bims-exocan 2022-09-11 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2022‒09‒11
24 papers selected by
Muhammad Rizwan
COMSATS University

Exosomes carrying immune checkpoints, a promising therapeutic approach in cancer treatment.
The Oral Tumor Cell Exosome miR-10b Stimulates Cell Invasion and Relocation via AKT Signaling.
Radiated glioblastoma cell-derived exosomal circ_0012381 induce M2 polarization of microglia to promote the growth of glioblastoma by CCL2/CCR2 axis.
Delineating the role of extracellular vesicles in cancer metastasis: A comprehensive review.
Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs.
Exosome application in treatment and diagnosis of B-cell disorders: leukemias, multiple sclerosis, and arthritis rheumatoid.
Exosomes in the tumor microenvironment of sarcoma: from biological functions to clinical applications.
Extracellular Vesicles in Haematological Disorders: A Friend or a Foe?
Quantification of Serum Exosome Biomarkers Using 3D Nanoporous Gold and Spectrophotometry.
Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression.
Targeting NR1H/liver X receptor with dendrogenin A differentiates tumor cells to activate a new secretory pathway releasing immunogenic anti-tumor vesicles enriched in LC3-II-associated exosomes.
Engineered extracellular vesicles: A novel platform for cancer combination therapy and cancer immunotherapy.
Bioactivity of Exosomes Derived from Trained Natural Killer Cells versus Non-Trained One: More Functional and Antitumor Activity.
Delivery of human natural killer cell-derived exosomes for liver cancer therapy: an in vivo study in subcutaneous and orthotopic animal models.
Extracellular vesicles as an emerging drug delivery system for cancer treatment: Current strategies and recent advances.
Comparison of plasma- and saliva-derived exosomal miRNA profiles reveals diagnostic potential in head and neck cancer.
Circulating Tumour Cells, Cell Free DNA and Tumour-Educated Platelets as Reliable Prognostic and Management Biomarkers for the Liquid Biopsy in Multiple Myeloma.
Exosomes in Cancer Diagnosis and Therapy.
Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1.
Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway.
Brownian Motion Influence on AFM Exosomes' Size Measurements.
Erratum: Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis [Corrigendum].
A prognostic exosome-related LncRNA risk model correlates with the immune microenvironment in liver cancer.
Extracellular Vesicle-Derived Protein File from Peripheral Blood Predicts Immune-Related Adverse Events in Gastric Cancer Patients Receiving Immunotherapy.

Med Oncol. 2022 Sep 07. 39(12): 183

Exosomes carrying immune checkpoints, a promising therapeutic approach in cancer treatment.

Seyed Ziaeddin Rasihashemi, Hadi Sahrai, Erfan Rezazadeh-Gavgani, Yalda Yazdani, Amirreza Khalaji, Parisa Lotfinejad.

  Exosomes are a subgroup of extracellular vesicles generated by distinct cells. Tumor-derived extracellular vesicles convey immunological checkpoint molecules. TEXs as critical mediators in tumor development, metastasis, and immune escape have recently become the focus of scientific research. Exosomes are involved in the regulation of the immune system. Exosomes interact with target cells in the tumor microenvironment, changing their function based on the cargo they contain. Exosomal immune checkpoints might be exploited to track tumor immune evasion, treatment response, and patient prognosis while enhancing tumor cell proliferation and spread. This review focuses on tumor-derived exosomes, their immunosuppressive effects in mice models, and their role in cancer immunotherapy. Exosomes are being studied as possible cancer vaccines, with numerous uses in tumor immunotherapy. Exosomes can carry chemotherapeutics, siRNA, and monoclonal antibodies. Exosomes produced by macrophages might be used to treat cancer. These and other clinical consequences provide new doors for cancer treatment.

Keywords:  Cancer progression; Exosomal immune checkpoint; Exosome; Immune checkpoint; Tumor-derived exosomes

DOI:  https://doi.org/10.1007/s12032-022-01781-1
Contrast Media Mol Imaging. 2022 ;2022 3188992

The Oral Tumor Cell Exosome miR-10b Stimulates Cell Invasion and Relocation via AKT Signaling.

Xiang Li, Ting Yang, Chuanji Shu.

An exosome derived from a cancer cell has been identified to regulate intercellular communication. However, the roles of oral cancer-derived ectodomains in tumor metastasis need to be investigated further. We investigated their roles in oral cancer cells in this paper. The enforcing effect on oral cancer cells was attributed primarily to miR-10b, a gene with a high level in exosomes that is transferred to recipient cells via oral cancer-derived exosomes. Exosomes were obtained by exosome isolation reagents. Also, exosome identification and analysis were performed by electron microscopy. The expression of miRNAs was analyzed by qRT-PCR. Protein expression was analyzed by Western blot. Also, invasion and migration experiments were performed to assay and evaluate the function of exosomal miR-10b. Exosome-mediated transfer of miR-10b promoted oral cancer cell behaviors, according to the findings. Finally, it was discovered that AKT signaling participates in regulating exosome-mediated invasion and migration of oral cancer cells and its activation reduced the inhibitory effect of miR-10b knockdown on oral cancer cells. Exosomal miR-10b derived from oral cancer cells enhances cell invasion and migration by activating AKT signaling.

DOI: https://doi.org/10.1155/2022/3188992
J Transl Med. 2022 Sep 04. 20(1): 388

Radiated glioblastoma cell-derived exosomal circ_0012381 induce M2 polarization of microglia to promote the growth of glioblastoma by CCL2/CCR2 axis.

Chunzhi Zhang, Yuan Zhou, Ya Gao, Ze Zhu, Xianliang Zeng, Weizi Liang, Songwei Sun, Xiuli Chen, Hu Wang.

  BACKGROUND: Radiotherapy is the primary therapeutic option for glioblastoma. Some studies proved that radiotherapy increased the release of exosomes from cells. The mechanism by which these exosomes modify the phenotype of microglia in the tumor microenvironment to further determine the fate of irradiated glioblastoma cells remains to be elucidated.METHODS: We erected the co-culture system of glioblastoma cells and microglia. After radiation, we analyzing the immunophenotype of microglia and the proliferation of radiated glioblastoma cells. By whole transcriptome sequencing, we analyzed of circRNAs in exosomes from glioblastoma cells and microglia. We used some methods, which included RT-PCR, dual-luciferase reporter, et al., to identify how circ_0012381 from radiated glioblastoma cell-derived exosomes regulated the immunophenotype of microglia to further affect the proliferation of radiated glioblastoma cells.
RESULTS: Radiated glioblastoma cell-derived exosomes markedly induced M2 microglia polarization. These M2-polarized microglia promoted the proliferation of irradiated glioblastoma cells. Circ_0012381 expression was increased in the irradiated glioblastoma cells, and circ_0012381 entered the microglia via exosomes. Circ_0012381 induced M2 microglia polarization by sponging with miR-340-5p to increase ARG1 expression. M2-polarized microglia suppressed phagocytosis and promoted the growth of the irradiated glioblastoma cells by CCL2/CCR2 axis. Compared with the effects of radiotherapy alone, the inhibition of exosomes significantly inhibited the growth of irradiated glioblastoma cells in a zebrafish model.
CONCLUSIONS: Our data suggested that the inhibition of exosome secretion might represent a potential therapeutic strategy to increase the efficacy of radiotherapy in patients with glioblastoma.

Keywords:  Exosome; Glioblastoma; M2; Microglia; Radiotherapy

DOI:  https://doi.org/10.1186/s12967-022-03607-0
Front Immunol. 2022 ;13 966661

Delineating the role of extracellular vesicles in cancer metastasis: A comprehensive review.

Misba Majood, Sonali Rawat, Sujata Mohanty.

  Extracellular vesicles (EVs) are subcellular messengers that aid in the formation and spread of cancer by enabling tumor-stroma communication. EVs develop from the very porous structure of late endosomes and hold information on both the intrinsic "status" of the cell and the extracellular signals absorbed by the cells from their surroundings. These EVs contain physiologically useful components, including as nucleic acids, lipids, and proteins, which have been found to activate important signaling pathways in tumor and tumor microenvironment (TME) cells, aggravating tumor growth. We highlight critical cell biology mechanisms that link EVS formation to cargo sorting in cancer cells in this review.Sorting out the signals that control EVs creation, cargo, and delivery will aid our understanding of carcinogenesis. Furthermore, we reviewed how cancer development and spreading behaviors are affected by coordinated communication between malignant and non-malignant cells. Herein, we studied the reciprocal exchanges via EVs in various cancer types. Further research into the pathophysiological functions of various EVs in tumor growth is likely to lead to the discovery of new biomarkers in liquid biopsy and the development of tumor-specific therapies.

Keywords:  Carcinogenesis; Extracellular vesicles (EVs); biomarker; cargo sorting; liquid biopsy; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2022.966661
Int J Mol Sci. 2022 Aug 23. pii: 9512. [Epub ahead of print]23(17):

Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs.

Xiangyu Chu, Yinmo Yang, Xiaodong Tian.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive tumors, characterized by a low rate of early diagnosis, strong invasiveness, and early metastasis. The abundant stromal cells, dense extracellular matrix, and lack of blood supply in PDAC limit the penetration of chemotherapeutic drugs, resulting in poor efficacy of the current treatment regimens. Cancer-associated fibroblasts (CAFs) are the major stromal cells in the tumor microenvironment. Tumor cells can secrete exosomes to promote the generation of activated CAFs, meanwhile exosomes secreted by CAFs help promote tumor progression. The aberrant expression of miRNAs in exosomes is involved in the interaction between tumor cells and CAFs, which provides the possibility for the application of exosomal miRNAs in the diagnosis and treatment of PDAC. The current article reviews the mechanism of exosomal miRNAs in the crosstalk between PDAC cells and CAFs in the tumor microenvironment, in order to improve the understanding of TME regulation and provide evidence for designing diagnostic and therapeutic targets against exosome miRNA in human PDAC.

Keywords:  PDAC; cancer-associated fibroblasts; exosomal miRNAs; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms23179512
Cell Mol Biol Lett. 2022 Sep 05. 27(1): 74

Exosome application in treatment and diagnosis of B-cell disorders: leukemias, multiple sclerosis, and arthritis rheumatoid.

Mohsen Karami Fath, Jalil Azami, Niloofar Jaafari, Mahsa Akbari Oryani, Nafiseh Jafari, Alireza Karim Poor, Ali Azargoonjahromi, Mohsen Nabi-Afjadi, Zahra Payandeh, Hamidreza Zalpoor, Dariush Shanehbandi.

  Exosomes, known as a type of extracellular vesicles (EVs), are lipid particles comprising heterogeneous contents such as nucleic acids, proteins, and DNA. These bi-layered particles are naturally released into the extracellular periphery by a variety of cells such as neoplastic cells. Given that exosomes have unique properties, they can be used as vectors and carriers of biological and medicinal particles like drugs for delivering to the desired areas. The proteins and RNAs being encompassed by the circulating exosomes in B-cell malignancies are deemed as the promising sources for diagnostic and prognostic biomarkers, as well as therapeutic agents. Exosomes can also provide a "snapshot" view of the tumor and metastatic landscape at any particular time. Further, clinical research has shown that exosomes are produced by immune cells such as dendritic cells can stimulate the immune system, so these exosomes can be used in antitumor vaccines. Despite the great potential of exosomes in the fields of diagnostic and treatment, further studies are in need for these purposes to reach a convergence notion. This review highlights the applications of exosomes in multiple immune-related diseases, including chronic lymphocytic leukemia, multiple sclerosis, and arthritis rheumatoid, as well as explaining sundry aspects of exosome therapy and the function of exosomes in diagnosing diseases.

Keywords:  Acute myeloid leukemia; Cancer; Chronic lymphocytic leukemia; Exosome; Multiple sclerosis; Rheumatic arthritis

DOI:  https://doi.org/10.1186/s11658-022-00377-x
J Nanobiotechnology. 2022 Sep 05. 20(1): 403

Exosomes in the tumor microenvironment of sarcoma: from biological functions to clinical applications.

Huali Ye, Xin Hu, Yang Wen, Chongqi Tu, Francis Hornicek, Zhenfeng Duan, Li Min.

  The current diagnosis and treatment of sarcoma continue to show limited timeliness and efficacy. In order to enable the early detection and management of sarcoma, increasing attentions have been given to the tumor microenvironment (TME). TME is a dynamic network composed of multiple cells, extracellular matrix, vasculature, and exosomes. Exosomes are nano-sized extracellular vesicles derived from various cells in the TME. The major function of exosomes is to promote cancer progress and metastasis through mediating bidirectional cellular communications between sarcoma cells and TME cells. Due to the content specificity, cell tropism, and bioavailability, exosomes have been regarded as promising diagnostic and prognostic biomarkers, and therapeutic vehicles for sarcoma. This review summarizes recent studies on the roles of exosomes in TME of sarcoma, and explores the emerging clinical applications.

Keywords:  Clinical application; Communication; Exosomes; Sarcoma; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12951-022-01609-0
Int J Mol Sci. 2022 Sep 04. pii: 10118. [Epub ahead of print]23(17):

Extracellular Vesicles in Haematological Disorders: A Friend or a Foe?

Ioanna Lazana.

  Extracellular vesicles (EVs) have emerged as important mediators of homeostasis, immune modulation and intercellular communication. They are released by every cell of the human body and accordingly detected in a variety of body fluids. Interestingly, their expression can be upregulated under various conditions, such as stress, hypoxia, irradiation, inflammation, etc. Their cargo, which is variable and may include lipids, proteins, RNAs and DNA, reflects that of the parental cell, which offers a significant diagnostic potential to EVs. In line with this, an increasing number of studies have reported the important contribution of cancer-derived EVs in altering the tumour microenvironment and allowing for cancer progression and metastasis. As such, cancer-derived EVs may be used to monitor the development and progression of disease and to evaluate the potential response to treatment, which has generated much excitement in the field of oncology and particularly in haemato-oncology. Finally, EVs are able to transfer their cargo to target cells, modifying the properties of the recipient cell, which offers great therapeutic potential for EVs (either by specific drug delivery or by delivery of siRNAs and other inhibitory proteins). In this manuscript, we review the potential diagnostic use and therapeutic options of EVs in the context of haematological malignancies.

Keywords:  exosomes; extracellular vesicles; haematological malignancies

DOI:  https://doi.org/10.3390/ijms231710118
Sensors (Basel). 2022 Aug 24. pii: 6347. [Epub ahead of print]22(17):

Quantification of Serum Exosome Biomarkers Using 3D Nanoporous Gold and Spectrophotometry.

Amera Al Mannai, Tareq Al-Ansari, Khaled M Saoud.

  Tumor-derived exosomes may provide biomarkers for cancer treatment. Using sputtering technology, an affinity-based device to capture exosomes was developed using nanoporous substrate (NPG)-coated silicon microscopy. Immunology-based techniques detect and purify exosomes using gold coating with a specific antigen. Inverted fluorescent microscopy was used to detect target exosomes quantitatively utilizing fluorescent nanospheres as the label. We quantified the expression of CD63 surface protein markers on exosomes from conditioned culture media of breast cancer cells. The exosomes that targeted specific proteins with controls were statistically analyzed and compared to those that targeted non-specific proteins. Results from SEM showed that the exosomes were circular, between 30 and 150 nanometers in size. The porous gold substrates captured more exosomes than the nonporous substrates. Nitric acid treatments at different times resulted in a variety of pore sizes. Despite the increase in the size of the pores, the number of exosomes found in the porous gold substrate treated for 10 min nearly doubled compared to the one treated for 5 min. In this work, a fluorescence biosensor was developed to detect breast cancer exosomes using nanoporous gold substrates (NPG). Assay and model exosomes of specific breast cancer cells showed that exosomes exhibit diagnostic surface protein markers, reflecting the protein profile of their parent cells. Furthermore, the specific binding between the exosome surface antibodies and the targets identified the CD63 biomarkers on the exosome, suggesting these markers' diagnostic potential. This study can accelerate exosome research in determining tumor-related exosomes and develop novel cancer diagnostic methods.

Keywords:  breast cancer; detection; exosomes; none porous gold nanoparticles; porous gold

DOI:  https://doi.org/10.3390/s22176347
Oncogene. 2022 Sep 09.

Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression.

Ming Li, Hao Xu, Yanhua Qi, Ziwen Pan, Boyan Li, Zijie Gao, Rongrong Zhao, Hao Xue, Gang Li.

Exosomes can selectively secrete harmful metabolic substances from cells to maintain cellular homeostasis, and complex crosstalk occurs between exosomes and tumor-associated macrophages (TAMs) in the glioma immune microenvironment. However, the precise mechanisms by which these exosome-encapsulated cargos create an immunosuppressive microenvironment remain unclear. Herein, we investigated the effect of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We performed sequencing analysis of cerebrospinal fluid (CSF) and tumor tissues from glioma patients to identify functional microRNAs (miRNAs). High levels of miR-3591-3p were found in CSF and GDEs but not in normal brain tissue or glial cells. Functionally, GDEs and miR-3591-3p significantly induced M2 macrophage polarization and increased the secretion of IL10 and TGFβ1, which in turn promoted glioma invasion and migration. Moreover, miR-3591-3p overexpression in glioma cell lines resulted in G2/M arrest and markedly increased apoptosis. Mechanistically, miR-3591-3p can directly target CBLB and MAPK1 in macrophages and glioma cells, respectively, and further activate the JAK2/PI3K/AKT/mTOR, JAK2/STAT3, and MAPK signaling pathways. In vivo experiments confirmed that macrophages lentivirally transduced with miR-3591-3p can significantly promote glioma progression. Thus, our study demonstrates that tumor-suppressive miR-3591-3p in glioma cells can be secreted via exosomes and target TAMs to induce the formation of an immunosuppressive microenvironment. Collectively, these findings provide new insights into the role of glioma exosomal miRNAs in mediating the establishment of an immunosuppressive tumor microenvironment and show that miR-3591-3p may be a valuable biomarker and that blocking the encapsulation of miR-3591-3p into exosomes may become a novel immunotherapeutic strategy for glioma.

DOI: https://doi.org/10.1038/s41388-022-02457-w
Autophagy. 2022 Sep 05. 1-3

Targeting NR1H/liver X receptor with dendrogenin A differentiates tumor cells to activate a new secretory pathway releasing immunogenic anti-tumor vesicles enriched in LC3-II-associated exosomes.

Philippe de Medina, Julio Bunay, Marc Poirot, Michel Record, Sandrine Silvente-Poirot.

  Normal cells secrete small extracellular vesicles (sEV), containing exosomes and/or ectosomes, which play a beneficial role in monitoring tissue integrity and immune response, whereas cancer cells constitutively secrete sEV, which contribute to inhibit the immune defenses and promote tumor progression and aggressiveness. Therefore, there is a great interest in reprograming tumor sEV functions toward normal ones. We hypothesized that this could be realized by inducing tumor cell re-differentiation with dendrogenin A (DDA), an endogenous oxysterol and a ligand of NR1 H/LXR (nuclear receptor subfamily 1 group H). At low doses, DDA induces tumor cell differentiation, tumor growth inhibition and immune cell infiltration into tumors. At high doses, DDA induces lethal macroautophagy/autophagy in tumors by increasing LC3 expression at the mRNA and protein level, through NR1H2/LXRβ. In the present study, we showed that low doses of DDA re-differentiate tumor cells by interacting with NR1H2. This results in an increased formation of multivesicular bodies (MVB) in tumor cells and an enhanced secretion of LC3-II-associated exosome-enriched sEV, with immune and anticancer properties. This study highlights the original LC3-II-associated exosome secretory pathway driven by the DDA-NR1H2 complex and paves the way to the development of new therapeutic strategies against pro-tumor exosomes.

Keywords:  Cancer; LC3; LXR; exosome; immunotherapy; oxysterol

DOI:  https://doi.org/10.1080/15548627.2022.2116175
Life Sci. 2022 Sep 05. pii: S0024-3205(22)00635-X. [Epub ahead of print] 120935

Engineered extracellular vesicles: A novel platform for cancer combination therapy and cancer immunotherapy.

Mahdi Ahmadi, Mehdi Hassanpour, Jafar Rezaie.

  Extracellular vesicles (EVs), phospholipid membrane-bound vesicles, produced by most cells, contribute to cell-cell communication. They transfer several proteins, lipids, and nucleic acids between cells both locally and systemically. Owing to the biocompatibility and immune activity of EVs, therapeutic approaches using these vesicles as drug delivery systems are being developed. Different methods are used to design more effective engineered EVs, which can serve as smart tools in cancer therapy and immunotherapy. Recent progress in the field of targeted-cancer therapy has led to the gradual use of engineered EVs in combinational therapy to combat heterogeneous tumor cells and multifaceted tumor microenvironments. The high plasticity, loading ability, and genetic manipulation capability of engineered EVs have made them the ideal platforms to realize numerous combinations of cancer therapy approaches. From the combination therapy view, engineered EVs can co-deliver chemotherapy with various therapeutic agents to target tumor cells effectively, further taking part in immunotherapy-related cancer combination therapy. However, a greater number of studies were done in pre-clinical platforms and the clinical translation of these studies needs further scrutiny because some challenges are associated with the application of engineered EVs. Given the many therapeutic potentials of engineered EVs, this review discusses their function in various cancer combination therapy and immunotherapy-related cancer combination therapy. In addition, this review describes the opportunities and challenges associated with the clinical application of engineered EVs.

Keywords:  Combination-therapy; Engineered EVs; Exosomal therapy and therapeutics; Extracellular vesicles; Immunotherapy

DOI:  https://doi.org/10.1016/j.lfs.2022.120935
Biomed Res Int. 2022 ;2022 5396628

Bioactivity of Exosomes Derived from Trained Natural Killer Cells versus Non-Trained One: More Functional and Antitumor Activity.

Fateme Mohammadi, Zahra Sadat Hashemi, Ramin Sarrami Forooshani, Shaban Alizadeh.

Background: Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system, capable of killing viral-infected and cancerous cells. NK cell-mediated immunotherapy has remarkably changed the current paradigm of cancer treatment in recent years. It emerged as a safe and effective therapeutic approach for patients with advanced-stage leukemia. Several immune-escape mechanisms can be enacted by cancer cells to avoid NK-mediated killing. Exosomes released by NK cells that carry proteins and miRNAs can exert an antitumor effect. In the present study, we hypothesized that maybe exosomes derived from trained natural killer cells show more antitumor effect in comparison to non-trained one.Methods: PBMC was separated by the Ficoll method and cultured with IL-2 for 21 days to expand NK cells. The NK cells were co-cultured with K562 for 72 hours and exosome-derived co-cultured (as trained) and natural killer cell-derived exosomes (as non-trained) were extracted by Exo kit. The exosomes were confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM), flow cytometry, and western blotting. The K562 cells were separately treated by trained and non-trained exosomes and MTT assay, apoptosis, and real-time PCR were performed.
Results: Based on flow cytometry, CD56 marker was 89.7% and 40.1% for NK cells and NK-derived exosomes, respectively. CD63 and CD9 were positive for exosomes by western blotting. The morphology of exosome was confirmed by TEM. Treated K562 cells by trained exosomes indicated the diminished cell viability and higher apoptosis. Furthermore, the trained exosomes showed up-regulation in both P53 and caspase3 genes as compared with non-trained sample. Discussion. Trained Exos showed a potent inhibitory effect on proliferation and induced apoptosis on K562 cell lines compared to the same dose of non-trained Exos. According to the results of qRT-PCR, trained Exos exerted an antitumor activity through up-regulation of caspase 3 and P53 in the apoptotic signaling pathway in tumor cells. Our findings indicate an effective action of trained Exos against cancer cells.

DOI: https://doi.org/10.1155/2022/5396628
Drug Deliv. 2022 Dec;29(1): 2897-2911

Delivery of human natural killer cell-derived exosomes for liver cancer therapy: an in vivo study in subcutaneous and orthotopic animal models.

Ho Yong Kim, Hyun-Ki Min, Hyeong-Woo Song, Ami Yoo, Seonmin Lee, Kyu-Pyo Kim, Jong-Oh Park, You Hee Choi, Eunpyo Choi.

  Exosomes are nanosized extracellular vesicles secreted by various cell types, including those of the immune system, such as natural killer (NK) cells. They play a role in intercellular communication by transporting signal molecules between the cells. Recent studies have reported that NK cell-derived exosomes (NK-exo) contain cytotoxic proteins-induced cell death. However, the characteristics and potential functions of NK-exo, especially for the liver cancer are poorly understood. In this study, we investigated the anti-tumor effects of NK-exo in the primary liver cancer, hepatocellular carcinoma (HCC), using the orthotopic and subcutaneous tumor model. We found that NK-exo expressed both typical exosomal markers (e.g. CD63, CD81, and Alix) and cytotoxic proteins (e.g. perforin, granzyme B, FasL, and TRAIL). NK-exo were selectively taken up by HCC cells (e.g. Hep3B, HepG2, and Huh 7). Interestingly, Hep3B cells induced the highest cytotoxicity compared with HepG2 and Huh7 cells, and substantially enhanced the apoptosis by NK-exo. Furthermore, we demonstrated that NK-exo inhibited the phosphorylation of serine/threonine protein kinases (e.g. AKT and ERK1/2), and enhanced the activation of specific apoptosis markers (e.g. caspase-3, -7, -8, -9, and PARP) in Hep3B cells. NK-exo also exhibit the active targeting ability and potent therapeutic effects in both orthotopic and subcutaneous HCC mouse models. Overall, these results suggest that NK-exo indicate strong anti-tumor effects in HCC, which are mediated by novel regulatory mechanisms involved in serine/threonine kinase pathway-associated cell proliferation and caspase activation pathway-associated apoptosis.

Keywords:  Natural killer cells; exosomes; hepatocellular carcinoma; liver cancer therapy

DOI:  https://doi.org/10.1080/10717544.2022.2118898
Biomed Pharmacother. 2022 Sep;pii: S0753-3322(22)00869-1. [Epub ahead of print]153 113480

Extracellular vesicles as an emerging drug delivery system for cancer treatment: Current strategies and recent advances.

Zhenggang Wang, Haokun Mo, Zhiyi He, Anmin Chen, Peng Cheng.

  Cancer is one of the primary causes of death worldwide, and its morbidity and mortality rates are increasing rapidly. However, standard treatment modalities (surgery, radiotherapy, chemotherapy, and immunotherapy) often fail to achieve a satisfactory therapeutic effect. Extracellular vesicles (EVs) are natural nano-sized lipid bilayer vesicles secreted from cells. Owing to their advantages of low toxicity, high biocompatibility, low immunogenicity, and inherent targeting, EVs can be exploited as drug delivery vectors for cancer treatment. In this review, we summarize the research progress of EV-based drug delivery systems in cancer treatment by focusing on four aspects: sources, cargo types, cargo loading methods and modification strategies. Finally, current challenges and future perspectives are discussed.

Keywords:  Cancer treatment; Drug delivery systems; Extracellular vesicles; Nanomedicine

DOI:  https://doi.org/10.1016/j.biopha.2022.113480
Front Cell Dev Biol. 2022 ;10 971596

Comparison of plasma- and saliva-derived exosomal miRNA profiles reveals diagnostic potential in head and neck cancer.

Linda Hofmann, Tsima Abou Kors, Jasmin Ezić, Beate Niesler, Ralph Röth, Sonja Ludwig, Simon Laban, Patrick J Schuler, Thomas K Hoffmann, Cornelia Brunner, Valentin Medyany, Marie-Nicole Theodoraki.

  Background: Head and neck squamous cell carcinomas (HNSCC) lack tumor-specific biomarkers. Exosomes from HNSCC patients carry immunomodulatory molecules, and correlate with clinical parameters. We compared miRNA profiles of plasma- and saliva-derived exosomes to reveal liquid biomarker candidates for HNSCC. Methods: Exosomes were isolated by differential ultracentrifugation from corresponding plasma and saliva samples from 11 HNSCC patients and five healthy donors (HD). Exosomal miRNA profiles, as determined by nCounter® SPRINT technology, were analyzed regarding their diagnostic and prognostic potential, correlated to clinical data and integrated into network analysis. Results: 119 miRNAs overlapped between plasma- and saliva-derived exosomes of HNSCC patients, from which 29 tumor-exclusive miRNAs, associated with TP53, TGFB1, PRDM1, FOX O 1 and CDH1 signaling, were selected. By intra-correlation of tumor-exclusive miRNAs from plasma and saliva, top 10 miRNA candidates with the strongest correlation emerged as diagnostic panels to discriminate cancer and healthy as well as potentially prognostic panels for disease-free survival (DFS). Further, exosomal miRNAs were differentially represented in human papillomavirus (HPV) positive and negative as well as low and high stage disease. Conclusion: A plasma- and a saliva-derived panel of tumor-exclusive exosomal miRNAs hold great potential as liquid biopsy for discrimination between cancer and healthy as well as HPV status and disease stage. Exosomal miRNAs from both biofluids represent a promising tool for future biomarker studies, emphasizing the possibility to substitute plasma by less-invasive saliva collection.

Keywords:  HNSCC; HPV; exosomes; liquid biopsy; miRNA; plasma; saliva

DOI:  https://doi.org/10.3389/fcell.2022.971596
Cancers (Basel). 2022 Aug 26. pii: 4136. [Epub ahead of print]14(17):

Circulating Tumour Cells, Cell Free DNA and Tumour-Educated Platelets as Reliable Prognostic and Management Biomarkers for the Liquid Biopsy in Multiple Myeloma.

Alessandro Allegra, Gabriella Cancemi, Giuseppe Mirabile, Alessandro Tonacci, Caterina Musolino, Sebastiano Gangemi.

  Liquid biopsy is one of the fastest emerging fields in cancer evaluation. Circulating tumour cells and tumour-originated DNA in plasma have become the new targets for their possible employ in tumour diagnosis, and liquid biopsy can define tumour burden without invasive procedures. Multiple Myeloma, one of the most frequent hematologic tumors, has been the target of therapeutic progresses in the last few years. Bone marrow aspirate is the traditional tool for diagnosis, prognosis, and genetic evaluation in multiple myeloma patients. However, this painful procedure presents a relevant drawback for regular disease examination as it requires an invasive practice. Moreover, new data demonstrated that a sole bone marrow aspirate is incapable of expressing the multifaceted multiple myeloma genetic heterogeneity. In this review, we report the emerging usefulness of the assessment of circulating tumour cells, cell-free DNA, extracellular RNA, cell-free proteins, extracellular vesicles, and tumour-educated platelets to evaluate the changing mutational profile of multiple myeloma, as early markers of disease, reliable predictors of prognosis, and as useful tools to perform less invasive monitoring in multiple myeloma.

Keywords:  cancer biomarkers; cell free DNA; circulating tumour cells; exosomes; liquid biopsy; miRNAs; multiple myeloma; prognosis; tumour-educated platelet

DOI:  https://doi.org/10.3390/cancers14174136
Int J Mol Sci. 2022 Sep 01. pii: 9930. [Epub ahead of print]23(17):

Exosomes in Cancer Diagnosis and Therapy.

Aamir Ahmad.

Cancer affects millions of people worldwide every year [...].

DOI: https://doi.org/10.3390/ijms23179930
J Hematol Oncol. 2022 Sep 06. 15(1): 128

Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1.

Jiewei Lin, Xinjing Wang, Shuyu Zhai, Minmin Shi, Chenghong Peng, Xiaxing Deng, Da Fu, Jiancheng Wang, Baiyong Shen.

  BACKGROUND: circRNA has been established to play a pivotal role in tumorigenesis development in a variety of cancers; nevertheless, the biological functions and molecular mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer remain largely unknown.METHODS: Differentially expressed circRNAs in exosomes between hypoxic exosomes and normoxic exosomes in PC cells were verified by RNA sequencing. The expression of circPDK1 in PC tumors and PC patients was evaluated by qRT-PCR and ISH, and the biological functions of circPDK1 in PC were verified through a series of in vitro and in vivo experiments. Using Western blotting, Co-IP, RNA pull-down, ChIP, RIP, dual-luciferase assays, and rescue experiments, the underlying mechanism of circPDK1 was verified.
RESULTS: CircPDK1 was highly abundant in PC tumor tissues and serum exosomes and was associated with poor survival. Exosomal circPDK1 significantly promoted PC cell proliferation, migration, and glycolysis both in vitro and in vivo. Mechanistically, circPDK1 could be activated by HIF1A at the transcriptional level and sponges miR-628-3p to activate the BPTF/c-myc axis. In addition, circPDK1 serves as a scaffold that enhances the interaction between UBE2O and BIN1, inducing the UBE2O-mediated degradation of BIN1.
CONCLUSIONS: We found that circPDK1 was activated by HIF1A at the transcriptional level by modulating the miR-628-3p/BPTF axis and degrading BIN1. Exosomal circPDK1 is a promising biomarker for PC diagnosis and prognosis and represents a potential therapeutic target for PC.

Keywords:  Exosomes; Hypoxia; Pancreatic cancer; Ubiquitination; ceRNA; circRNA

DOI:  https://doi.org/10.1186/s13045-022-01348-7
J Extracell Vesicles. 2022 Sep;11(9): e12264

Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway.

Xiduan Wei, Jingjia Ye, Yameng Pei, Chunting Wang, Hongzhen Yang, Jingyuan Tian, Guangxu Si, Yao Ma, Kun Wang, Gang Liu.

  Pattern-recognition receptors (PRRs) have been shown to promote tumour metastasis via sensing tumour cell-derived small extracellular vesicles (EVs). Nucleotide-binding oligomerisation domain 1 (NOD1), a cytoplasmic PRR, plays a role in colorectal cancer (CRC) by detecting bacterial products. However, the precise mechanisms underlying the effects of NOD1, following identification of CRC cell-derived EVs (CRC-EVs), to potentiate CRC liver metastasis (CRC-LM), remain poorly understood. Here, we demonstrate that CRC-EVs activate NOD1 in macrophages to initiate secretion of inflammatory cytokines and chemokines. NOD1-activated macrophages also promote CRC cell migration, while in a murine model of liver metastasis (LM), NOD1-deficient mice exhibit reduced metastasis following CRC-EV treatment. Furthermore, cell division cycle 42 (CDC42), a small Rho guanosine-5'-triphosphate (GTP)ase, is delivered by CRC-EVs into macrophages where it activates NOD1. In addition, EVs from the plasma of patients with CRC-LM mediate NOD1 activation in human peripheral blood mononuclear cells. Moreover, high NOD1 expression in tumour tissues is associated with poor prognosis of CRC-LM. Our findings suggest that CRC-EVs activate NOD1 to promote tumour metastasis, thus, NOD1 may serve as a potential target in the diagnosis and treatment of CRC-LM.

Keywords:  NOD1 signalling; colorectal cancer; extracellular vesicles; metastatic liver

DOI:  https://doi.org/10.1002/jev2.12264
Int J Mol Sci. 2022 Sep 03. pii: 10074. [Epub ahead of print]23(17):

Brownian Motion Influence on AFM Exosomes' Size Measurements.

Katarzyna Życieńska, Beata Pszczółkowska, Beata Brzozowska, Maciej Kamiński, Tomasz Lorenc, Wioletta Olejarz, Sławomir Sęk, Józef Ginter.

  Extracellular vesicles are evaluated by nanoparticle tracking analysis (NTA), providing information on their hydrodynamic diameters, and by atomic force microscopy (AFM) to calculate their geometric diameters. The aim of this study is to explore the influence of Brownian movements in a sample drop and preparation time on imaging-based measurements and to determine the relationship between the geometric and hydrodynamic sizes of the extracellular vesicles measured by the AFM and the NTA, respectively. Exosomes derived from the human prostate cancer cell line PC3 were evaluated by NTA and AFM, and those results were compared with Monte Carlo simulations. The mean size, evaluated by AFM shortly after application on the mica substrate, is less than its real value. It obtains the correct value faster for a thinner sample drop. Fitting the log-normal distribution to the geometric and hydrodynamic diameters leads to the conclusion that the latter could arise from the former by linear scaling by a factor that could be used to characterize the analyzed extracellular vesicles. The size of the vesicles attached to the mica substrate depends on time. The effect of Brownian motion and stretch of the lipid bilayer should be considered in the context of exosome AFM studies.

Keywords:  Brownian motion; atomic force microscopy (AFM); exosomes; extracellular vesicles; nanoparticle tracking analysis (NTA); prostate cancer

DOI:  https://doi.org/10.3390/ijms231710074
J Hepatocell Carcinoma. 2022 ;9 853-854

Erratum: Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis [Corrigendum].

[This corrects the article DOI: 10.2147/JHC.S327339.].

DOI: https://doi.org/10.2147/JHC.S386422
Front Genet. 2022 ;13 965329

A prognostic exosome-related LncRNA risk model correlates with the immune microenvironment in liver cancer.

Duntao Su, Zeyu Zhang, Zhijie Xu, Fada Xia, Yuanliang Yan.

  Background: Emerging studies have shown the important roles of long noncoding RNAs (lncRNAs) in the occurrence and development of liver cancer. However, the exosome-related lncRNA signature in liver cancer remains to be clarified. Methods: We obtained 371 tumor specimens and 50 normal tissues from the TCGA database. These samples were randomly divided into the training queue and verification queue. The exosome-related lncRNA risk model was verified by correlation analysis, Lasso regression analysis, and Cox regression analysis. The differences in the immune microenvironment in the two risk groups were obtained by analyzing the infiltration of different immune cells. Results: Five exosome-related lncRNAs associated (MKLN1-AS, TMCC1-AS1, AL031985.3, LINC01138, AC099850.3) with a poor prognosis were identified and used to construct the signature. Receiver operating curve (ROC) and survival curves were used to confirm the predictive ability of this signature. Based on multivariate regression analysis in the training cohort (HR: 3.033, 95% CI: 1.762-5.220) and validation cohort (HR: 1.998, 95% CI: 1.065-3.751), the risk score was found to be an independent risk factor for patient prognosis. Subsequently, a nomogram was constructed to predict the 1-, 3-, 5-years survival rates of liver cancer patients. Moreover, this signature was also related to overexpressed immune checkpoints (PD-1, B7-H3, VSIR, PD-L1, LAG3, TIGIT and CTLA4). Conclusion: Our study showed that exosome-related lncRNAs and the corresponding nomogram could be used as a better index to predict the outcome and immune regulation of liver cancer patients. This signature might provide a new idea for the immunotherapy of liver cancer in the future.

Keywords:  exosomes; liver cancer; lncRNAs; prognostic signature; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fgene.2022.965329
Cancers (Basel). 2022 Aug 28. pii: 4167. [Epub ahead of print]14(17):

Extracellular Vesicle-Derived Protein File from Peripheral Blood Predicts Immune-Related Adverse Events in Gastric Cancer Patients Receiving Immunotherapy.

Fangli Jiang, Zhening Zhang, Xiaoyi Chong, Lin Shen, Meng Fan, Xuan Liu, Jin An, Zhi Peng, Cheng Zhang.

  Immune checkpoint inhibitors (ICIs) initiate a new stage for gastric cancer (GC) therapeutics, and plenty of patients have already benefited from ICIs. Liquid biopsy promotes the development of precision medicine of GC. However, due to the lack of precision biomarkers of immune-related adverse events (irAEs), the safety of ICIs-treated GC patients cannot be guaranteed. In our study, GC patients treated with ICIs were included for investigating the correlation between irAEs of ICIs and corresponding outcomes. We also explored the potential of biomarkers of irAEs via EV-derived proteins. Dynamic plasma was taken from 102 ICIs-treated GC patients generated retrospectively or prospectively, who were divided into discovery and validating cohorts. Plasma EV-derived protein profiles were described, and two EV-proteins, inducible T-cell co-stimulator (EV-ICOS) and indoleamine 2,3-dioxygenase 1(EV-IDO1), from 42 vital proteins were screened to predict the prognosis of ICIs with irAEs. Our work is the first to propose that EV-proteins can predict ICIs-corresponding irAEs, which can be conducive to the diagnosis and treatment of GC patients, and to facilitate the screening of beneficiaries.

Keywords:  ICOS; IDO1; exosomes; immune checkpoint inhibitors; immune-related adverse events

DOI:  https://doi.org/10.3390/cancers14174167