bims-exocan 2022-10-30 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022–10–30
twenty-two papers selected by
Muhammad Rizwan, COMSATS University

Pancreatic Cancer-Derived Exosomes Promote the Proliferation, Invasion, and Metastasis of Pancreatic Cancer by the miR-3960/TFAP2A Axis.
Melanoma-derived exosomes: Versatile extracellular vesicles for diagnosis, metastasis, immune modulation, and treatment of melanoma.
Tumor-derived exosomal non-coding RNAs as diagnostic biomarkers in cancer.
Exosomes in the tumor microenvironment: Promoting cancer progression.
Applications of Exosomes in Diagnosing Muscle Invasive Bladder Cancer.
Tumor-Derived Exosomal miR-29b Reduces Angiogenesis in Pancreatic Cancer by Silencing ROBO1 and SRGAP2.
Role of Extracellular Vesicles in Thyroid Physiology and Diseases: Implications for Diagnosis and Treatment.
Exosomal ncRNAs facilitate interactive 'dialogue' between tumor cells and tumor-associated macrophages.
Docetaxel-resistant triple-negative breast cancer cell-derived exosomal lncRNA LINC00667 reduces the chemosensitivity of breast cancer cells to docetaxel <em>via</em> targeting miR-200b-3p/Bcl-2 axis.
An Exosomal miRNA Biomarker for the Detection of Pancreatic Ductal Adenocarcinoma.
PRR34-AS1 promotes exosome secretion of VEGF and TGF-β via recruiting DDX3X to stabilize Rab27a mRNA in hepatocellular carcinoma.
Salivary Exosomal MicroRNA-486-5p and MicroRNA-10b-5p in Oral and Oropharyngeal Squamous Cell Carcinoma.
si-PDGFRβ-Loaded Exosomes Suppress the Progression of Glioma by Inhibiting the Oxidative Associated PI3K/Akt/EZH2 Signaling Pathway.
IL-2 Modulates TAMs Derived Exosomal MiRNAs to Ameliorate Hepatocellular Carcinoma Development and Progression.
Loss of exosomal micro-RNA-200b-3p from hypoxia cancer-associated fibroblasts reduces sensitivity to 5-flourouracil in colorectal cancer through targeting high-mobility group box 3.
Phospholipase D and cancer metastasis: A focus on exosomes.
A Different Exosome Secretion Pattern Characterizes Patient-Derived Colorectal Cancer Multicellular Spheroids and Their Mouse Xenografts.
Exosomal Plasma Gelsolin Is an Immunosuppressive Mediator in the Ovarian Tumor Microenvironment and a Determinant of Chemoresistance.
Exosome-Mediated Transfer of miR-3613-5p Enhances Doxorubicin Resistance by Suppression of PTEN Expression in Breast Cancer Cells.
Circulating plasma exosomal long non-coding RNAs LINC00265, LINC00467, UCA1, and SNHG1 as biomarkers for diagnosis and treatment monitoring of acute myeloid leukemia.
The salivary exosomal microRNA as a potential biomarker in patients with periodontitis and oral cancers.
Exosomal hsa_circRNA_047733 integrated with clinical features for preoperative prediction of lymph node metastasis risk in oral squamous cell carcinoma.

J Oncol. 2022 ;2022 3590326

Pancreatic Cancer-Derived Exosomes Promote the Proliferation, Invasion, and Metastasis of Pancreatic Cancer by the miR-3960/TFAP2A Axis.

Jinhong Wu.

Background: The microRNAs (miRNAs) in cancer-derived exosomes have the ability to change tumor microenvironment. This study aims to investigate the role of miRNA in cancer-derived exosomes in pancreatic cancer (PC).
Methods: Based on the analysis of PC-derived and healthy exosomes by bioinformatics analysis and quantitative real-time PCR validation, the miR-3960 was identified to be the most significantly different miRNA, and TFAP2A proved as its potential target gene. Besides, the exosomes were isolated from PANC-1 cells and identified. After that, PANC-1 cells were treated with the isolated exosomes or transfected with miR-3960 mimics or si-TFAP2A, the effect of PC-derived exosomes, as well as the miR-3960/TFAP2A axis in PC cells, were assessed by the CCK-8, EDU staining, Transwell, cell colony formation, and flow cytometry assays. Furthermore, the effects of exosomes and the miR-3960/TFAP2A axis on PC tumor growth were observed in tumor-bearing mice by the measurement of tumor weight and volume, and hematoxylin-eosin staining. Moreover, the expressions of TFAP2A/PTEN/AKT signaling proteins were detected by Western blot.
Results: PC-derived exosomes were isolated successfully and proved to have promotion effects on the proliferation, metastasis, and invasion of PC cells both in vitro and tumor growth in vivo. Also, the PC-derived exosomes upregulated the TFAP2A, Bcl-2, and p-AKT/AKT protein levels, and inhibited PTEN and Bax levels and PANC-1 cell apoptosis. Overexpression of miR-3960 antagonized the promotion effect of exosomes on PC cells and the TFAP2A/PTEN/AKT signaling pathway, inhibiting the growth of tumors. Besides, si-TFAP2A enhanced the inhibitory effect of miR-3960 in PC.
Conclusion: MiR-3960 antagonizes the promotion effect of tumor-derived exosomes on the proliferation, invasion, and metastasis of PC via suppressing TFAP2A.

DOI: https://doi.org/10.1155/2022/3590326
Int Immunopharmacol. 2022 Oct 20. pii: S1567-5769(22)00804-9. [Epub ahead of print]113(Pt A): 109320

Melanoma-derived exosomes: Versatile extracellular vesicles for diagnosis, metastasis, immune modulation, and treatment of melanoma.

Seyedeh Alia Moosavian, Maryam Hashemi, Leila Etemad, Sara Daneshmand, Zahra Salmasi.

  Malignant melanoma is one of the most aggressive human neoplasms responsible for the majority of skin cancer-related deaths in its advanced stages. Achieving a thorough knowledge of reliable tumor-originated biomarkers and molecular mechanisms can provide many practical approaches and guide the way towards the design of rational curative therapies to improve the survival rate of patients. Cancer cells, including melanoma cells, release high amounts of a broad family of nanovesicles, containing different biochemical messages. Exosomes are a type of extracellular vesicles (EVs) that are generated by different cell populations and participate in the intercellular communication of surrounding and distant cells/tissues. Exosome cargo consists of several biologically active proteins and genomic components. Tumor cells tend to release exosomes throughout the tumor microenvironment, which affects the biological performance of recipient cells. Recent evidence provides new perspective in melanoma management, showing that melanoma-derived exosomes (MEXs) may represent a valuable tool for melanoma diagnosis and treatment. This review presents a summary of the potential role of MEXs in the early diagnosis of melanoma. More importantly, we also discuss the capacity of MEXs in reproducing numerous tumor-related functions required for angiogenesis, immune system modulation, induction of migration and metastatic spread, tumor chemotherapy resistance, and melanoma tumor progression and survival. Considering the advent of novel bioengineering and immunotherapy approaches, natural exosomes can be exerted as nanocarriers and cancer vaccines to facilitate the conduction of more efficient cancer treatment.

Keywords:  Exosomes; Extracellular vesicles; Melanoma; Metastasis; Vaccine

DOI:  https://doi.org/10.1016/j.intimp.2022.109320
Cell Mol Life Sci. 2022 Oct 29. 79(11): 572

Tumor-derived exosomal non-coding RNAs as diagnostic biomarkers in cancer.

Nasim Ebrahimi, Ferdos Faghihkhorasani, Siavash Seifollahy Fakhr, Parichehr Roozbahani Moghaddam, Elnaz Yazdani, Zahra Kheradmand, Fatemeh Rezaei-Tazangi, Samaneh Adelian, Halimeh Mobarak, Michael R Hamblin, Amir Reza Aref.

  Almost all clinical oncologists agree that the discovery of reliable, accessible, and non-invasive biomarkers is necessary to decrease cancer mortality. It is possible to employ reliable biomarkers to diagnose cancer in the early stages, predict the patient prognosis, follow up the response to treatment, and estimate the risk of disease recurrence with high sensitivity and specificity. Extracellular vesicles (EVs), especially exosomes, have been the focus of translational research to develop such biomarkers over the past decade. The abundance and distribution of exosomes in bodily fluids, including serum, saliva, and urine, as well as their ability to transport various biomolecules (nucleic acids, proteins, and lipids) derived from their parent cells, make exosomes reliable, accessible, and potent biomarkers for diagnosis and follow-up of solid and hematopoietic tumors. In addition, exosomes play a vital role in various cellular processes, including tumor progression, by participating in intercellular communication. Although these advantages underline the high potential of tumor-derived exosomes as diagnostic biomarkers, the lack of standardized effective methods for their isolation, identification, and precise characterization makes their application challenging in clinical settings. We discuss the importance of non-coding RNAs (ncRNAs) in cellular processes, and the role of tumor-derived exosomes containing ncRNAs as potential biomarkers in several types of cancer. In addition, the advantages and challenges of these studies for translation into clinical applications are covered.

Keywords:  Cancer prognosis; Diagnostic biomarkers; Early diagnosis; Non-coding RNAs; Tumor-derived exosomes

DOI:  https://doi.org/10.1007/s00018-022-04552-3
Front Immunol. 2022 ;13 1025218

Exosomes in the tumor microenvironment: Promoting cancer progression.

Ye Jin, Jianming Xing, Kejin Xu, Da Liu, Yue Zhuo.

  Exosomes, which are extracellular vesicles produced by endosomes, are important performers of intercellular communication functions. For more than three decades, there has been a growing awareness of exosomes as the contents of the tumor microenvironment and their intimate connection to the development of cancer. The composition, generation, and uptake of exosomes as well as their roles in tumor metastasis, angiogenesis, and immunosuppression are discussed in this paper. In order to stop the progression of cancer, it is crucial to find new diagnostic biomarkers and therapeutic targets for the disease. Knowing the biological characteristics of exosomes and their functions in tumor development helps in this endeavor.

Keywords:  angiogenesis; cancer; exosomes; immunosuppression; metastasis; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1025218
Pharmaceutics. 2022 Sep 23. pii: 2027. [Epub ahead of print]14(10):

Applications of Exosomes in Diagnosing Muscle Invasive Bladder Cancer.

Jillian Marie Walker, Padraic O'Malley, Mei He.

  Muscle Invasive Bladder Cancer (MIBC) is a subset of bladder cancer with a significant risk for metastases and death. It accounts for nearly 25% of bladder cancer diagnoses. A diagnostic work-up for MIBC is inclusive of urologic evaluation, radiographic imaging with a CT scan, urinalysis, and cystoscopy. These evaluations, especially cystoscopy, are invasive and carry the risk of secondary health concerns. Non-invasive diagnostics such as urine cytology are an attractive alternative currently being investigated to mitigate the requirement for cystoscopy. A pitfall in urine cytology is the lack of available options with high reliability, specificity, and sensitivity to malignant bladder cells. Exosomes are a novel biomarker source which could resolve some of the concerns with urine cytology, due to the high specificity as the surrogates of tumor cells. This review serves to define muscle invasive bladder cancer, current urine cytology methods, the role of exosomes in MIBC, and exosomes application as a diagnostic tool in MIBC. Urinary exosomes as the specific populations of extracellular vesicles could provide additional biomarkers with specificity and sensitivity to bladder malignancies, which are a consistent source of cellular information to direct clinicians for developing treatment strategies. Given its strong presence and differentiation ability between normal and cancerous cells, exosome-based urine cytology is highly promising in providing a perspective of a patient's bladder cancer.

Keywords:  biomarkers; bladder cancer diagnosis; bladder cancer screening; exosomes; muscle invasive bladder cancer

DOI:  https://doi.org/10.3390/pharmaceutics14102027
J Immunol Res. 2022 ;2022 4769385

Tumor-Derived Exosomal miR-29b Reduces Angiogenesis in Pancreatic Cancer by Silencing ROBO1 and SRGAP2.

Lihua Wang, Lei Yang, Tingting Zhuang, Xiuqing Shi.

Background: Exosomal miR-29b reportedly plays a role during cancer metastasis. However, its exact function and underlying mechanism during pancreatic cancer (PC) have not been investigated.
Methods: Exosomes from PC cells were prepared and identified. Transmission electron microscopy (TEM) and confocal microscopy were used to examine structural characteristics of the exosomes and verify their internalization by human umbilical vein endothelial cells (HUVECs). The tube formation and migration abilities of HUVECs were detected. VEGF content was assessed by ELISA. GW4869 was used to suppress exosome release. Luciferase reporter assays were performed to verify the predicted interaction of miR-29b with ROBO1 and SRGAP2 mRNA.
Results: Exosomal miRNA-29b was differentially expressed in the conditioned medium of PC cells. Exosomes from PC cells were verified by TEM and western blotting. Treatment with the exosomal inhibitor (GW4869) prevented an increase in miR-29b expression and recused the reduced VEGF expression and tube formation and migration abilities of HUVECs cocultured with BxPC3 and AsPC-1 cells that overexpressed miR-29b. Furthermore, the downregulation of ROBO1 and SRGAP2 in cocultured HUVECs was also reduced after additional treatment with GW4869. After incubation with miR-29b exosomes, HUVECs had lower VEGF concentrations and reduced migration and tube formation rates; however, those effects were eliminated by subsequent transfection with the miR-29b inhibitor. Luciferase reporter assays verified the interaction of miR-29b with ROBO1 and SRGAP2. That interaction was also supported by rescue assays showing that overexpression of ROBO1 and SRGAP2 also reduced the antiangiogenic effect of exosomal miR-29b in HUVECs.
Conclusion: Exosomal miR-29b originating from PC cells protected HUVECs from PC cell-induced angiogenesis by attenuating ROBO1 and SRGAP2 expression. Our findings suggest a strategy for treating PC.

DOI: https://doi.org/10.1155/2022/4769385
Biomedicines. 2022 Oct 15. pii: 2585. [Epub ahead of print]10(10):

Role of Extracellular Vesicles in Thyroid Physiology and Diseases: Implications for Diagnosis and Treatment.

Ophélie Delcorte, Jonathan Degosserie, Christophe E Pierreux.

  Extracellular vesicles are spherical subcellular structures delimited by a lipid bilayer and released by most cells in the human body. They are loaded with a myriad of molecules (i.e., nucleic acids and proteins) depending on their cell of origin and provide the ability to transmit a message to surrounding or distant target cells. In several organs, including the thyroid, abundant recent literature reports that extracellular vesicles are responsible for intercellular communication in physiological and pathological processes, and that their utilization as a potential biomarker of pathological states (i.e., cancer, autoimmune diseases) or as therapeutic delivery vehicles promise clinical options. In this review, we present the current knowledge and understanding regarding the role of extracellular vesicles in developing thyroid diseases and diagnosis.

Keywords:  Hashimoto; biomarker; exosomes; extracellular vesicles; graves; therapy; thyroid; thyroid cancer

DOI:  https://doi.org/10.3390/biomedicines10102585
Cancer Lett. 2022 Oct 25. pii: S0304-3835(22)00462-1. [Epub ahead of print] 215975

Exosomal ncRNAs facilitate interactive 'dialogue' between tumor cells and tumor-associated macrophages.

Xintong Zhou, Qi Liu, Xiaomin Wang, Xiaoyu Yao, Baogang Zhang, Jibiao Wu, Changgang Sun.

  As a biological carrier, exosomes participate in the communication between various kinds of cells, and can mediate the interactive 'dialogue' between tumor cells and tumor-associated macrophages (TAMs). TAMs are the most abundant cell population in the tumor stroma and are an important part of the tumor immune microenvironment. Various stimulating factors in the tumor microenvironment influence the polarization of TAMs into multiple phenotypes, such as M1 and M2. It plays a dual role in tumor immunity by both promoting and inhibiting tumor growth. Exosome-encapsulated non-coding RNAs (ncRNAs) participate in the interactive 'dialogue' between exosome-mediated TAMs and tumor cells. Tumor-derived exosomal ncRNAs can promote macrophage polarization, whereas exosomal ncRNAs derived from TAMs can affect tumor proliferation, metastasis, angiogenesis, and chemotherapy resistance. The present review summarizes the dual effects of exosomal ncRNAs on tumor cells and TAMs, and discusses the application of exosomal ncRNAs as a potential diagnostic or prognostic marker and drug delivery system, to provide a new perspective and potential therapeutic drugs on targeting exosomes and macrophages in the treatment of tumors.

Keywords:  Biomarkers; Clinical trials; Drug delivery; Macrophage polarization; Natural compounds; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2022.215975
Eur J Histochem. 2022 Oct 25. 66(4):

Docetaxel-resistant triple-negative breast cancer cell-derived exosomal lncRNA LINC00667 reduces the chemosensitivity of breast cancer cells to docetaxel <em>via</em> targeting miR-200b-3p/Bcl-2 axis.

Jindong Li, Jie Kang, Weiyan Liu, Jiazhe Liu, Gaofeng Pan, Anwei Mao, Qing Zhang, Jingfeng Lu, Junbin Ding, Hongchang Li.

Development of docetaxel (TXT) resistance is a major obstacle for triple-negative breast cancer (TNBC) treatment. Additionally, chemoresistant cell-derived exosomes were able to change the chemo-response of chemosensitive recipient cells via transportation of lncRNAs. It has been shown that lncRNA LINC00667 level was significantly elevated in breast cancer tissues. Therefore, we explored whether LINC00667 level is increased in TXT-resistant TNBC cell-derived exosomes. In addition, whether exosomal LINC00667 derived from TXT-resistant TNBC cell could affect TXT sensitivity in TXT-sensitive TNBC cells was investigated as well. In the present study, exosomes were isolated from the TXT-resistant TNBC cells and from TXT-sensitive TNBC cells. Next, the level of LINC00667 in the isolated exosomes was detected with RT-qPCR. We found that LINC00667 expression was obviously elevated in TXT-resistant TNBC cell-derived exosomes compared to that in TXT-sensitive TNBC cell-derived exosomes. In addition, LINC00667 could be transferred from TXT-resistant TNBC cells to TNBC cells via exosomes. Moreover, TXT-resistant TNBC cell secreted exosomal LINC00667 markedly reduced the sensitivity of TNBC cells to TXT via upregulation of Bcl-2. Meanwhile, downregulation of LINC00667 notably enhanced the sensitivity of TXT-resistant TNBC cells to TXT through downregulation of Bcl-2. Additionally, LINC00667 was considered to be a ceRNA to sponge miR-200b-3p, thereby elevating Bcl-2 expression. Collectively, TXT-resistant TNBC cell-derived exosomal LINC00667 could decrease the chemosensitivity of TNBC cells to TXT via regulating miR-200b-3p/Bcl-2 axis. These findings suggested that LINC00667 might serve as a promising target for enhancing sensitivity of TNBC cells to TXT therapy.

DOI: https://doi.org/10.4081/ejh.2022.3529
Biosensors (Basel). 2022 Oct 06. pii: 831. [Epub ahead of print]12(10):

An Exosomal miRNA Biomarker for the Detection of Pancreatic Ductal Adenocarcinoma.

Amy Makler, Ramaswamy Narayanan, Waseem Asghar.

  Pancreatic ductal adenocarcinoma (PDAC) remains a difficult tumor to diagnose and treat. To date, PDAC lacks routine screening with no markers available for early detection. Exosomes are 40-150 nm-sized extracellular vesicles that contain DNA, RNA, and proteins. These exosomes are released by all cell types into circulation and thus can be harvested from patient body fluids, thereby facilitating a non-invasive method for PDAC detection. A bioinformatics analysis was conducted utilizing publicly available miRNA pancreatic cancer expression and genome databases. Through this analysis, we identified 18 miRNA with strong potential for PDAC detection. From this analysis, 10 (MIR31, MIR93, MIR133A1, MIR210, MIR330, MIR339, MIR425, MIR429, MIR1208, and MIR3620) were chosen due to high copy number variation as well as their potential to differentiate patients with chronic pancreatitis, neoplasms, and PDAC. These 10 were examined for their mature miRNA expression patterns, giving rise to 18 mature miRs for further analysis. Exosomal RNA from cell culture media was analyzed via RTqPCR and seven mature miRs exhibited statistical significance (miR-31-5p, miR-31-3p, miR-210-3p, miR-339-5p, miR-425-5p, miR-425-3p, and miR-429). These identified biomarkers can potentially be used for early detection of PDAC.

Keywords:  biomarker; cancer; diagnostics; exosomes; miRNA; pancreatic cancer

DOI:  https://doi.org/10.3390/bios12100831
J Transl Med. 2022 Oct 27. 20(1): 491

PRR34-AS1 promotes exosome secretion of VEGF and TGF-β via recruiting DDX3X to stabilize Rab27a mRNA in hepatocellular carcinoma.

Zhilei Zhang, Ye Zhou, Yuming Jia, Chao Wang, Meng Zhang, Zhuo Xu.

   BACKGROUND: Exosomes are deemed to be an important tool of intercellular communicators in cancer cells. Our study investigated the role of PRR34 long non-coding RNA antisense RNA 1 (PRR34-AS1) in regulating exosome secretion in hepatocellular carcinoma (HCC) cells.
METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) analyzed the expression of PRR34-AS1. We assessed the function of PRR34-AS1 on the biological changes of THLE-3 cells and HCC cells. The downstream interaction between RNAS was assessed by mechanistic experiments.
RESULTS: PRR34-AS1 expression was upregulated in HCC cells in comparison to THLE-3 cells. PRR34-AS1 depletion repressed HCC cell proliferation, migration and invasion as well as EMT phenotype, while PRR34-AS1 up-regulation accelerated the malignant phenotypes of THLE-3 cells. PRR34-AS1 recruited DDX3X to stabilize the mRNA level of exosomal protein Rab27a. Moreover, PRR34-AS1 facilitated the malignant phenotypes of THLE-3 cells by elevating Rab27a expression to promote the exosome secretion of VEGF and TGF-β in HCC cells.
CONCLUSIONS: The current study revealed a novel function of PRR34-AS1 in accelerating exosome secretion in HCC cells and offered an insight into lncRNA function in the regulation of tumor cell biology.

Keywords:  Exosome; Hepatocellular carcinoma; PRR34-AS1; Rab27a

DOI:  https://doi.org/10.1186/s12967-022-03628-9
Medicina (Kaunas). 2022 Oct 18. pii: 1478. [Epub ahead of print]58(10):

Salivary Exosomal MicroRNA-486-5p and MicroRNA-10b-5p in Oral and Oropharyngeal Squamous Cell Carcinoma.

Cosmin Ioan Faur, Rareș Călin Roman, Ancuța Jurj, Lajos Raduly, Oana Almășan, Horațiu Rotaru, Magdalena Chirilă, Mădălina Anca Moldovan, Mihaela Hedeșiu, Cristian Dinu.

  Background and Objectives: The research aimed at evaluating the capacity of salivary exosomal miR-10b-5p and miR-486-5p for oral and oropharyngeal cancer detection. Materials and Methods: The saliva samples were harvested from histopathological diagnosed oral and oropharyngeal squamous cell carcinoma patients and healthy volunteer subjects. The exosomes were isolated by differential ultracentrifugation and quantified by Nano Track Analysis. The microRNAs were extracted and quantified from salivary exosomes by quantitative Real-Time Polymerase Chain Reaction. Results: This research comprised fifty participants. When compared to healthy controls, salivary exosomal miR-486-5p was elevated and miR-10b-5p was reduced in oral and oropharyngeal squamous cell carcinoma. Moreover, miR-486-5p had a high expression level in stage II of cancer in comparison to the other cancer stages. The cancer samples presented an increased exosome dimension compared to the control samples. Conclusions: Salivary exosomal miR-10b-5p and miR-486-5p have an altered expression in oral and oropharyngeal cancer.

Keywords:  head and neck neoplasms; liquid biopsy; microRNA; oral malignancy; oropharyngeal cancer; salivary exosomes

DOI:  https://doi.org/10.3390/medicina58101478
Oxid Med Cell Longev. 2022 ;2022 5081439

si-PDGFRβ-Loaded Exosomes Suppress the Progression of Glioma by Inhibiting the Oxidative Associated PI3K/Akt/EZH2 Signaling Pathway.

Yuping Li, Hailong Yu, Qiang Ma, Min Wei, Xiaoguang Liu, Yajie Qi, Chen Li, Lun Dong, Hengzhu Zhang.

This study investigated the possibility of exosomes loaded with si-PDGFRβ ability to suppress the progression of glioma. Common gliomas develop from neuroglial progenitor cells. Many variables affect the survival rate and occurrence of gliomas. Understanding oxidative stress processes and creating new, efficient treatments are crucial because oxidative stress is linked to the development of brain tumors. For this purpose, selected clinical samples were subjected to various tests like quantitative real-time PCR, Cignal Finder RTK signaling 7-pathway reporter array analysis, CCK-8 analysis, flow cytometry, and immunoblotting. Here, we demonstrated that PDGFRβ expression was increased in glioma patients. Following that, cell-derived exosomes were extracted and collected and traced in vivo, and selected tissue samples were subjected to immunohistochemical analysis. The results indicated that the knockdown of PDGFRβ (si-PDGFRβ) inhibited the proliferation of glioma cells. Besides this, si-PDGFRβ-loaded exosomes induced a similar antitumor effect in glioma cells. The anticancer effect of si-PDGFRβ-loaded exosomes was mediated by the inactivation of the PI3K/Akt/EZH2 pathway. Finally, we verified that this exosome delivery system, si-PDGFRβ-loaded exosomes, had robust targeting and no associated toxicity. In conclusion, the study confirmed that si-PDGFRβ-loaded exosomes inhibit glioma progression via inactivating the PI3K/Akt/EZH2 signaling pathway.

DOI: https://doi.org/10.1155/2022/5081439
J Oncol. 2022 ;2022 3445350

IL-2 Modulates TAMs Derived Exosomal MiRNAs to Ameliorate Hepatocellular Carcinoma Development and Progression.

Hao Chen, Chao Tang, Chun Tan, Fei Wu, Zhenhan Li, Wenyan Ji, Linming Lu, Chongjun Xu, Zhengchao Shen, Yanqiang Huang.

Background. Interleukin-2 (IL-2) is proved to play an irreplaceable role in antitumor regulation in numerous experimental and clinical trials. Tumor-associated macrophages (TAMs) are able to release exosomes to promote the development and progression of hepatocellular carcinoma (HCC) as essential component of microenvironment. In this study, our intention is to explore the effects of the exosomes from TAMs with IL-2 treatment on HCC development. TAMs were collected and cultured from HCC tissues. The exosomes from the TAMs treated with IL-2 (ExoIL2-TAM) or not (ExoTAM) were identified and used to treat HCC cells in vivo and in vitro. The proliferation, apoptosis, and metastasis of HCC cells were measured. The changes of miRNAs in exosomes were explored to clarify the possible mechanisms. Both decrease of cell proliferation and metastasis and increase of apoptosis were observed with ExoIL2-TAM treatment compared with ExoTAM in vivo and in vitro. miR-375 was obviously augmented in ExoIL2-TAM and HCC cells treated with ExoIL2-TAM. Taken together, IL-2 may modulate exosomal miRNAs from TAMs to ameliorate hepatocellular carcinoma development. This study provides a new perspective to explain the mechanism by which IL-2 inhibits hepatocellular carcinoma and implies the potential clinical value of exosomal miRNAs released by TAMs.

DOI: https://doi.org/10.1155/2022/3445350
Front Oncol. 2022 ;12 920131

Loss of exosomal micro-RNA-200b-3p from hypoxia cancer-associated fibroblasts reduces sensitivity to 5-flourouracil in colorectal cancer through targeting high-mobility group box 3.

Hang Yuan, Bingchen Chen, Rui Chai, Wenjing Gong, Ziang Wan, Boan Zheng, Xinye Hu, Yang Guo, Shan Gao, Qiaoqiong Dai, Peng Yu, Shiliang Tu.

  Hypoxia-mediated tumor progression is a major problem in colorectal cancer (CRC). MicroRNA (miR)-200b-3p can attenuate tumorigenesis in CRC, while exosomal miRNAs derived from cancer-associated fibroblasts (CAFs) can promote cancer progression. Nevertheless, the function of exosomal miR-200b-3p derived from CAFs in CRC remains unclear. In this study, CAFs and normal fibroblasts (NFs) were isolated from CRC and adjacent normal tissues. Next, exosomes were isolated from the supernatants of CAFs cultured under normoxia and hypoxia. Cell viability was tested using the cell counting kit-8 assay, and flow cytometry was used to assess cell apoptosis. Cell invasion and migration were evaluated using the transwell assay. Dual-luciferase was used to investigate the relationship between miR-200b-3p and high-mobility group box 3 (HMBG3). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the miR-200b-3p and HMBG3 level. Our results found that the miR-200b-3p level was sharply reduced in CRC tissues compared to adjacent normal tissues. Additionally, the miR-200b-3p level was reduced in exosomes derived from hypoxic CAFs compared to exosomes derived from CAFs under normoxia. Exosomes derived from hypoxic CAFs weakened the sensitivity of CRC cells to 5-fluorouracil (5-FU) compared to hypoxic CAFs-derived exosomes. However, hypoxic CAFs-derived exosomes with upregulated miR-200b-3p increased the sensitivity of CRC cells to 5-fluorouracil (5-FU) compared to hypoxic CAFs-derived exosomes. In addition, HMBG3 was identified as the downstream target of miR-200b-3p in CRC cells, and its overexpression partially reversed the anti-tumor effect of the miR-200b-3p agomir on CRC via the mediation of the β-catenin/c-Myc axis. Furthermore, compared to exosomes derived from normoxia CAFs, exosomes derived from hypoxic CAFs weakened the therapeutic effects of 5-FU on CRC in vivo via the upregulation of HMGB3 levels. Collectively, the loss of exosomal miR-200b-3p in hypoxia CAFs reduced the sensitivity to 5-FU in CRC by targeting HMGB3. Thus, our research outlines a novel method for the treatment of CRC.

Keywords:  HMGB3; exosome; hypoxia; miR-200b-3p; miR-200b-3p directly targets HMGB3 CAFs

DOI:  https://doi.org/10.3389/fonc.2022.920131
Adv Biol Regul. 2022 Oct 14. pii: S2212-4926(22)00064-1. [Epub ahead of print] 100924

Phospholipase D and cancer metastasis: A focus on exosomes.

Alexander Wolf, Emeline Tanguy, Qili Wang, Stéphane Gasman, Nicolas Vitale.

  In mammals, phospholipase D (PLD) enzymes involve 6 isoforms, of which only three have established lipase activity to produce the signaling lipid phosphatidic acid (PA). This phospholipase activity has been postulated to contribute to cancer progression for over three decades now, but the exact mechanisms involved have yet to be uncovered. Indeed, using various models, an altered PLD activity has been proposed altogether to increase cell survival rate, promote angiogenesis, boost rapamycin resistance, and favor metastasis. Although for some part, the molecular pathways by which this increase in PA is pro-oncogenic are partially known, the pleiotropic functions of PA make it quite difficult to distinguish which among these simple signaling pathways is responsible for each of these PLD facets. In this review, we will describe an additional potential contribution of PA generated by PLD1 and PLD2 in the biogenesis, secretion, and uptake of exosomes. Those extracellular vesicles are now viewed as membrane vehicles that carry informative molecules able to modify the fate of receiving cells at distance from the original tumor to favor homing of metastasis. The perspectives for a better understanding of these complex role of PLDs will be discussed.

Keywords:  Extracellular vesicles; Metastasis; Multivesicular bodies; Phosphatidic acid; Phospholipase D; Tumor

DOI:  https://doi.org/10.1016/j.jbior.2022.100924
Biology (Basel). 2022 Sep 29. pii: 1427. [Epub ahead of print]11(10):

A Different Exosome Secretion Pattern Characterizes Patient-Derived Colorectal Cancer Multicellular Spheroids and Their Mouse Xenografts.

Michela Relucenti, Federica Francescangeli, Maria Laura De Angelis, Vito D'Andrea, Selenia Miglietta, Orlando Donfrancesco, Xiaobo Li, Rui Chen, Ann Zeuner, Giuseppe Familiari.

  Up-to-date in vitro and in vivo preclinical models expressing the patient-specific cancer lineage responsible for CRC and its metastatic behavior and responsiveness to therapy are needed. Exosomes' role in tumorigenesis and the metastatic process was demonstrated, and the material content and size of the exosomes are associated with a poor prognosis of CRC. Exosomes are generally imagined after their recovery from blood serum as isolated entities, and our work aims to investigate them "in situ" in their native environment by scanning and transmission electron microscopy to understand their secretion modalities. We studied CRC stem cells in patient-derived multicellular tumor spheroids (MTSs) and in their mouse xenograft to find possible differences in terms of exosome amount, size, and secretion site between in vitro and in vivo models. We observed that MTSs' exosome secretion patterns depend on their structural complexity: few-layer MTSs show a lesser exosome secretion, limited to the apical domain of cancer cells, secretion increases in multilayered MTSs, and it develops from apical and basolateral cancer cells domains. In xenograft models, exosome secretion occurs from all cancer cell domains, and it is quantitatively greater than that observed in MTSs. This difference in exosome secretion pattern between MTSs and xenografts may be due to the influence of surrounding non-tumor cells.

Keywords:  colorectal cancer; exosomes; scanning electron microscopy; spheroid; transmission electron microscopy; xenograft

DOI:  https://doi.org/10.3390/biology11101427
Cells. 2022 Oct 20. pii: 3305. [Epub ahead of print]11(20):

Exosomal Plasma Gelsolin Is an Immunosuppressive Mediator in the Ovarian Tumor Microenvironment and a Determinant of Chemoresistance.

Toshimichi Onuma, Meshach Asare-Werehene, Yoshio Yoshida, Benjamin K Tsang.

  Ovarian Cancer (OVCA) is the most fatal gynecologic cancer and has a 5-year survival rate less than 45%. This is mainly due to late diagnosis and drug resistance. Overexpression of plasma gelsolin (pGSN) is key contributing factor to OVCA chemoresistance and immunosuppression. Gelsolin (GSN) is a multifunctional protein that regulates the activity of actin filaments by cleavage, capping, and nucleation. Generally, it plays an important role in cytoskeletal remodeling. GSN has three isoforms: cytosolic GSN, plasma GSN (pGSN), and gelsolin-3. Exosomes containing pGSN are released and contribute to the progression of OVCA. This review describes how pGSN overexpression inhibits chemotherapy-induced apoptosis and triggers positive feedback loops of pGSN expression. It also describes the mechanisms by which exosomal pGSN promotes apoptosis and dysfunction in tumor-killing immune cells. A discussion on the potential of pGSN as a prognostic, diagnostic, and therapeutic marker is also presented herein.

Keywords:  T cells; apoptosis; chemoresistance; extracellular vesicles (EVs); immune cells; macrophages; ovarian cancer; plasma gelsolin (pGSN); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cells11203305
J Oncol. 2022 ;2022 9494910

Exosome-Mediated Transfer of miR-3613-5p Enhances Doxorubicin Resistance by Suppression of PTEN Expression in Breast Cancer Cells.

Lin Luo, Xin Zhang, Yiliyaer Rousuli, Alibiyati Aini.

Breast cancer is the most common malignancy among women worldwide, and patients easily develop resistance to the first-line drug doxorubicin. To elucidate the molecular mechanism of drug resistance in breast cancer is imperative. Exosomes mediate the crosstalk between neighboring cells and intercellular communication. Incorporation of miRNAs into exosomes prevents the degradation and facilitates the intercellular communication, which has been indicated in regulation of drug resistance. qRT-PCR revealed that miR-3613-5p is upregulated in drug-resistant breast cancer, and miR-3613-5p exists in exosomes. It is predicted that miR-3613-5p can bind to the tumor suppressor gene PTEN. In this study, our results showed that miR-3613-5p was upregulated in drug-resistant tissue and in exosomes of breast cancer cells resistant to doxorubicin. CCK8, crystal violet staining, and flow cytometry analysis demonstrated that exosome mediated miR-3613-5p transfer and enhanced the resistance to doxorubicin of breast cancer cells. Western blotting showed that miR-3613-5p could target PTEN and regulate the expression of PTEN. Exosome-mediated transfer of miR-3613-5p enhanced the resistance to doxorubicin by inhibition of PTEN in breast cancer cells.

DOI: https://doi.org/10.1155/2022/9494910
Front Oncol. 2022 ;12 1033143

Circulating plasma exosomal long non-coding RNAs LINC00265, LINC00467, UCA1, and SNHG1 as biomarkers for diagnosis and treatment monitoring of acute myeloid leukemia.

Qiaoling Xiao, Can Lin, Meixi Peng, Jun Ren, Yipei Jing, Li Lei, Yonghong Tao, Junpeng Huang, Jing Yang, Minghui Sun, Jing Wu, Zailin Yang, Zesong Yang, Ling Zhang.

  Exosomal long non-coding RNAs (lncRNAs) have emerged as a cell-free biomarker for clinical evaluation of cancers. However, the potential clinical applications of exosomal lncRNAs in acute myeloid leukemia (AML) remain unclear. Herein, we attempted to identify plasma exosomal lncRNAs as prospective biomarkers for AML. In this study, plasma exosomes were first successfully extracted from AML patients and healthy donors (HD). Subsequently, the downregulated plasma exosomal lncRNAs (LINC00265, LINC00467, and UCA1) and the upregulated plasma exosomal lncRNA (SNHG1) were identified in AML patients (n=65) compared to HD (n=20). Notably, individual exosomal LINC00265, LINC00467, UCA1, or SNHG1 had a capability for discriminating AML patients from HD, and their combination displayed better efficiency. Furthermore, exosomal LINC00265 and LINC00467 were increased expressed in patients achieving complete remission after chemotherapy. Importantly, there was upregulation of exosomal LINC00265 and downregulation of exosomal SNHG1 upon allogeneic hematopoietic stem cell transplantation. Additionally, these lncRNAs were high stability in plasma exosomes. Exosomal LINC00265, LINC00467, UCA1, and SNHG1 may act as promising cell-free biomarkers for AML diagnosis and treatment monitoring and provide a new frontier of liquid biopsy for this type of cancer.

Keywords:  LINC00265; LINC00467; SNHG1; UCA1; acute myeloid leukemia; biomarker; exosome; long non-coding RNA

DOI:  https://doi.org/10.3389/fonc.2022.1033143
Chem Biol Drug Des. 2022 Oct 27.

The salivary exosomal microRNA as a potential biomarker in patients with periodontitis and oral cancers.

Zahra Safari, Alireza Firouzi, Nika Rezaeikalantari, Sanaz Mohammadi, Nikta Ranjbar, Hooman Shahpori, Pouya Khaleghi, Mobina Bagherianlemraski, Shakiba Zandi, Sona Rafieyan.

  Periodontitis and oral cancers are the most common oral diseases in the human population. The early diagnosis of oral diseases allows the efficient therapy of the patient. During oral diseases, resident cells in the affected tissue secrete exosomal microRNAs (miRNAs) into saliva. As these miRNAs have a crucial role in the pathogenesis of oral diseases, they have been suggested as non-invasive and validated biomarkers in predicting periodontitis severity and cancer progression. Several attempts have been performed to evaluate the expression of salivary exosomal miRNAs in patients with periodontitis and oral cancers. Some miRNAs are differentially expressed in the saliva of the affected patients when compared to healthy individuals. These miRNAs are reviewed in this narrative review. Collectively, it seems that salivary exosomal microRNAs could be used as a diagnostic biomarker in oral diseases. However, further studies are required to validate them.

Keywords:  Biomarker; Exosome; MicroRNA; Oral cancers; Periodontal disease; Saliva

DOI:  https://doi.org/10.1111/cbdd.14159
J Oral Pathol Med. 2022 Oct 27.

Exosomal hsa_circRNA_047733 integrated with clinical features for preoperative prediction of lymph node metastasis risk in oral squamous cell carcinoma.

Qingrong Deng, Yujia Chen, Lisong Lin, Jing Lin, Huiying Wang, Yu Qiu, Lizhen Pan, Xiaoyan Zheng, Lihong Wei, Jing Wang, Fengqiong Liu, Baochang He, Fa Chen.

   BACKGROUND: To evaluate whether exosomal circRNAs could serve as diagnostic biomarkers for the accurate preoperative prediction of lymph node metastasis (LNM) risk in oral squamous cell carcinoma (OSCC) patients.
METHODS: A combinative strategy of exosomal circRNAs microarray and qRT-PCR verification was employed to dig LNM-related circRNA signatures. Then, a dynamic nomogram was developed based on candidate circRNAs and preoperative clinical features and the calibration, discrimination, and clinical use of the nomogram were evaluated.
RESULTS: According to the microarray, three circRNAs derived from the tumor were associated with preoperative LNM risk, including hsa_circRNA_047733, hsa_circRNA_024144 and hsa_circRNA_403472. The hsa_circRNA_047733 was further verified to be significantly downregulated in patients with LNM (+) as compared to those with LNM (-) (P=0.007). Patients with the higher expression of hsa_circRNA_047733 showed a lower risk of LNM (multivariate-adjusted OR=0.22, 95%CI: 0.06-0.83). The bioinformatics prediction showed that hsa_circRNA_047733 might sponge miR-4464/miR-4748 to regulate RPS21 expression. A dynamic nomogram integrating exosomal hsa_circRNA_047733 with five clinicopathological characteristics (tumor site, leukocyte level, maximum tumor diameter and LNM reported by MRI and preoperative biopsy differentiation) was developed. The model displayed an excellent discrimination ability (AUC=0.868, 95%CI: 0.781-0.955) and great calibration. The decision curve revealed a higher net benefit superior to the baseline model at an 80% threshold probability.
CONCLUSION: The data provide preliminary evidence that exosomal hsa_circRNA_047733 might be a novel biomarker for the LNM of OSCC. The hsa_circRNA_047733-based dynamic nomogram could serve as a convenient preoperative assessment tool to predict the risk of LNM for OSCC patients.

Keywords:  Circular RNA; Exosome; Lymph node metastasis; Nomogram; Oral squamous cell carcinoma

DOI:  https://doi.org/10.1111/jop.13379