bims-exocan 2023-01-29 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2023–01–29
nine papers selected by
Muhammad Rizwan, COMSATS University

Immunosuppressive functions of melanoma cell-derived exosomes in plasma of melanoma patients.
Research advances in the understanding of how exosomes regulate ferroptosis in cancer.
Treatment dependent impact of plasma-derived exosomes from head and neck cancer patients on the epithelial-to-mesenchymal transition.
Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.
Extracellular vesicles and melanoma: New perspectives on tumor microenvironment and metastasis.
Extracellular vesicles derived from dental mesenchymal stem/stromal cells with gemcitabine as cargo have an inhibitory effect on the growth of pancreatic carcinoma cell lines in vitro.
Mesenchymal stromal/stem cell-derived exosomes and genitourinary cancers: A mini review.
Exosomal miRNA-profiling of pleural effusion in lung adenocarcinoma and tuberculosis.
Extracellular vesicles as a liquid biopsy for melanoma: are we there yet?

Front Cell Dev Biol. 2022 ;10 1080925

Immunosuppressive functions of melanoma cell-derived exosomes in plasma of melanoma patients.

Theresa L Whiteside.

  Tumor-derived exosomes (TEX) are a subset of small extracellular vesicles (sEV) present in all body fluids of patients with cancer. In plasma of patients with metastatic melanoma, numbers of exosomes produced by melanoma cells called MTEX are elevated. To study the role of MTEX in melanoma progression, immunoaffinity-based separation of MTEX from total plasma exosomes was performed. The surface of MTEX was decorated by various checkpoint inhibitory proteins, and upon coincubation with immune recipient cells, MTEX suppressed anti-tumor functions of these cells. MTEX emerge as a major mechanism of immune suppression in melanoma and thus might play a role in promoting melanoma progression.

Keywords:  exosomes; immune capture; immune suppression; melanoma; melanoma cell-derived exosomes (MTEX); small extracellular vesicles

DOI:  https://doi.org/10.3389/fcell.2022.1080925
Clin Transl Oncol. 2023 Jan 27.

Research advances in the understanding of how exosomes regulate ferroptosis in cancer.

Jiaxuan Liu.

  Exosomes are extracellular vesicles that can release different bioactive substances to affect tumor cells and cell death pathways. As an important mediator of cell communication, exosomes participate in the occurrence and development of a variety of diseases. Ferroptosis, one of the newly defined forms of regulated cell death, is characterized by massive accumulation of iron ions and lipid peroxidation. An increasing number of studies have shown that ferroptosis plays an important role in malignant tumors. Moreover, exosomes have been recognized for their potential in cancer therapy based on ferroptosis. To further describe how could exosomes regulate ferroptosis in cancer and provide better understanding of the mechanisms involved, this paper reviews the definition as well as the underlying molecular mechanisms of ferroptosis, including iron metabolism, amino acid metabolism, lipid metabolism and so on. Then, we illustrated how could exosomes regulate the ferroptosis pathway and suggested their promising potential as a novel tumor therapy for cancer patients. Finally, we described the perspectives of ferroptosis by exosomes in tumor treatment. Therefore, exosomes have the potential to regulate ferroptosis in clinical cancer treatment.

Keywords:  Cancer; Exosome; Ferroptosis

DOI:  https://doi.org/10.1007/s12094-023-03089-6
Front Oncol. 2022 ;12 1043199

Treatment dependent impact of plasma-derived exosomes from head and neck cancer patients on the epithelial-to-mesenchymal transition.

Linda Hofmann, Marie Waizenegger, Ralph Röth, Stefanie Schmitteckert, Daphne Engelhardt, Patrick J Schuler, Simon Laban, Thomas K Hoffmann, Cornelia Brunner, Marie-Nicole Theodoraki.

   Background: Epithelial to mesenchymal transition (EMT) is a key process in carcinogenesis of head and neck squamous cell carcinoma (HNSCC), contributing to tumor invasiveness, distant metastasis, and recurrence. Exosomes are known mediators and regulators of EMT. Here, we analyze the impact of exosomes that were primed by conventional therapy on EMT modulation.
Methods: Plasmas of n = 22 HNSCC patients were collected before and after standard of care surgery and adjuvant or primary (chemo)radiotherapy. Exosomes were isolated by size exclusion chromatography. Upon co-incubation of exosomes with HNSCC cells, the cellular EMT profile was analyzed by flow cytometry and RT-qPCR. Wound healing assays were performed to evaluate migratory potential of exosome-treated cells.
Results: Reduction of total exosome protein after therapy and in vitro exosome induced EMT profiles were dependent on the type of treatment. Exosomal TFG-β and miRNA cargo were partly responsible for observed exosome induced EMT changes. Exosomes from recurrent patients induced higher tumor cell migration after therapy than exosomes from disease-free patients.
Conclusions: HNSCC patients' exosomes from timepoints before and after therapy were able to confer therapy induced EMT modulation in vitro and have the potential to monitor the EMT process. Exosome induced changes in migratory potential emerged as discriminants of therapy outcome.

Keywords:  EMT; HNSCC; conventional therapy; exosomes; recurrence

DOI:  https://doi.org/10.3389/fonc.2022.1043199
J Transl Med. 2023 Jan 21. 21(1): 40

Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.

Pengyu Liu, Wenxuan Wang, Fei Wang, Jiaqi Fan, Jinan Guo, Tao Wu, Dongliang Lu, Qingchun Zhou, Zhuohao Liu, Yuliang Wang, Zhiqun Shang, Franky Leung Chan, Wei Yang, Xin Li, Shan-Chao Zhao, Qingyou Zheng, Fei Wang, Dinglan Wu.

   BACKGROUND: Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC.
METHODS: Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models.
RESULTS: Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis.
CONCLUSION: Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

Keywords:  Biomarkers; CRPC; Exosomes; Metabolomics; PCa; Proteomics

DOI:  https://doi.org/10.1186/s12967-022-03860-3
Front Cell Dev Biol. 2022 ;10 1061982

Extracellular vesicles and melanoma: New perspectives on tumor microenvironment and metastasis.

Alberto Benito-Martín, Miriam Galvonas Jasiulionis, Susana García-Silva.

  Secreted extracellular vesicles (EVs) are lipid bilayer particles without functional nucleus naturally released from cells which constitute an intercellular communication system. There is a broad spectrum of vesicles shed by cells based on their physical properties such as size (small EVs and large EVs), biogenesis, cargo and functions, which provide an increasingly heterogenous landscape. In addition, they are involved in multiple physiological and pathological processes. In cancer, EV release is opted by tumor cells as a beneficial process for tumor progression. Cutaneous melanoma is a cancer that originates from the melanocyte lineage and shows a favorable prognosis at early stages. However, when melanoma cells acquire invasive capacity, it constitutes the most aggressive and deadly skin cancer. In this context, extracellular vesicles have been shown their relevance in facilitating melanoma progression through the modulation of the microenvironment and metastatic spreading. In agreement with the melanosome secretory capacity of melanocytes, melanoma cells display an enhanced EV shedding activity that has contributed to the utility of melanoma models for unravelling EV cargo and functions within a cancer scenario. In this review, we provide an in-depth overview of the characteristics of melanoma-derived EVs and their role in melanoma progression highlighting key advances and remaining open questions in the field.

Keywords:  extracellular vesicles; melanoma; melanosomes; metastasis; microenvironment; pre-metastatic niche; vesicular cargo

DOI:  https://doi.org/10.3389/fcell.2022.1061982
Mol Cell Probes. 2023 Jan 24. pii: S0890-8508(23)00003-8. [Epub ahead of print] 101894

Extracellular vesicles derived from dental mesenchymal stem/stromal cells with gemcitabine as cargo have an inhibitory effect on the growth of pancreatic carcinoma cell lines in vitro.

Daniela Klimova, Jana Jakubechova, Ursula Altanerova, Andreas Nicodemou, Jakub Styk, Tomas Szemes, Vanda Repiska, Cestmir Altaner.

  Extracellular vesicles (EVs) are nowadays a target of interest in cancer therapy as a successful drug delivering tool. Based on their many beneficial biocompatible properties are designed to transport nucleic acids, proteins, various nanomaterials or chemotherapeutics. Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) possess their tumor-homing abilities. This inspired us to engineer the MSC's EVs to be packed with chemotherapeutic agents and deliver it as a Trojan horse directly into tumor cells. In our study, human dental pulp MSCs (DP-MSCs) were cultivated with gemcitabine (GCB), which led to its absorption by the cells and subsequent secretion of the drug out into conditioned media in EVs. Concentrated conditioned media containing small EVs (potentially exosomes) significantly inhibited the cell growth of pancreatic carcinoma cell lines in vitro. DP-MSCs were simultaneously engineered to express a suicide gene fused yeast cytosinedeaminase:uracilphosphoribosyltransferase (yCD::UPRT). The product of the suicide gene converts non-toxic prodrug 5-fluorocytosine (5-FC) to highly cytotoxic chemotherapeutic drug 5-fluorouracil (5-FU) in the recipient cancer cells. Conversion of 5-FC to 5-FU had an additional effect on cancer cell's growth inhibition. Our results showed a therapeutic potential for DP-MSC-EVs to be designed for successful delivering of chemotherapeutic drugs, together with prodrug suicide gene therapy system.

Keywords:  5-Fluorocytosine; 5-Fluorouracil; Dental mesenchymal stem/stromal cells; Extracellular vesicles; Gemcitabine; Suicide gene

DOI:  https://doi.org/10.1016/j.mcp.2023.101894
Front Cell Dev Biol. 2022 ;10 1115786

Mesenchymal stromal/stem cell-derived exosomes and genitourinary cancers: A mini review.

Aria Salehpour, Saule Balmagambetova, Nadiar Mussin, Asset Kaliyev, Farhad Rahmanifar.

  Mesenchymal stromal/stem cell- (MSC-) derived exosomes are gaining popularity for their involvement in tissue repair and repressing various tumors through extensive patterns. Nevertheless, the impact of extracellular vesicles produced by stem cells on tumor formation and progression is controversial and seems to depend on several factors. The utilization of MSCs' various capabilities in urogenital neoplasms is widely regarded as a potential future therapeutic as well. These genitourinary neoplasms include prostatic neoplasms, ovarian neoplasms, cervical neoplasms, endometrial neoplasms, bladder neoplasms, and renal cell neoplasms. The present study has concentrated on the most recent information on genitourinary neoplasms employing MSCs derived exosomes' many capabilities, such as delivering effective RNAs, extensive tissue compatibility, and specificity with tumor identification without inherent limitations of cell therapy.

Keywords:  Exosomes; Genitourinary neoplasms; MSCs; Mesenchymal Stromal/Stem Cell; Reproductive cancers; Reproductive neoplasms; Urogenital neoplasms; miRNAs

DOI:  https://doi.org/10.3389/fcell.2022.1115786
Front Surg. 2022 ;9 1050242

Exosomal miRNA-profiling of pleural effusion in lung adenocarcinoma and tuberculosis.

Xuede Zhang, Lingling Bao, Guohua Yu, Haifeng Wang.

   Background: Pleural effusion (PE) caused by lung cancer is prevalent, and it is difficult to differentiate it from PE caused by tuberculosis. Exosome-based liquid biopsy offers a non-invasive technique to diagnose benign and malignant PE. Exosomal miRNAs are potential diagnostic markers and play an essential role in signal transduction and biological processes in tumor development. We hypothesized that exosomal miRNA expression profiles in PE would contribute to identifying its diagnostic markers and elucidating the molecular basis of PE formation in lung cancer.
Methods: The exosomes from PE caused by lung adenocarcinoma (LUAD) and pulmonary tuberculosis were isolated and verified by transmission electron microscopy. The exosomal miRNA profiles were identified using deep sequencing and validated with quantitative real-time PCR (qRT-PCR). We performed bioinformatic analysis for differentially expressed miRNAs to explore how exosomal miRNAs regulate pleural effusion.
Results: We identified 99 upregulated and 91 downregulated miRNAs in malignant pleural effusion (MPE) compared to tuberculous pleural effusion (TPE). Seven differentially expressed miRNAs (DEmiRNAs) were validated by qRT-PCR, out of which 5 (71.4%) were confirmed through sequencing. Gene Ontology (GO) analysis revealed that most exosomal miRNAs target genes were involved in regulating cellular processes and nitrogen compound metabolism. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, the exosomal miRNAs target genes were mainly involved in Fc gamma R-mediated phagocytosis, Rap1 signaling pathway, and breast cancer. The hub genes, including ITGAM, FOXO1, MAPK14, YWHAB, GRIN1, and PRF1, were screened through plug-in cytoHubba. The PFR1 was identified as a critical gene in MPE formation using single-cell sequencing analysis. Additionally, we hypothesized that tumor cells affected natural killer cells and promoted the generation of PE in LUAD via the exosomal hsa-miR-3120-5p-PRF1 axis.
Conclusions: We identified exosomal miRNA profiles in LUAD-MPE and TPE, which may help in the differential diagnosis of MPE and TPE. Bioinformatic analysis revealed that these miRNAs might affect PE generation through tumor immune response in LUAD. Our results provided a new theoretical basis for understanding the function of exosomal miRNAs in LUAD-MPE.

Keywords:  bioinformatic analysis; exosomes; lung adenocarcinoma; miRNAs; pleural effusions

DOI:  https://doi.org/10.3389/fsurg.2022.1050242
Semin Cancer Biol. 2023 Jan 24. pii: S1044-579X(23)00014-7. [Epub ahead of print]

Extracellular vesicles as a liquid biopsy for melanoma: are we there yet?

Lidia B Medhin, Aaron B Beasley, Lydia Warburton, Benhur Amanuel, Elin S Gray.

  Melanoma is the most aggressive form of skin cancer owing to its high propensity to metastasise in distant organs and develop resistance to treatment. The scarce treatment options available for melanoma underscore the need for biomarkers to guide treatment decisions. In this context, an attractive alternative to overcome the limitations of repeated tissue sampling is the analysis of peripheral blood samples, referred to as 'liquid biopsy'. In particular, the analysis of extracellular vesicles (EVs) has emerged as a promising candidate due to their role in orchestrating cancer dissemination, immune modulation, and drug resistance. As we gain insights into the role of EVs in cancer and melanoma their potential for clinical use is becoming apparent. Herein, we critically summarise the current evidence supporting EVs as biomarkers for melanoma diagnosis, prognostication, therapy response prediction, and drug resistance. EVs are proposed as a candidate biomarker for predicting therapeutic response to immune checkpoint inhibition. However, to realise the potential of EV analysis for clinical decision-making strong clinical validation is required, underscoring the need for further research in this area.

Keywords:  Melanoma; biomarkers; extracellular vesicles; liquid biopsy

DOI:  https://doi.org/10.1016/j.semcancer.2023.01.008