bims-exocan 2022-09-04 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022–09–04
eightteen papers selected by
Muhammad Rizwan, COMSATS University

Exosomics in Oral Cancer Diagnosis, Prognosis, and Therapeutics- An emergent and imperative non-invasive natural nanoparticle-based approach.
Alternating exosomes and their mimetics as an emergent strategy for targeted cancer therapy.
Molecular actions of exosomes and their theragnostics in colorectal cancer: current findings and limitations.
Hypoxic glioma-derived extracellular vesicles harboring MicroRNA-10b-5p enhance M2 polarization of macrophages to promote the development of glioma.
Extracellular vesicles and particles impact the systemic landscape of cancer.
Diagnostic and prognostic role of liquid biopsy in non-small cell lung cancer: evaluation of circulating biomarkers.
Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p.
Fucosylated exosomal miRNAs as promising biomarkers for the diagnosis of early lung adenocarcinoma.
Overcoming Obstacles in Liquid Biopsy Developments for Prostate Cancer.
Research Development on Exosome Separation Technology.
Exosomal B7-H4 from irradiated glioblastoma cells contributes to increase FoxP3 expression of differentiating Th1 cells and promotes tumor growth.
Exosomal protein angiopoietin-like 4 mediated radioresistance of lung cancer by inhibiting ferroptosis under hypoxic microenvironment.
m6A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.
Lung-specific exosomes for co-delivery of CD47 blockade and cisplatin for the treatment of non-small cell lung cancer.
"A novel serum extracellular vesicle protein signature to monitor glioblastoma tumor progression".
Exosomal MicroRNA signature acts as an efficient biomarker for non-invasive diagnosis of gallbladder carcinoma.
In situ hybridization to detect DNA amplification in extracellular vesicles.
The Role of Exosome MicroRNA-103 in the Proliferation and Invasion of Hepatoma Cells and Its Mechanism.

Crit Rev Oncol Hematol. 2022 Aug 25. pii: S1040-8428(22)00223-2. [Epub ahead of print] 103799

Exosomics in Oral Cancer Diagnosis, Prognosis, and Therapeutics- An emergent and imperative non-invasive natural nanoparticle-based approach.

Afsareen Bano, Ravina Vats, Pooja Yadav, Rashmi Bhardwaj.

  Exosomes- the natural nanoparticles belonging to heterogeneous vesicles are released via nearly all sorts of cells, including tumour cells, to operate intercellular communication. Selective packaging of exosomes amid nucleic acids, phospholipids, and proteins makes them ideal for intercellular communications occurring among different cells. The existence of exosomes has been validated in various biofluids, including saliva. Being non-invasive and in direct contact with oral malignant cells, saliva establishes itself as a preeminent source of early cancer biomarkers. In context, the role and providence of both recipient and donor secreting cells are persuaded through exosomal cargo.Several studies have emphasized the influence of exosomal contents in different stages of cancer development, reconciling interactions betweentumour cells and their surrounding niche. More explicitly, a transformation of exosomal contents such as nucleic acids, lipids, and proteins can endorse tumour progression and help ascertain a secluded pre-metastatic niche crammed with substances that errand cancer cell proliferation,angiogenesis, metastasis, and drug resistance. The blooming field of exosomes has directed the evolution of high-end isolation and characterization techniques along with the development of an entirely new field- exosomics that comprises complete analysis of exosomal cargo in various physiological conditions, including oral cancer. Researchers have discovered multiple pathways involved in exosome biogenesis to understandnumerousevents associated with cancer progression. Tissue-specific packaging of exosomes makes them a novel source of prognostic and diagnostic biomarkers and potential therapeutic targets. The extent of the current review confers the contemporary perception of the versatile task of exosomes, especially salivary exosomes, as potential biomarkers in the progression and diagnosis as well as therapeutics of oral cancers and their potential employment in clinical applications. AVAILABILITY OF DATA AND MATERIALS: The materials that support the conclusion of this review have been included within the article.

Keywords:  Diagnostics; Oral cancer; Proteomics; Salivaryexosomes; Transcriptomics

DOI:  https://doi.org/10.1016/j.critrevonc.2022.103799
Front Mol Biosci. 2022 ;9 939050

Alternating exosomes and their mimetics as an emergent strategy for targeted cancer therapy.

Lokesh Chandra Mishra, Utkarsh Pandey, Abhikarsh Gupta, Jyotsna Gupta, Monal Sharma, Gauri Mishra.

  Exosomes, a subtype of the class of extracellular vesicles and nano-sized particles, have a specific membrane structure that makes them an alternative proposition to combat with cancer through slight modification. As constituents of all most all the primary body fluids, exosomes establish the status of intercellular communication. Exosomes have specific proteins/mRNAs and miRNAs which serve as biomarkers, imparting a prognostic tool in clinical and disease pathologies. They have efficient intrinsic targeting potential and efficacy. Engineered exosomes are employed to deliver therapeutic cargos to the targeted tumor cell or the recipient. Exosomes from cancer cells bring about changes in fibroblast via TGFβ/Smad pathway, augmenting the tumor growth. These extracellular vesicles are multidimensional in terms of the functions that they perform. We herein discuss the uptake and biogenesis of exosomes, their role in various facets of cancer studies, cell-to-cell communication and modification for therapeutic and diagnostic use.

Keywords:  biomarker; exosome; exosome mimetics; targeted delivery; therapeutics

DOI:  https://doi.org/10.3389/fmolb.2022.939050
Cell Oncol (Dordr). 2022 Sep 01.

Molecular actions of exosomes and their theragnostics in colorectal cancer: current findings and limitations.

Wen-Chun Lin, Chun-Chi Lin, Yen-Yu Lin, Wen-Hao Yang, Yuh-Ching Twu, Hao-Wei Teng, Wei-Lun Hwang.

  Extracellular vesicles (EVs) are cell-released, membranous structures essential for intercellular communication. The biochemical compositions and physiological impacts of exosomes, lipid-bound, endosomal origin EVs, have been focused on, especially on the tumor-host interactions in a defined tumor microenvironment (TME). Despite recent progress in targeted therapy and cancer immunotherapy in colorectal cancer (CRC), cancer patients still suffer from distal metastasis and tumor relapse, suggesting unmet needs for biomarkers directing therapeutic interventions and predicting treatment responsiveness. As exosomes are indispensable for intercellular communication and high exosome abundance makes them feasible biomarker molecules, this review discusses exosome heterogeneity and how exosomes orchestrate the interplay among tumor cells, cancer stem cells (CSCs) and host cells, including stromal cells, endothelial cells and immunocytes, in the CRC TME. This review also discusses mechanisms for loading exosomal contents and potential exosomal DNA, RNA and protein biomarkers for early CRC detection. Finally, we summarize the diagnostic and therapeutic exosomes in clinical trials. We envision that detecting and targeting cancer-specific exosomes could provide therapeutic advances in developing personalized cancer medicine.

Keywords:  Cancer Biomarker; Colorectal Cancer; Extracellular Vesicles; Tumor Heterogeneity; Tumor Microenvironment

DOI:  https://doi.org/10.1007/s13402-022-00711-7
CNS Neurosci Ther. 2022 Sep 02.

Hypoxic glioma-derived extracellular vesicles harboring MicroRNA-10b-5p enhance M2 polarization of macrophages to promote the development of glioma.

Bingzhen Li, Cheng Yang, Zhanpeng Zhu, Hao Chen, Bin Qi.

   INTRODUCTION: The delivery of biomolecules by tumor cell-secreted extracellular vesicles (EVs) is linked to the development of glioma. Here, the present study was implemented to explore the functional significance of hypoxic glioma cell-derived EVs carrying microRNA-10b-5 (miR-10b-5p) on glioma with the involvement of polarization of M2 macrophages.
METHODS: EVs were isolated from hypoxia-stimulated glioma cells, and their role in polarization of M2 macrophages was studied by co-culturing with macrophages. miR-10b-5p expression in glioma tissues, glioma-derived EVs, and macrophages co-cultured with EVs was characterized. Interaction among miR-10b-5p, NEDD4L, and PIK3CA was analyzed. The macrophages or glioma cells were transfected with overexpressing plasmid or shRNA to study the effects of miR-10b-5p/NEDD4L/PIK3CA on M2 macrophage polarization, and glioma cell proliferation, migration, and invasion in vitro and in vivo.
RESULTS: Promotive role of hypoxia-stimulated glioma-derived EVs in macrophage M2 polarization was confirmed. Elevation of miR-10b-5p occurred in glioma tissues, glioma-derived EVs and macrophages co-cultured with EVs, and stimulated M2 polarization of macrophages. NEDD4L was a target gene of miR-10b-5p. Overexpression of NEDD4L could inhibit PI3K/AKT pathway through increase in ubiquitination and degradation of PIK3CA. Hypoxic glioma-derived EVs harboring upregulated miR-10b-5p triggered an M2 phenotype in macrophages as well as enhanced aggressive tumor biology of glioma cells via inhibition of PIK3CA/PI3K/AKT pathway by targeting NEDD4L.
CONCLUSIONS: In summary, miR-10b-5p delivered by hypoxic glioma-derived EVs accelerated macrophages M2 polarization to promote the progression of glioma via NEDD4L/PIK3CA/PI3K/AKT axis.

Keywords:  extracellular vesicles; glioma; microRNA-10b-5; neuronal precursor cell expressed developmentally downregulated 4-like; phosphatidylinositol-4, 5-bisphosphate 3-kinase

DOI:  https://doi.org/10.1111/cns.13905
EMBO J. 2022 Sep 02. e109288

Extracellular vesicles and particles impact the systemic landscape of cancer.

Serena Lucotti, Candia M Kenific, Haiying Zhang, David Lyden.

  Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.

Keywords:  biomarkers; cancer; extracellular vesicles and particles; metastasis; therapeutic deliverables

DOI:  https://doi.org/10.15252/embj.2021109288
Explor Target Antitumor Ther. 2020 ;1(5): 343-354

Diagnostic and prognostic role of liquid biopsy in non-small cell lung cancer: evaluation of circulating biomarkers.

Giovanni Vicidomini, Roberto Cascone, Annalisa Carlucci, Alfonso Fiorelli, Marina Di Domenico, Mario Santini.

  Lung cancer is still one of the main causes of cancer-related death, together with prostate and colorectal cancers in males and breast and colorectal cancers in females. The prognosis for non-small cell lung cancer (NSCLC) is strictly dependent on feasibility of a complete surgical resection of the tumor at diagnosis. Since surgery is indicated only in early stages tumors, it is necessary to anticipate the timing of diagnosis in clinical practice. In the diagnostic and therapeutic pathway for NSCLC, sampling of neoplastic tissue is usually obtained using invasive methods that are not free from disadvantages and complications. A valid alternative to the standard biopsy is the liquid biopsy (LB), that is, the analysis of samples from peripheral blood, urine, and other biological fluids, with a simple and non-invasive collection. In particular, it is possible to detect in the blood different tumor derivatives, such as cell-free DNA (cfDNA) with its subtype circulating tumor DNA (ctDNA), cell-free RNA (cfRNA), and circulating tumor cells (CTCs). Plasma-based testing seems to have several advantages over tumor tissue biopsy; firstly, it reduces medical costs, risk of complications related to invasive procedures, and turnaround times; moreover, the analysis of genes alteration, such as EGFR, ALK, ROS1, and BRAF is faster and safer with this method, compared to tissue biopsy. Despite all these advantages, the evidences in literatures indicate that assays performed on liquid biopsies have a low sensitivity, making them unsuitable for screening in lung cancer at the current state. This is caused by lack of standardization in sampling and preparation of specimen and by the low concentration of biomarkers in the bloodstream. Instead, routinely use of LB should be preferred in revaluation of patients with advanced NSCLC resistant to chemotherapy, due to onset of new mutations.

Keywords:  Liquid biopsy; circulating tumor DNA; circulating tumor cells; exosomes; lung cancer

DOI:  https://doi.org/10.37349/etat.2020.00020
BMC Cancer. 2022 Aug 27. 22(1): 928

Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p.

Xiaojun Li, Qiusheng Lan, Wei Lai, Heng Wu, Heyang Xu, Kai Fang, Zhonghua Chu, Yujie Zeng.

   INTRODUCTION: Neuroendocrine differentiation (NED) in colorectal cancer (CRC) cells has been known for decades, and our previous meta-analysis indicated that CRC patients with neuroendocrine differentiation have a lower 5-year survival rate. In recent years, an increasing number of studies have found that exosome-derived long non-coding RNAs (lncRNAs) play important roles in cancer progression and metastasis. However, the functions and mechanism of exosome-derived lncRNAs in CRC with neuroendocrine differentiation are not yet fully clear.
MATERIALS AND METHODS: The clinical significance of NED was assessed in a retrospective study of 105 patients. Next-generation sequencing and bioinformatics analysis were conducted to select lnc-HOXB8-1:2 for further study. Using immunohistochemistry, qRT-PCR, western blot, transwell assay, immunofluorescence assay, fluorescence in situ hybridization assay and dual-luciferase reporter assay, the oncogenic role of exosome-derived lnc-HOXB8-1:2 was determined in CRC with NED. The mechanism underlying the lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was also explored.
RESULTS: NED was a risk factor for the progression and mortality of CRC. lnc-HOXB8-1:2, derived from exosomes secreted by neuroendocrine differentiated colon cancer cells, was identified in our study. The proportion of M2 macrophages and the migration and invasion capacities of tumor-associated macrophages (TAMs) markedly increased after the addition of neuroendocrine differentiated CRC cell-derived exosomes. More excitingly, the expression of lnc-HOXB8-1:2 and the protein level of CXCR3 were also upregulated in TAMs. The lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was predicted via miRanda software and confirmed by the dual-luciferase reporter assay. Furthermore, the increased expression of lnc-HOXB8-1:2 was accompanied by downregulation of hsa-miR-6825-5p expression and upregulation of CXCR3 protein levels. Overexpression of hsa-miR-6825-5p also reduced CXCR3 expression.
CONCLUSION: lnc-HOXB8-1:2 in exosomes derived from neuroendocrine differentiated CRC cells acted as a ceRNA competitively binding hsa-miR-6825-5p to upregulate CXCR3 expression and leading to TAM infiltration and M2 polarization, which promotes neuroendocrine differentiated CRC progression.

Keywords:  Colorectal cancer; Exosome; Neuroendocrine differentiation; Tumor-associated macrophage; lnc-HOXB8-1:2

DOI:  https://doi.org/10.1186/s12885-022-09926-1
Front Oncol. 2022 ;12 935184

Fucosylated exosomal miRNAs as promising biomarkers for the diagnosis of early lung adenocarcinoma.

Xiongfeng Chen, Lili Yu, Kun Hao, Xiaoqing Yin, Mingshu Tu, Liqing Cai, Liangming Zhang, Xiaojie Pan, Qi Gao, Yi Huang.

   Background: Considering the absence of apparent symptoms at the early stage, most patients with lung adenocarcinoma (LUAD) present at an advanced stage, leading to a dismal 5-year survival rate of <20%. Thus, finding perspective non-invasive biomarkers for early LUAD is very essential.
Methods: We developed a fucose-captured strategy based on lentil lectin-magnetic beads to isolate fucosylated exosomes from serum. Then, a prospective study was conducted to define the diagnostic value of serum exosomal miRNAs for early LUAD. A total of 310 participants were enrolled, including 146 LUAD, 98 benign pulmonary nodules (BPNs), and 66 healthy controls (HCs). Firstly, exosome miRNAs in the discovery cohort (n = 24) were profiled by small RNA sequencing. Secondly, 12 differentially expressed miRNAs (DEmiRs) were selected for further screening in a screening cohort (n = 64) by qRT-PCR. Finally, four candidate miRNAs were selected for further validation in a validating cohort (n = 222).
Results: This study demonstrated the feasibility of a fucose-captured strategy for the isolation of fucosylated exosomes from serum, evidenced with exosomal characteristics identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting, as well as rapid and convenient operation of <10 min. Furthermore, a miRNA panel for early LUAD composed of miR4732-5p, miR451a, miR486-5p, and miR139-3p was defined with an AUC of 0.8554 at 91.07% sensitivity and 66.36% specificity.
Conclusions: The fucose-captured strategy provides a reliable, as well as rapid and convenient, approach for the isolation of tumor-derived exosomes from serum. A four-fucosylated exosomal miRNA panel presents good performance for early LUAD diagnosis.

Keywords:  biomarker; early LUAD diagnosis; fucose-captured strategy; lung adenocarcinoma; serum exosomal miRNA

DOI:  https://doi.org/10.3389/fonc.2022.935184
Onco Targets Ther. 2022 ;15 897-912

Overcoming Obstacles in Liquid Biopsy Developments for Prostate Cancer.

Albert Jang, Grant P Rauterkus, Ulka N Vaishampayan, Pedro C Barata.

  Prostate cancer is one of the most common malignancies in men. Over time, it can metastasize and become lethal once it exhausts hormonal therapies and transitions into castration-resistant prostate cancer (CRPC). Several therapies have been recently approved for advanced prostate cancer, but identifying biomarkers for current treatments and searching for more effective treatments are urgently needed. Liquid biopsy is a powerful tool for isolating genetic material, proteins, and whole tumor cells from the blood. In recent decades, this technology has rapidly advanced, allowing for better insights into the pathogenesis and treatment response in different stages of prostate cancer. In this review, we summarize important clinical studies involving liquid biopsies in prostate cancer with a focus on advanced disease, notably regarding circulating tumor DNA, circulating tumor cells, and exosomes. We highlight the progress and the challenges that still exist for these technologies. Finally, we discuss promising avenues that will further expand the importance of liquid biopsy in the care for prostate cancer patients.

Keywords:  advanced prostate cancer; circulating tumor DNA; circulating tumor cells; exosomes; liquid biopsy

DOI:  https://doi.org/10.2147/OTT.S285758
J Membr Biol. 2022 Aug 30.

Research Development on Exosome Separation Technology.

Wei-Ming Xu, Ao Li, Jia-Jun Chen, En-Jie Sun.

  Exosomes are special extracellular vesicles secreted by cells, which are of great significance in the basic research of life science and clinical application and has become a hot research field with rapid development in recent 10 years. Therefore, the isolation and separation of exosomes is particularly important for the research and application of exosomes. This paper aims to review the research progress of exosome isolation and separation methods in recent years, including ultracentrifugation, ultrafiltration, size‑exclusion chromatography, precipitation, immunomagnetic bead capture method, aptamer-based isolation, and isolation methods based on microfluidic technology. It is generally accepted that most of the existing methods have limitations, for example, ultracentrifugation is time-consuming and laborious, and immunomagnetic bead capture method and aptamer-based separation method have small sample processing capacity and high cost. As a result, we also introduce some common situations in which two or more methods are combined for use. Finally, the separation and isolation methods including all those presented in this review were compared and summarized.

Keywords:  Affinity separation; Exosomes; Isolation of exosomes; Microfluidic methods; Purification of exosomes

DOI:  https://doi.org/10.1007/s00232-022-00260-y
Redox Biol. 2022 Aug 27. pii: S2213-2317(22)00226-9. [Epub ahead of print]56 102454

Exosomal B7-H4 from irradiated glioblastoma cells contributes to increase FoxP3 expression of differentiating Th1 cells and promotes tumor growth.

Yunhong Tian, Chunshan Liu, Zhiyong Li, Meiling Ai, Baiyao Wang, Kunpeng Du, Wei Liu, Hongmei Wang, Peng Yu, Chengcong Chen, Jie Lin, Anan Xu, Rong Li, Weijun Zhang, Yawei Yuan.

   BACKGROUND: Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor. Although numerous postoperative therapeutic strategies have already been developed, including radiotherapy, tumors inevitably recur after several years of treatment. The coinhibitory molecule B7-H4 negatively regulates T cell immune responses and promotes immune escape. Exosomes mediate intercellular communication and initiate immune evasion in the tumor microenvironment (TME).
OBJECTIVE: This study aimed to determine whether B7-H4 is upregulated by radiation and loaded into exosomes, thus contributing to immunosuppression and enhancing tumor growth.
METHODS: Iodixanol density-gradient centrifugation and flow cytometry were used to verify exosomal B7-H4. Naïve T cells were differentiated into Th1 cells, with or without exosomes. T cell-secreted cytokines and markers of T cell subsets were measured. Mechanistically, the roles of B7-H4, and ALIX in GBM were analyzed using databases and tissue samples. Co-immunoprecipitation, and pull-down assays were used to tested the direct interactions between ATM and ALIX or STAT3. In vitro ATM kinase assays, western blotting, and site-directed mutation were used to assess ATM-mediated STAT3 phosphorylation. Finally, the contribution of exosomal B7-H4 to immunosuppression and tumor growth was investigated in vivo.
RESULTS: Exosomes from irradiated GBM cells decreased the anti-tumor immune response of T cell in vitro and in vivo via delivered B7-H4. Mechanistically, irradiation promoted exosome biogenesis by increasing the ATM-ALIX interaction. Furthermore, the ATM-phosphorylated STAT3 was found to directly binds to the B7-H4 promoter to increase its expression. Finally, the radiation-induced increase in exosomal B7-H4 induced FoxP3 expression during Th1 cell differentiation via the activated STAT1 pathway. In vivo, exosomal B7-H4 decreased the radiation sensitivity of GBM cells, and reduced the survival of GBM mice model.
CONCLUSION: This study showed that radiation-enhanced exosomal B7-H4 promoted immunosuppression and tumor growth, hence defining a direct link between irradiation and anti-tumor immune responses. Our results suggest that co-administration of radiotherapy with anti-B7-H4 therapy could improve local tumor control and identify exosomal B7-H4 as a potential tumor biomarker.

Keywords:  B7-H4; Exosome; Glioblastoma (GBM); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.redox.2022.102454
Br J Cancer. 2022 Sep 01.

Exosomal protein angiopoietin-like 4 mediated radioresistance of lung cancer by inhibiting ferroptosis under hypoxic microenvironment.

Yuhong Zhang, Xinglong Liu, Liang Zeng, Xinrui Zhao, Qianping Chen, Yan Pan, Yang Bai, Chunlin Shao, Jianghong Zhang.

BACKGROUND: Hypoxia-mediated radioresistance is a major reason for the adverse radiotherapy outcome of non-small cell lung cancer (NSCLC) in clinical, but the underlying molecular mechanisms are still obscure.
METHODS: Cellular and exosomal ANGPTL4 proteins under different oxygen status were examined. Colony survival, lipid peroxidation and hallmark proteins were employed to determine the correlation between ferroptosis and radioresistance. Gene regulations, western blot and xenograft models were used to explore the underlying mechanisms of the role of ANGPTL4 in radioresistance.
RESULTS: ANGPTL4 had a much higher level in hypoxic NSCLC cells compared to normoxic cells. Up- or down- regulation of ANGPTL4 positively interrelated to the radioresistance of NSCLC cells and xenograft tumours. GPX4-elicited ferroptosis suppression and lipid peroxidation decrease were authenticated to be involved in the hypoxia-induced radioresistance. ANGPTL4 encapsulated in the exosomes from hypoxic cells was absorbed by neighbouring normoxic cells, resulting in radioresistance of these bystander cells in a GPX4-dependent manner, which was diminished when ANGPTL4 was downregulated in the donor exosomes.
CONCLUSION: Hypoxia-induced ANGPTL4 rendered radioresistance of NSCLC through at least two parallel pathways of intracellular ANGPTL4 and exosomal ANGPTL4, suggesting that ANGPTL4 might applicable as a therapeutic target to improve the therapeutic efficacy of NSCLC.

DOI: https://doi.org/10.1038/s41416-022-01956-7
Oxid Med Cell Longev. 2022 ;2022 9451480

m6A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

Junjie Zheng, Panpan Feng, Dawei Chen, Cuiyu Zhang, Yuge Ji, Yanting Liu, Xiaohua Fan, Jingxin Li.

Recent studies have highlighted the biological significance of exosomes and m6A modifications in immunity. Nonetheless, it remains unclear whether the m6A modification gene in exosomes of body fluid has potential roles in the tumor microenvironment (TME). Herein, we identified three different m6A-related exosomal gene modification patterns based on 59 m6A-related exosomal genes, which instructed distinguishing characteristics of TME in colon cancer (CC). We demonstrated that these patterns could predict the stage of tumor inflammation, subtypes, genetic variation, and patient prognosis. Furthermore, we developed a scoring mode-m6A-related exosomal gene score (MREGS)-by detecting the level of m6A modification in exosomes to classify immune phenotypes. Low MREGS, characterized by prominent survival and immune activation, was linked to a better response to anti-PDL1 immunotherapy. In contrast, the higher MREGS group displayed remarkable stromal activation, high activity of innate immunocytes, and a lower survival rate. Hence, this work provides a novel approach for evaluating TME cell infiltration in colon cancer and guiding more effective immunotherapy strategies.

DOI: https://doi.org/10.1155/2022/9451480
Thorac Cancer. 2022 Aug 27.

Lung-specific exosomes for co-delivery of CD47 blockade and cisplatin for the treatment of non-small cell lung cancer.

Zhilei Cui, Zhengshang Ruan, Junxiang Zeng, Jinyuan Sun, Wenjing Ye, Weiguo Xu, Xuejun Guo, Linlin Zhang, Lin Song.

  A cluster of differentiation 47 (CD47) and immune-modulatory protein for myeloid cells has been implicated in cisplatin (CDDP) resistance. Exosome delivery of drugs has shown great potential for targeted drug delivery in the treatment of various diseases. In the current study, we explored the approach of co-delivering CDDP and CD47 antibody with MDA-MB-231 cell-derived exosome 231-exo (CaCE) and assessed the phagocytosis activity of bone marrow flow cytometry derived macrophages (BMDM) against co-cultured A549 cells. CD8+ T-cell proliferation was examined with flow cytometry analysis. In vivo, we used the Lewis lung carcinoma (LLC) tumor-bearing mouse model and assessed survival rate, tumor weight, phagocytosis, and T-cell proliferation, as well as cytokine levels in tumors analyzed by enzyme-linked immunoassay (ELISA). Although co-administration of CDDP with anti-CD47 (CDDP and aCD47) showed a significant antitumor effect, CaCE had an even more dramatic anticancer effect in survival rate and tumor weight. We observed increased phagocytosis activity selectively against lung tumor cells in vivo and in vitro with exosome CaCE treatment. CaCE treatment also increased T-cell proliferation compared to the vehicle treatment and co-administration groups. Furthermore, immunostimulatory interleukin (IL)-12p and interferon (IFN)-γ were increased, whereas transforming growth factor β (TGF-β) were decreased, indicating the improved CDDP anticancer effect is related to a tumor microenvironmental change. Our study demonstrates a dramatically improved anticancer effect of CDDP when administered by exosome co-delivery with anti-CD47.

Keywords:  CDDP; CaCE; anticancer; exosome delivery

DOI:  https://doi.org/10.1111/1759-7714.14606
Int J Cancer. 2022 Aug 27.

"A novel serum extracellular vesicle protein signature to monitor glioblastoma tumor progression".

Theophilos Tzaridis, Johannes Weller, Daniel Bachurski, Farhad Shakeri, Christina Schaub, Peter Hau, Andreas Buness, Uwe Schlegel, Joachim-Peter Steinbach, Clemens Seidel, Roland Goldbrunner, Niklas Schäfer, Robert J Wechsler-Reya, Michael Hallek, Björn Scheffler, Martin Glas, Lothar Haeberle, Ulrich Herrlinger, Christoph Coch, Katrin S Reiners, Gunther Hartmann.

  Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In this study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n=67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA, and histone H3 as compared to serum EVs from healthy volunteers (p value range: <0.0001 - 0.08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44, and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA, and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA, and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making.

Keywords:  Biomarkers; extracellular vesicles; glioblastoma; protein-signature; tumor-progression

DOI:  https://doi.org/10.1002/ijc.34261
iScience. 2022 Sep 16. 25(9): 104816

Exosomal MicroRNA signature acts as an efficient biomarker for non-invasive diagnosis of gallbladder carcinoma.

Pinghua Yang, Fengliang Song, Xinwei Yang, Xingzhou Yan, Xinyu Huang, Zhengjun Qiu, Zhijian Wen, Chi Liang, Xianglei Xin, Zhengqin Lei, Kecheng Zhang, Jue Yang, Hu Liu, Hongcheng Wang, Shijun Xiang, Liang Li, Baohua Zhang, Hongyang Wang.

  Through a three-step study that relies on biomarker discovery, training, and validation, we identified a set of five exosomal microRNAs (miRNAs) that can be used to evaluate the risk of gallbladder carcinoma (GBC), including miR-552-3p, miR-581, miR-4433a-3p, miR-496, and miR-203b-3p. When validated in 102 GBC patients and 112 chronic cholecystitis patients from multiple medical centers, the AUC of this combinatorial biomarker was 0.905, with a sensitivity of 81.37% and a specificity of 86.61%. The performance of this biomarker is superior to that of the standard biomarkers CA199 and CEA and is suited for GBC early diagnosis. The multi-clinicopathological features and prognosis of GBC patients were significantly associated with this biomarker. After building a miRNA-target gene regulation network, cell functions and signaling pathways regulated by these five miRNAs were examined. This biomarker signature can be used in the development of a noninvasive tool for GBC diagnosis, screening and prognosis prediction.

Keywords:  Cancer; Cancer systems biology; Health sciences

DOI:  https://doi.org/10.1016/j.isci.2022.104816
J Extracell Vesicles. 2022 Sep;11(9): e12251

In situ hybridization to detect DNA amplification in extracellular vesicles.

Lucia Casadei, Patricia Sarchet, Fernanda Costas C de Faria, Federica Calore, Giovanni Nigita, Sayumi Tahara, Luciano Cascione, Martin Wabitsch, Francis J Hornicek, Valerie Grignol, Carlo M Croce, Raphael E Pollock.

  EVs have emerged as an important component in tumour initiation, progression and metastasis. Although notable progresses have been made, the detection of EV cargoes remain significantly challenging for researchers to practically use; faster and more convenient methods are required to validate the EV cargoes, especially as biomarkers. Here we show, the possibility of examining embedded EVs as substrates to be used for detecting DNA amplification through ultrasensitive in situ hybridization (ISH). This methodology allows the visualization of DNA targets in a more direct manner, without time consuming optimization steps or particular expertise. Additionally, formalin-fixed paraffin-embedded (FFPE) blocks of EVs allows long-term preservation of samples, permitting future studies. We report here: (i) the successful isolation of EVs from liposarcoma tissues; (ii) the EV embedding in FFPE blocks (iii) the successful selective, specific ultrasensitive ISH examination of EVs derived from tissues, cell line, and sera; (iv) and the detection of MDM2 DNA amplification in EVs from liposarcoma tissues, cell lines and sera. Ultrasensitive ISH on EVs would enable cargo study while the application of ISH to serum EVs, could represent a possible novel methodology for diagnostic confirmation. Modification of probes may enable researchers to detect targets and specific DNA alterations directly in tumour EVs, thereby facilitating detection, diagnosis, and improved understanding of tumour biology relevant to many cancer types.

Keywords:  EV embedding; EV in situ hybridization; EVs; FISH; extracellular vesicles (EVs); sarcoma; tissue

DOI:  https://doi.org/10.1002/jev2.12251
Cell Mol Biol (Noisy-le-grand). 2022 May 31. 68(5): 47-53

The Role of Exosome MicroRNA-103 in the Proliferation and Invasion of Hepatoma Cells and Its Mechanism.

Yushi Lin, Fengmei Shi, Junyao Yan, Zhongyuan Sui, Bo Sun, Guangwei Xu.

Liver cancer (HCC) is a common malignant tumor whose incidence is increasing worldwide, but existing chemotherapeutic agents are not ideally effective drugs and have considerable resistance to chemotherapy. Exosome microRNA-103 plays an important role in the proliferation and invasion of liver cancer cells. The purpose of this article is to investigate the role and mechanism of exosome microRNA-103 in hepatocellular carcinoma cell proliferation and invasion. 84 patients with hepatocellular carcinoma diagnosed in a hospital from June 2017 to June 2020 were selected. The average age was 60.13±6.99 years. When the patient was fasting, 3 mL of peripheral venous blood was taken. And 50 healthy control groups were established, with an average age of 59.98±8.18 years old. 3 ml of peripheral venous blood was collected on an empty stomach to compare the cell proliferation rate and invasion rate. The results of the study showed that the number of stage III hepatocellular carcinoma cells invaded at 6h was 68.9, and it changed to 89.4 at 12h, and 106.4 at 24h; compared with that, the cell invasion rate in stage IV was higher. The number of stage IV hepatocellular carcinoma invasions at 6h was 68, which changed to 94.5 at 12h and 112.4 at 24h.

DOI: https://doi.org/10.14715/cmb/2022.68.5.6