosomal lncRNA PTENP1 in the progression of bladder cancer (BC). Methods of BMSC were identified by detecting surface markers through flow cytometry. Exosomes from BMSC were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blot analysis of exosome markers. Cellular internalization of BMSC-derived exosomes (BMSC-Exo) into BC cells was detected by confocal microscopy. CCK-8, colony formation, flow cytometry, wound healing, and transwell assays were adopted to estimate cell proliferation, apoptosis, migration, and invasion abilities, respectively. Interplay between miR-17 and lncRNA PTENP1 or SCARA5 was verified by dual-luciferase reporter, RNA pull down, and/or RNA immunoprecipitation (RIP) assays. Tumor xenograft assay was conducted in nude mice to study the role of exosomal lncRNA PTENP1 in BC progression in vivo. We showed exosomal lncRNA PTENP1 can be delivered into and suppress the malignant phenotypes of BC cells. LncRNA PTENP1 was identified as a sponge of miR-17, and SCARA5 was identified as a target gene of miR-17. The exosomes derived from PTENP1-overexpressing BMSC (BMSCOE-PTENP1-Exo) abolished the promotive effects of miR-17 overexpression or SCARA5 knockdown on the malignant phenotypes of BC cells. Moreover, exosomal lncRNA PTENP1 was demonstrated to inhibit BC tumor growth in nude mice by miR-17/SCARA5 axis. In conclusion, BMSC-derived exosomal PTENP1 suppressed the BC progression by upregulating the expression of SCARA5 via sponging miR-17, offering a potential novel therapeutic target for BC therapy.

Keywords:  Bladder cancer; MicroRNA-17; SCARA5; bone marrow mesenchymal stem cells; exosomes; long non-coding RNA PTENP1

DOI:  https://doi.org/10.1080/15384047.2022.2102360
Pathol Oncol Res. 2022 ;28 1610344

Tumor-Derived Exosomal RNA From Fine-Needle Aspiration Supernatant as a Novel Liquid Biopsy for Molecular Diagnosis of Cancer.

Guorong Li, Dongdong Liu, Pascale Flandrin, Yang Zhang, Claude Lambert, Nora Mallouk, Michèle Cottier.

  Background: We hypothesized that the fine needle aspiration (FNA) supernatant from tumor might contain tumor-derived exosomes. The objective of this pilot study was to test if tumor-derived exosomal RNA could be found in FNA supernatants for molecular diagnosis of cancer. Methods: 10 FNA samples from pancreatic tumor were included. After the routine recuperation of cellular material by centrifugation, the cell-free Cytolyt liquid was collected instead of being discarded. 10 ml Cytolyt was used to isolate the exosomes. Transmission electronic microscopy (TEM) was used to examine the presence of exosomes. The exosomal marker CD63 was analyzed by flow cytometry. The exosomal RNA was extracted. RT-qPCR was performed to detect the GAPDH and the tumor marker of glypican 1 gene expression. Results: TEM confirmed the presence of exosomes from FNA supernatants. Flow cytometry showed a strong positive expression of exosome marker CD63. The concentration of exosomal RNA ranged from 18.81 to 354.75 ng/μl with an average of 81.76 ng/μl. The average exosomal RNA quantity was 1390.01 ng (range from 319.77 to 6030.75 ng) with an average 260/280 ratio of 2.12. GAPDH was detectable in all samples. Exosomal glypican 1 was detected in all samples of pancreatic ductal adenorcarcinomas (3/3) and absent from benign cystic samples (3/3). Furthermore, exosomal glypican 1 was positive in one sample with a non-contributive cytology and in one sample in which no malignant cell was found. Conclusion: This is the first report that the supernatants from FNA biopsy may contain tumor-derived exosomal RNA. These tumor-derived exosomes from FNA may provide a new liquid biopsy for the molecular diagnosis of cancer.

Keywords:  FNA supernatant; exosomes; glypican 1; liquid biopsy; molecular diagnosis; pancreatic adenocarcinoma

DOI:  https://doi.org/10.3389/pore.2022.1610344
Curr Oncol. 2022 Jul 29. 29(8): 5383-5406

Exosomal Non-Coding RNAs: New Insights into the Biology of Hepatocellular Carcinoma.

Qian Zhang, Hanlin Li, Yang Liu, Jian Li, Chunling Wu, Hua Tang.

  Exosomes, extracellular vesicles with a diameter of 40 to 160 nm, are among the smallest extracellular vesicles released by cells. They deliver different cargoes, including proteins, DNAs, and RNAs, and facilitate communication between cells to coordinate a variety of physiological and pathological functions. Hepatocellular carcinoma (HCC) is the sixth common malignant tumor and the fourth leading cause of cancer-related death worldwide. Its molecular mechanism remains largely unknown, and there is a lack of reliable and noninvasive biomarkers for early diagnosis and prognosis prediction. Mounting evidence has shown that exosomes carry a variety of ncRNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which play critical roles in the occurrence and progression of HCC. In this review, we summarize the recent findings of exosomal miRNAs, lncRNAs, and circRNAs in HCC from their impact on the development of HCC to their potential applications in the diagnosis and treatment of HCC.

Keywords:  exosome; hepatocellular carcinoma; long non-coding RNA; microRNA; tumor microenvironment

DOI:  https://doi.org/10.3390/curroncol29080427
Transl Oncol. 2022 Aug 17. pii: S1936-5233(22)00138-3. [Epub ahead of print]25 101479

Cancer-derived exosomal circ_0038138 enhances glycolysis, growth, and metastasis of gastric adenocarcinoma via the miR-198/EZH2 axis.

Yuanyuan Zheng, Ping Li, Jianghui Ma, Chengxi Yang, Saimin Dai, Changyong Zhao.

  This study aims to decipher the impact and downstream mechanisms of the bioinformatically identified circ_0038138 delivered by cancer-derived exosomes in gastric adenocarcinoma (GAC). Expression of circ_0038138 in clinical GAC tissues and exosomes (Exos) from clinical plasma samples (plasma-Exos) was predicted by bioinformatics analysis and validated by RT-qPCR. The binding affinity between circ_0038138, miR-198 and EZH2 was identified using luciferase activity, RIP, and RNA pull-down assays. GAC cells (AGS) were co-cultured with Exos isolated from GAC cell supernatant (GC9811-P). After co-culture, the behaviors of GAC cells including proliferation and glycolysis were assessed to identify the biological effect of exosomal circ_0038138. Also, in vivo effects of exosomal circ_0038138 on the tumorigenesis and lung metastasis of GAC cells were evaluated by developing nude mouse xenograft and metastatic models. circ_0038138 upregulation was detected in GAC tissues and plasma-Exos. Exos delivered circ_0038138 to GAC cells and potentiated the proliferative, migratory, invasive, and glycolytic potentials of GAC cells. Mechanistically, circ_0038138 competitively bound to miR-198, which in turn targeted EZH2 by binding to its 3'-UTR. Silencing of EZH2 promoted CXXC4 expression and inhibited Wnt/β-catenin pathway activation, thus repressing the malignancy and glycolysis of GAC cells. In vivo assay confirmed that exosomal circ_0038138 induced tumorigenesis and lung metastasis by regulating the miR-198/EZH2 axis. Collectively, our work suggests that the Exo-mediated transfer of circ_0038138 potentially facilitates the glycolysis, growth and metastasis of GAC cells via miR-198/EZH2 axis, which offers a potential prognostic marker and a therapeutic target for GAC.

Keywords:  EZH2; Exosomes; Gastric adenocarcinoma; circ_0038138; microRNA-198

DOI:  https://doi.org/10.1016/j.tranon.2022.101479
Front Oncol. 2022 ;12 945376

Small extracellular vesicle DNA-mediated horizontal gene transfer as a driving force for tumor evolution: Facts and riddles.

Gábor Valcz, Beáta Újvári, Edit I Buzás, Tibor Krenács, Sándor Spisák, Ágnes Kittel, Zsolt Tulassay, Péter Igaz, István Takács, Béla Molnár.

  The basis of the conventional gene-centric view on tumor evolution is that vertically inherited mutations largely define the properties of tumor cells. In recent years, however, accumulating evidence shows that both the tumor cells and their microenvironment may acquire external, non-vertically inherited genetic properties via horizontal gene transfer (HGT), particularly through small extracellular vesicles (sEVs). Many phases of sEV-mediated HGT have been described, such as DNA packaging into small vesicles, their release, uptake by recipient cells, and incorporation of sEV-DNA into the recipient genome to modify the phenotype and properties of cells. Recent techniques in sEV separation, genome sequencing and editing, as well as the identification of new secretion mechanisms, shed light on a number of additional details of this phenomenon. Here, we discuss the key features of this form of gene transfer and make an attempt to draw relevant conclusions on the contribution of HGT to tumor evolution.

Keywords:  cell-cell communication; exosomes; extracellular vesicles; horizontal gene transfer; tumor evolution

DOI:  https://doi.org/10.3389/fonc.2022.945376
Cell Cycle. 2022 Aug 25. 1-12

Cancer-associated fibroblast-released extracellular vesicles carrying miR-199a-5p induces the progression of gastric cancer through regulation of FKBP5-mediated AKT1/mTORC1 signaling pathway.

Yan Wang, Tao Li, Lei Yang, Xunlei Zhang, Xiaoli Wang, Xiaoqin Su, Congfei Ji, Zhenxin Wang.

  Accumulating evidence has unfolded the significance of extracellular vesicles (EVs) in diseases and cancers. Here, we attempted to discuss the role of cancer-associated fibroblasts (CAFs)-derived EVs containing miR-199a-5p in gastric tumorigenesis. Upregulated miR-199a-5p was first identified in cancer cells. Then, we selected CAFs for isolation of EVs which were co-cultured with AGS cells. We observed successful delivery of miR-199a-5p via CAF-derived EVs. Besides, miR-199a-5p promoted malignant properties of AGS cells. Moreover, miR-199a-5p downregulated FKBP5, leading to upregulated phosphorylation level of AKT1, which promoted the malignant phenotypes of AGS cells by activating mammalian target of rapamycin complex 1(mTORC1). Exosomal miR-199a-5p from CAFs promoted gastric tumorigenesis in vivo. Our findings point toward the critical role of CAFs-derived EVs carrying miR-199a-5p in gastric cancer progression.

Keywords:  AKT1; Cancer-associated fibroblasts; FKBP5; extracellular vesicles; gastric cancer; mTORC1; microRNA-199a-5p

DOI:  https://doi.org/10.1080/15384101.2022.2105092
Pharm Res. 2022 Aug 24.

Activation of Inflammation by MCF-7 Cells-Derived Small Extracellular Vesicles (sEV): Comparison of Three Different Isolation Methods of sEV.

Kohei Suzuki, Masataka Nakano, Shimon Nakashima, Tatsuki Fukami, Miki Nakajima.

   PURPOSE: Small extracellular vesicles (sEV) containing proteins and RNAs play important roles as intercellular signal mediators. A critical issue is that there are multiple methods to prepare sEV fractions. The purpose of this study was to examine whether cancer cell-derived sEV fractions prepared by different isolation methods show similar responses for the induction of inflammatory cytokines in macrophages.
METHODS: sEV fractions from the conditioned medium of MCF-7 cells were prepared by ultracentrifugation (UC), the MagCapture Exosome Isolation Kit PS (PS), or the ExoQuick-TC kit (EQ). The mRNA levels of inflammatory cytokines in differentiated THP-1 cells treated with the sEV fractions were evaluated.
RESULTS: The yields of sEV fractions obtained from 1 mL conditioned medium by UC, PS, or EQ were 3.2×108 particles (0.27 μg protein), 12.8×108 particles (0.87 μg protein) and 23.5 ×108 particles (4.50 μg protein), respectively. The average particle sizes in the UC, PS, and EQ fractions were 184.8 ± 1.8 nm, 157.8 ± 1.3 nm and 165.8 ± 1.1 nm, respectively. CD9 and CD81, markers of sEV, were most highly detected in the PS fraction, followed by the EQ and UC fractions. These results suggest that PS gave sEV with relatively high purity, and many protein contaminants appear to be included in the EQ fraction. The mRNA levels of inflammatory cytokines in THP-1 macrophages were most prominently increased by treatment with the UC fraction, followed by the EQ and PS fractions, suggesting that contaminants rather than sEV may largely induce an inflammatory response.
CONCLUSION: The isolation method affects the evaluation of sEV function.

Keywords:  cell-to-cell communication; exosomes; extracellular vesicles; isolation method

DOI:  https://doi.org/10.1007/s11095-022-03368-x
Clin Transl Oncol. 2022 Aug 26.

Blockade of exosome release alters HER2 trafficking to the plasma membrane and gives a boost to Trastuzumab.

Reza Hosseini, Leila Asef-Kabiri, Hamzeh Sarvnaz, Alireza Ghanavatinejad, Fatemeh Rezayat, Nahid Eskandari, Mohammad Esmaeil Akbari.

   OBJECTIVE(S): Exosomal HER2 has been evidenced to interfere with antibody-induced anti-tumor effects. However, whether the blockade of HER2+ exosomes release would affect antibody-mediated tumor inhibition has yet to be investigated.
METHODS: Exosomes derived from BT-474, SK-BR3 and SK-OV3 (HER2-overexpressing tumor cells) and MDA-MB-231 cells (HER2 negative) were purified and characterized by bicinchoninic acid (BCA) assay, western blotting and Transmission electron microscopy (TEM). Inhibition of exosome release was achieved by neutral sphingomyelinase-2 (nSMase-2) inhibitor, GW4869. The effects of exosome blockade on the anti-proliferative effects, apoptosis induction, and antibody-mediated cellular cytotoxicity (ADCC) activity of Trastuzumab were examined using MTT, flow cytometry, and LDH release assays. Also, the effects of exosome inhibition on the surface expression and endocytosis/internalization of HER2 were studied by flow cytometry.
RESULTS: Purified exosomes derived from HER2 overexpressing cancer cells were positive for HER2 protein. Blockade of exosome release was able to significantly improve apoptosis induction, anti-proliferative and ADCC responses of Trastuzumab dose dependently. The pretreatment of Trastuzumab/purified NK cells, but not PBMCs, with HER2+ exosomes could also decrease the ADCC effects of Trastuzumab. Exosome inhibition also remarkably downregulated surface HER2 levels in a time-dependent manner, but does not affect its endocytosis/internalization.
CONCLUSION: Based on our findings, HER2+ exosomes may benefit tumor progression by dually suppressing Trastuzumab-induced tumor growth inhibition and cytotoxicity of NK cells. It seems that concomitant blocking of exosome release might be an effective approach for improving the therapeutic effects of Trastuzumab, and potentially other HER2-directed mAbs. In addition, the exosome secretion pathway possibly contributes to the HER2 trafficking to plasma membrane, since the blockade of exosome secretion decreased surface HER2 levels.

Keywords:  ADCC; Exosome; HER2; NK cells; Trastuzumab; Tumor

DOI:  https://doi.org/10.1007/s12094-022-02925-5
J Exp Clin Cancer Res. 2022 Aug 24. 41(1): 258

Identification of novel early pancreatic cancer biomarkers KIF5B and SFRP2 from "first contact" interactions in the tumor microenvironment.

Harrys Kishore Charles Jacob, Rossana Signorelli, John Lalith Charles Richard, Tyler Kashuv, Shweta Lavania, Ashley Middleton, Beatriz Aguilar Gomez, Anthony Ferrantella, Haleh Amirian, Junyi Tao, Ayse Burcu Ergonul, Melinda Minucci Boone, Marco Hadisurya, Weiguo Andy Tao, Anton Iliuk, Manoj Kumar Kashyap, Monica Garcia-Buitrago, Rajinder Dawra, Ashok Kumar Saluja.

   BACKGROUND: Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for late diagnosis of pancreatic cancer. It is a multifactorial disease and warrants a novel approach to identify early biomarkers.
METHODS: In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking tumor-microenvironment interactions between pancreatic cancer epithelial and stromal cells were analyzed using high throughput mass spectrometry. The biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and associated early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on a mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer.
RESULTS: The EVome of co-cultured epithelial and stromal cells is different from individual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation, which was assessed by changes in the distant organ metastases. However, they did induce significant changes in the early microbiome, as indicated by differences in α and β-diversities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and in liver and soft tissue metastases.
CONCLUSIONS: Proteomic characterization of EVs derived from mimicking conditions of epithelial and stromal cells in the tumor-microenvironment resulted in the identification of several proteins, some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education, but modulate changes in the early murine microbiome. Among all the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2), KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer.

Keywords:  EVtrap; Extracellular Vesicles; Hybrid TMA; KIF5B; LOXL2; MMP3; Microbiome; PDAC progression; Pancreatic Cancer; Pre-Metastatic Niche; Proteomics; SFRP2; Tumor-Microenvironment

DOI:  https://doi.org/10.1186/s13046-022-02425-y
J Nanobiotechnology. 2022 Aug 23. 20(1): 385

ROS triggered local delivery of stealth exosomes to tumors for enhanced chemo/photodynamic therapy.

Zhuo Wan, Xueqi Gan, Ruiyan Mei, Jianbin Du, Wen Fan, Mengying Wei, Guodong Yang, Weiwei Qin, Zhuoli Zhu, Li Liu.

   BACKGROUND: Exosomes are recognized as effective platforms for targeted delivery for their high physicochemical stability and biocompatibility. However, most of the exosomes are inevitably and rapidly cleared by mononuclear phagocytic system (MPS) during cancer therapy. How to engineer exosome to enhance the delivery efficiency is being intensively explored. In this study, we have constructed mPEG2000-TK-CP05 decorated exosomes as effective delivery platforms to achieve enhanced photodynamic/chemical cancer therapy.
RESULTS: Exosomes were coated with CP05-TK-mPEG2000, in which CP05 is a peptide with high affinity to exosomal CD63 and TK could be cleaved by ROS. The resulted exosomes, namely stealth Exo, were electroporated to load RB (photosensitizer Rose Bengal) and Dox (Doxorubicin). We verified that the Stealth Exo@RB (Stealth Exo additionally loaded with RB) could escape MPS while accumulate in the tumor region efficiently in the xenograft model when laser irradiation conducted locally. Additionally, we revealed that the Stealth Exo serves as an efficient platform for Dox delivery. Dox, together with the RB mediated photodynamic therapy induce tumor cell damage synergistically in the tumor region. Moreover, the proposed switchable stealth exosomes minimized the dose of toxic Dox and thus allowed robust tumor immune response.
CONCLUSIONS: Our results indicated that the proposed Stealth Exo greatly improves both the accessibility and efficiency of drug delivery, with minimal chemical or genetic engineering. The proposed Stealth Exo serve as a promising and powerful drug delivery nanoplatform in cancer treatment.

Keywords:  Cancer; Exosomes; Photodynamic therapy; ROS-responsive; Targeted delivery

DOI:  https://doi.org/10.1186/s12951-022-01591-7
Mol Biotechnol. 2022 Aug 23.

Landscape of Clinically Relevant Exosomal tRNA-Derived Non-coding RNAs.

Padmanaban S Suresh, Sanu Thankachan, Thejaswini Venkatesh.

  Exosomes are extra-cellular vesicles that are < 150 nm that is formed by invagination of the plasma membrane and are released as vesicles. These contain proteins, RNA, and DNA as their cargo. In recent times, the non-coding RNA (ncRNA) present within exosomes has been studied extensively in the context of sorting, localization, and their potential as biomarkers. For example, miR-1246, miR-1290, miR-21, and miR-23a are exosomal biomarkers of cancer, and YBX1 (Y-Box Binding Protein 1) is attributed to exosomal RNA sorting. Transfer RNA-derived fragments are a class of small ncRNAs that were discovered in 2009. They are classified as tRFs (tRNA-derived fragments) and tsRNAs (tRNA halves). Interestingly, these tRNA-derived ncRNAs are emerging as biomarkers in various diseases, and these are found in exosomes. To date, the literature has covered only the biomarker potential of plasma/serum tRNA-derived ncRNAs. Hence, in the current review, we discuss the exosomal tRNA-derived fragments that are clinically relevant in pathological conditions.

Keywords:  Exosomes; tRF; tsRNA

DOI:  https://doi.org/10.1007/s12033-022-00546-5
Biomedicines. 2022 Aug 04. pii: 1886. [Epub ahead of print]10(8):

miRNome and Proteome Profiling of Small Extracellular Vesicles Secreted by Human Glioblastoma Cell Lines and Primary Cancer Stem Cells.

Ingrid Cifola, Federica Fratini, Beatrice Cardinali, Valentina Palmieri, Giuliana Gatti, Tommaso Selmi, Sara Donzelli, Andrea Sacconi, Valeriana Cesarini, Hany E Marei, Massimilano Papi, Giovanni Blandino, Carlo Cenciarelli, Germana Falcone, Igea D'Agnano.

  Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite available therapeutic interventions, it is very difficult to treat, and a cure is not yet available. The intra-tumoral GBM heterogeneity is a crucial factor contributing to poor clinical outcomes. GBM derives from a small heterogeneous population of cancer stem cells (CSCs). In cancer tissue, CSCs are concentrated within the so-called niches, where they progress from a slowly proliferating phase. CSCs, as most tumor cells, release extracellular vesicles (EVs) into the surrounding microenvironment. To explore the role of EVs in CSCs and GBM tumor cells, we investigated the miRNA and protein content of the small EVs (sEVs) secreted by two GBM-established cell lines and by GBM primary CSCs using omics analysis. Our data indicate that GBM-sEVs are selectively enriched for miRNAs that are known to display tumor suppressor activity, while their protein cargo is enriched for oncoproteins and tumor-associated proteins. Conversely, among the most up-regulated miRNAs in CSC-sEVs, we also found pro-tumor miRNAs and proteins related to stemness, cell proliferation, and apoptosis. Collectively, our findings support the hypothesis that sEVs selectively incorporate different miRNAs and proteins belonging both to fundamental processes (e.g., cell proliferation, cell death, stemness) as well as to more specialized ones (e.g., EMT, membrane docking, cell junction organization, ncRNA processing).

Keywords:  cancer stem cells; extracellular vesicles; glioblastoma; miRNAs; proteome

DOI:  https://doi.org/10.3390/biomedicines10081886
Bioengineering (Basel). 2022 Aug 03. pii: 363. [Epub ahead of print]9(8):

Naturally Equipped Urinary Exosomes Coated Poly (2-ethyl-2-oxazoline)-Poly (D, L-lactide) Nanocarriers for the Pre-Clinical Translation of Breast Cancer.

Jiang Ni, Yuanyuan Mi, Bei Wang, Yuting Zhu, Yang Ding, Yongjuan Ding, Xia Li.

  Recently, biomimetic nanoparticles for tumor-targeted therapy have attracted intensifying interest. Although exosomes are an excellent biomimetic material, numerous challenges are still hindering its clinical applications, such as low yield, insufficient targeting efficiency, and high cost. In this work, urinary exosomes (UEs) with high expression of CD9 and CD47 were extracted from breast cancer patients by a non-invasive method. Here, a nanotechnology approach is reported for tumor homologous targeting via CD9 and phagocytosis escape via CD47 through UE-coated poly (2-ethyl-2-oxazoline)-poly (D, L-lactide) (PEOz-PLA) nanoparticles (UEPP NPs). The cytotoxic agent doxorubicin (DOX)-loaded UEPP (UEPP-D) NPs with an initial particle size of 61.5 nm showed a burst release under acidic condition mimicking the tumor microenvironment. In vitro experiments revealed that UEPP-D NPs exhibited significantly improved cellular uptake, cytotoxicity, and apoptosis in MCF-7 cell lines as compared to DOX-loaded PEOz-PLA nanoparticles (PP-D NPs) and free DOX. More importantly, anti-phagocytosis and pharmacokinetic studies confirmed that UEPP-D NPs had superior immune escape ability and significantly prolonged the drug's bloodstream circulation in vivo. Finally, UEPP-D NPs showed a markedly higher antitumor efficacy and lower side-toxicity in MCF-7 tumor bearing nude mice model. Thus, this versatile nano-system with immune escape, homologous targeting, and rapid response release characteristics could be a promising tool for breast cancer treatment.

Keywords:  breast cancer; doxorubicin; membrane−coated biomimetic nanoparticles; poly (2−ethyl−2−oxazoline)−poly (D, L−lactide); urinary exosomes

DOI:  https://doi.org/10.3390/bioengineering9080363
J Nanobiotechnology. 2022 Aug 23. 20(1): 384

αvβ3 integrin-specific exosomes engineered with cyclopeptide for targeted delivery of triptolide against malignant melanoma.

Yongwei Gu, Yue Du, Liangdi Jiang, Xiaomeng Tang, Aixue Li, Yunan Zhao, Yitian Lang, Xiaoyan Liu, Jiyong Liu.

   BACKGROUND: Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy.
RESULTS: We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice.
CONCLUSION: The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.

Keywords:  Exosomes; Malignant melanoma; Targeted delivery; Triptolide; cRGD

DOI:  https://doi.org/10.1186/s12951-022-01597-1
Pathol Res Pract. 2022 Aug 17. pii: S0344-0338(22)00325-9. [Epub ahead of print]238 154081

Exosomal microRNAs in breast cancer and their potential in diagnosis, prognosis and treatment prediction.

Ghazale Faraji, Pedram Moeini, Mohammad Hasan Ranjbar.

  The significance of exosomal microRNAs (EmiRs) in breast cancer (BC) diagnosis has been widely addressed over the past decades. However, little information is still available regarding these reliable biomarkers' impacts on BC early diagnosis, prognosis, and treatment outcome predictions, but their great potential in spotting BC early and their predictive essence in BC prognosis and treatment results are promising against this common cancer. The present review focuses on the most recent findings and advancements of EmiRs applications in BC early diagnosis and treatment prediction and identifies current helpful EmiRs that are widely used in this regard.

Keywords:  Breast cancer; Diagnosis; Exosome; MicroRNA; Prognosis; Treatment

DOI:  https://doi.org/10.1016/j.prp.2022.154081
Cancer Sci. 2022 Aug 17.

Plasma exosomal DOK3 reflects immunological states in lung tumor and predicts prognosis of gefitinib treatment.

Ryosuke Ochiai, Kentaro Hayashi, Hiroshi Yamamoto, Risa Fujii, Naomi Saichi, Hiroki Shinchi, Tsuyoshi Ishida, Takeshi Honda, Tetsuo Shimizu, Noriyuki Matsutani, Nobuhiko Seki, Masafumi Kawamura, Koji Ueda.

  To identify liquid biomarkers that predict clinical outcomes of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), we enrolled patients with EGFR gene mutation-positive non-small-cell lung cancer who were intended to receive gefitinib treatment. Using plasma samples obtained prior to gefitinib treatment from 12 enrolled patients, we performed comprehensive proteomic analysis of plasma exosomes to explore proteins correlating with tumor reduction rate (TRR), progression-free survival (PFS), or overall survival (OS). Of the detected 1769 proteins, 119, 130, or 119 proteins demonstrated a strong correlation (|r| > 0.5) with TRR, PFS, or OS, respectively. Interestingly, 34 (29%), 41 (32%), or 27 (23%) of them, respectively, were functionally involved in the regulation of the immune response. CD8α chain was consistently listed as a molecule positively correlated with PFS and OS, suggesting that the long-lasting effects of gefitinib may be due to the antitumor effects of CD8+ T cells, as well as the induction of immunogenic apoptosis of tumor cells by blocking the EGFR signaling pathway. Notably, Doking Protein 3 (DOK3), a molecule involved in B-cell receptor signaling, and some immunoglobulin and complement molecules exhibited a clear correlation with PFS longevity of gefitinib treatment. Indeed, the strong expression of DOK3 in B cells was confirmed within tertiary lymphoid structures of lung cancer tissues derived from patients with long PFS. These findings suggest that the patients with active B-cell and T-cell immunity as a host immunological feature are more likely to benefit from gefitinib therapy. Circulating exosomal DOK3 has the potential as a predictive marker of response to gefitinib indicating this immunological feature.

Keywords:  DOK3; exosome; gefitinib; non-small-cell lung cancer; proteomics

DOI:  https://doi.org/10.1111/cas.15512
Hum Cell. 2022 Aug 25.

Pirfenidone promotes the levels of exosomal miR-200 to down-regulate ZEB1 and represses the epithelial-mesenchymal transition of non-small cell lung cancer cells.

Jingjing Liu, Liming Cao, Yuanyuan Li, Pengbo Deng, Pinhua Pan, Chengping Hu, Huaping Yang.

  Non-small cell lung cancer (NSCLC) is the malignancy with highest mortality and morbidity. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in the tumor microenvironment of NSCLC. This research is performed to explore the biological functions of pirfenidone (PFD) to repress the malignant phenotypes of NSCLC cells, and its regulatory effects on exosomal microRNA-200 (exo-miR-200) derived from CAFs. In the present work, we report that, exo-miR-200 secreted by CAFs restrains the migration, invasion and epithelial-mesenchymal transition (EMT) of NSCLC cells; PFD treatment promotes the secretion of exo-miR-200 from CAFs and enhances the tumor-suppressive properties of exo-miR-200 on NSCLC cells; zinc finger E-box binding homeobox 1 (ZEB1) is identified as a target of miR-200, and PFD treatment repressed the expression of ZEB1 in NSCLC cells via inducing the expression and secretion of miR-200 in CAFs. In conclusion, PFD-induced miR-200 overexpression in CAFs inhibits ZEB1 expression in NSCLC cells, and thus decelerates the migration, invasion and EMT process. Our study may provide clues for the treatment of NSCLC.

Keywords:  EMT; NSCLC; PFD; ZEB1; miR-200

DOI:  https://doi.org/10.1007/s13577-022-00766-6
Zhongguo Fei Ai Za Zhi. 2022 Aug 20. 25(8): 609-614

[Research Progress on the Application of Liquid Biopsy in the Diagnosis  and Treatment of Small Cell Lung Cancer].

Xiaomin Zhang, Mengyuan Xu, Xichuan Li, Yanjun Su.

  Small cell lung cancer (SCLC) is a malignant tumor with strong invasiveness and high mortality. It has the characteristics of easy metastasis, fast growth, high degree of malignancy and strong invasiveness. The prognosis of patients is generally poor. The current clinical diagnosis of SCLC is mainly based on tissue biopsy, which is invasive, long cycle time and high cost. In recent years, liquid biopsy has been gradually applied because of its non-invasive, comprehensive and real-time characteristics that traditional tissue biopsy does not have. The main detection objects of liquid biopsy include circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and exosomes in peripheral blood. The application of liquid biopsy in the clinical treatment of SCLC will help clinicians to improve the detailed diagnosis of SCLC patients, as well as the timely control and response to the treatment response of patients. .

Keywords:  Circulating tumour DNA; Circulating tumour cells; Exosomes; Liquid biopsy; Lung neoplasms

DOI:  https://doi.org/10.3779/j.issn.1009-3419.2022.101.22
Biochim Biophys Acta Mol Basis Dis. 2022 Aug 22. pii: S0925-4439(22)00199-5. [Epub ahead of print] 166528

Intercellular communication in the tumour microecosystem: Mediators and therapeutic approaches for hepatocellular carcinoma.

Wan-Ting Wang, Wei-Lin Jin, Xun Li.

  Hepatocellular carcinoma (HCC), one of the most common tumours worldwide, is one of the main causes of mortality in cancer patients. There are still numerous problems hindering its early diagnosis, which lead to late patients receiving treatment, and these problems need to be solved urgently. The tumour microecosystem is a complex network system comprising seven parts: the hypoxia niche, immune microenvironment, metabolic microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment. Intercellular communication is divided into direct contact and indirect communication. Direct contact communication includes gap junctions, tunneling nanotubes, and receptor-ligand interactions, whereas indirect communication includes exosomes, apoptotic vesicles, and soluble factors. Mechanical communication and cytoplasmic exchange are further means of intercellular communication. Intercellular communication mediates the crosstalk between the tumour microecosystem and the host as well as that between cells and cell-free components in the tumour microecosystem, causing changes in the tumour hallmarks of the HCC microecosystem such as changes in tumour proliferation, invasion, apoptosis, angiogenesis, metastasis, inflammatory response, gene mutation, immune escape, metabolic reprogramming, and therapeutic resistance. Here, we review the role of the above-mentioned intercellular communication in the HCC microecosystem and discuss the advantages of targeted intercellular communication in the clinical diagnosis and treatment of HCC. Finally, the current problems and prospects are discussed.

Keywords:  Exosomes; Hepatocellular carcinoma; Intercellular communication; Tumour microecosystem; Tunneling nanotubes

DOI:  https://doi.org/10.1016/j.bbadis.2022.166528
Life (Basel). 2022 Jul 28. pii: 1143. [Epub ahead of print]12(8):

Combination Therapy Comprising Paclitaxel and 5-Fluorouracil by Using Folic Acid Functionalized Bovine Milk Exosomes Improves the Therapeutic Efficacy against Breast Cancer.

Dulla Naveen Kumar, Aiswarya Chaudhuri, Deepa Dehari, Anusmita Shekher, Subash C Gupta, Shreyasi Majumdar, Sairam Krishnamurthy, Sanjay Singh, Dinesh Kumar, Ashish Kumar Agrawal.

  Paclitaxel (PAC) has been approved by FDA for clinical use (Taxol®), yet dose-dependent severe toxicity due to the adjuvant Cremophor EL® in combination with ethanol is a major drawback. The drawbacks of the current therapy can be overcome by (i) finding a suitable vehicle that cannot only bypass the above adjuvant but also be used to deliver drugs orally and (ii) combining the PAC with some other chemotherapeutics to have the enhanced therapeutic efficacy. In the current work, we have used folic acid (FA) functionalized bovine milk-derived exosomes for oral delivery of PAC in combination with 5-fluorouracil (5-FU). Exosomes before and after the drug loading were found to have a particle size in the range of 80-100 nm, polydispersity index (PDI ~0.20), zeta potential (~-25 mV), entrapment efficiency (~82%), practical drug loading (~28%) and sustained drug release for 48 h. Significant decreases in IC50 were observed in the case of exosomes loaded drugs which further improved following the FA functionalization. FA functionalized coumarin-6-loaded exosomes showed remarkably higher cellular uptake in comparison with free coumarin-6. Moreover, FA-functionalized drug-loaded exosomes showed a higher apoptotic index with better control over cell migration. Collectively, data suggested the enhanced efficacy of the combination following its loading to the folic acid functionalized exosomes against breast cancer.

Keywords:  5-fluorouracil; breast cancer; chemotherapy; co-delivery; exosomes; paclitaxel

DOI:  https://doi.org/10.3390/life12081143