bims-exocan Biomed News
on Exosomes roles in cancer
Issue of 2022–08–07
fiveteen papers selected by
Muhammad Rizwan, COMSATS University
  1. Role of exosomal microRNAs in cancer therapy and drug resistance mechanisms: focus on hepatocellular carcinoma.
  2. Role of extracellular vesicles in osteosarcoma.
  3. The value of exosome-derived noncoding RNAs in colorectal cancer proliferation, metastasis, and clinical applications.
  4. Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy.
  5. Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling.
  6. All-in-One Strategy for Downstream Molecular Profiling of Tumor-Derived Exosomes.
  7. BMI1 promotes cholangiocarcinoma progression and correlates with antitumor immunity in an exosome-dependent manner.
  8. Characterization of protein complexes in extracellular vesicles by intact extracellular vesicle crosslinking mass spectrometry (iEVXL).
  9. Recent advances in conventional and unconventional vesicular secretion pathways in the tumor microenvironment.
  10. Quantitative proteomics identifies proteins enriched in large and small extracellular vesicles.
  11. Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43.
  12. Cancer-associated fibroblasts-derived extracellular vesicles carrying lncRNA SNHG3 facilitate colorectal cancer cell proliferation via the miR-34b-5p/HuR/HOXC6 axis.
  13. Melanoma-derived small extracellular vesicles remodel the systemic onco-immunity via disrupting hematopoietic stem cell proliferation and differentiation.
  14. Ultrasensitive ELISA detection of proteins in separated lumen and membrane fractions of cancer cell exosomes.
  15. Extracellular vimentin is expressed at the rear of activated macrophage-like cells: Potential role in enhancement of migration and phagocytosis.
  1. Front Oncol. 2022 ;12 940056
    Role of exosomal microRNAs in cancer therapy and drug resistance mechanisms: focus on hepatocellular carcinoma.
    Veronica Zelli, Chiara Compagnoni, Roberta Capelli, Alessandra Corrente, Mauro Di Vito Nolfi, Francesca Zazzeroni, Edoardo Alesse, Alessandra Tessitore.
      Extracellular vesicles (EVs), defined as intercellular messengers that carry their cargos between cells, are involved in several physiological and pathological processes. These small membranous vesicles are released by most cells and contain biological molecules, including nucleic acids, proteins and lipids, which can modulate signaling pathways of nearby or distant recipient cells. Exosomes, one the most characterized classes of EVs, include, among others, microRNAs (miRNAs), small non-coding RNAs able to regulate the expression of several genes at post-transcriptional level. In cancer, exosomal miRNAs have been shown to influence tumor behavior and reshape tumor microenvironment. Furthermore, their possible involvement in drug resistance mechanisms has become evident in recent years. Hepatocellular carcinoma (HCC) is the major type of liver cancer, accounting for 75-85% of all liver tumors. Although the improvement in HCC treatment approaches, low therapeutic efficacy in patients with intermediate-advanced HCC is mainly related to the development of tumor metastases, high risk of recurrence and drug resistance. Exosomes have been shown to be involved in pathogenesis and progression of HCC, as well as in drug resistance, by regulating processes such as cell proliferation, epithelial-mesenchymal transition and immune response. Herein, we summarize the current knowledge about the involvement of exosomal miRNAs in HCC therapy, highlighting their role as modulators of therapeutic response, particularly chemotherapy and immunotherapy, as well as possible therapeutic tools.
    Keywords:  drug resistance; exosomes; hepatocellular carcinoma; miRNAs; therapy
    DOI:  https://doi.org/10.3389/fonc.2022.940056
  2. Int J Med Sci. 2022 ;19(8): 1216-1226
    Role of extracellular vesicles in osteosarcoma.
    Qifan Yang, Jing Liu, Bo Wu, Xinyu Wang, Ye Jiang, Dong Zhu.
      Osteosarcoma is a malignant bone tumor characterized by the direct production of osteoid tissue from tumor cells. Extracellular vesicles are membranous vesicles released by cells into the extracellular matrix, which exist widely in various body fluids and cell supernatants, and stably carry some important signaling molecules. They are involved in cell communication, cell migration, angiogenesis and tumor cell growth. Increasing evidence has shown that extracellular vesicles play a significant role in osteosarcoma development, progression, and metastatic process, indicating that extracellular vesicles can be use as biomarker vehicles in the diagnosis and prognosis of osteosarcoma. This review discusses the basic biological characteristics of extracellular vesicles and focuses on their application in osteosarcoma.
    Keywords:  chemotherapy resistance; extracellular vesicles; immune escape; microenvironment; osteosarcoma
    DOI:  https://doi.org/10.7150/ijms.74137
  3. Clin Transl Oncol. 2022 Aug 03.
    The value of exosome-derived noncoding RNAs in colorectal cancer proliferation, metastasis, and clinical applications.
    Wenjie Zhang, Zhengting Jiang, Dong Tang.
      Colorectal cancer (CRC) is the third most common cancer in the world today, and its incidence and mortality rates are increasing every year. The ease of proliferation and metastasis of CRC has long been an important reason for its high mortality rate. Exosomes serve as key mediators that mediate communication between tumor cells and various other cells. Non-coding RNAs (ncRNAs) have been shown to play a key role in apoptosis, immunosuppression and proliferation metastasis in cancer. ncRNAs are loaded on exosomes and initiate the onset of metastasis by promoting epithelial-mesenchymal transition (EMT) at the primary site of the tumor. Meanwhile, exosome-derived ncRNAs construct a pre-metastatic niche (PMN) for CRC metastasis by forming an inflammatory microenvironment in distant organs, immunosuppression, and promoting angiogenesis and remodeling of the extracellular matrix. Here, we summarize the specific mechanisms associated with exosome-derived ncRNAs promoting local invasion and metastasis in CRC. Finally, we focus on their value for clinical application in future CRC diagnosis and treatment.
    Keywords:  CRC; Clinical application; Exosome; Metastasis; ncRNAs
    DOI:  https://doi.org/10.1007/s12094-022-02908-6
  4. Drug Deliv. 2022 Dec;29(1): 2513-2538
    Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy.
    Manling Wu, Min Wang, Haoyuan Jia, Peipei Wu.
      Increasing evidences show that unmodified extracellular vesicles (EVs) derived from various cells can effectively inhibit the malignant progression of different types of tumors by delivering the bioactive molecules. Therefore, EVs are expected to be developed as emerging anticancer drugs. Meanwhile, unmodified EVs as an advanced and promising nanocarrier that is frequently used in targeted delivery therapeutic cargos and personalized reagents for the treatment and diagnosis of cancer. To improve the efficacy of EV-based treatments, researchers are trying to engineering EVs as an emerging nanomedicine translational therapy platform through biological, physical and chemical approaches, which can be broaden and altered to enhance their therapeutic capability. EVs loaded with therapeutic components such as tumor suppressor drugs, siRNAs, proteins, peptides, and conjugates exhibit significantly enhanced anti-tumor effects. Moreover, the design and preparation of tumor-targeted modified EVs greatly enhance the specificity and effectiveness of tumor therapy, and these strategies are expected to become novel ideas for tumor precision medicine. This review will focus on reviewing the latest research progress of functionalized EVs, clarifying the superior biological functions and powerful therapeutic potential of EVs, for researchers to explore new design concepts based on EVs and build next-generation nanomedicine therapeutic platforms.
    Keywords:  Engineered EVs; bioinspiration; cancer therapy; drug delivery; functionalization strategy
    DOI:  https://doi.org/10.1080/10717544.2022.2104404
  5. Nat Commun. 2022 Aug 01. 13(1): 4461
    Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling.
    Feng Xie, Xiaoxue Zhou, Peng Su, Heyu Li, Yifei Tu, Jinjin Du, Chen Pan, Xiang Wei, Min Zheng, Ke Jin, Liyan Miao, Chao Wang, Xuli Meng, Hans van Dam, Peter Ten Dijke, Long Zhang, Fangfang Zhou.
      Cancer immunotherapies have shown clinical success in various types of tumors but the patient response rate is low, particularly in breast cancer. Here we report that malignant breast cancer cells can transfer active TGF-β type II receptor (TβRII) via tumor-derived extracellular vesicles (TEV) and thereby stimulate TGF-β signaling in recipient cells. Up-take of extracellular vesicle-TβRII (EV-TβRII) in low-grade tumor cells initiates epithelial-to-mesenchymal transition (EMT), thus reinforcing cancer stemness and increasing metastasis in intracardial xenograft and orthotopic transplantation models. EV-TβRII delivered as cargo to CD8+ T cells induces the activation of SMAD3 which we demonstrated to associate and cooperate with TCF1 transcription factor to impose CD8+ T cell exhaustion, resulting in failure of immunotherapy. The levels of TβRII+ circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors.
    DOI:  https://doi.org/10.1038/s41467-022-31250-2
  6. ACS Appl Mater Interfaces. 2022 Aug 02.
    All-in-One Strategy for Downstream Molecular Profiling of Tumor-Derived Exosomes.
    Shurong Wang, Ying He, Jiayin Lu, Yuqing Wang, Xiaofeng Wu, Guoquan Yan, Xiaoni Fang, Baohong Liu.
      In light of the significance of exosomes in cancer diagnosis and treatment, it is important to understand the components and functions of exosomes. Herein, an all-in-one strategy has been proposed for comprehensive characterization of exosomal proteins based on nanoporous TiO2 clusters acting as both an extractor for exosome isolation and a nanoreactor for downstream molecular profiling. With the improved hydrophilicity and inherent properties of TiO2, exosomes can be captured by a versatile nanodevice through the specific binding and hydrophilicity interaction synergistically. The strong concerted effect between exosomes and nanodevices ensured high efficiency and specificity of exosome isolation with high recovery and low contaminations. Meanwhile, highly efficient downstream proteomic analysis of the purified exosomes was also enabled by the nanoporous TiO2 clusters. Benefiting from the porous structure of the nanodevice, the lysed exosomal proteins are highly concentrated in the nanopore to achieve high-efficiency in situ proteolytic digestion. Therefore, the unique features of the TiO2 clusters ensured that all the complex steps about isolation and analysis of exosomes were completed efficiently in one simple nanodevice. The concept was first proved with exosomes from cell culture medium, where a high number of identified total proteins and protein groups in exosomes were obtained. Taking advantage of these attractive merits, the first example of the integrated platform has been successfully applied to the analysis of exosomes in complex real-case samples. Not only 196 differential protein biomarker candidates were discovered, but also many more significant cellular components and functions related to gastric cancer were found. These results suggest that the nanoporous TiO2 cluster-based all-in-one strategy can serve as a simple, cost-effective, and integrated platform to facilitate comprehensive analysis of exosomes. Such an approach will provide a valuable tool for the study of exosome markers and their functions.
    Keywords:  downstream molecular profiling; exosomes; isolation; nanoporous TiO2 clusters; nanoreactor
    DOI:  https://doi.org/10.1021/acsami.2c07143
  7. Cell Mol Life Sci. 2022 Aug 06. 79(9): 469
    BMI1 promotes cholangiocarcinoma progression and correlates with antitumor immunity in an exosome-dependent manner.
    Zengli Liu, Chunxiao Hu, Lijie Zheng, Jialiang Liu, Kangshuai Li, Xingyong Li, Yue Wang, Wentao Mu, Tianli Chen, Anda Shi, Bo Qiu, Xin Zhang, Zongli Zhang, Yunfei Xu.
       BACKGROUND: Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. BMI1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of BMI1 in cholangiocarcinoma (CCA) are not well elucidated.
    METHODS: In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected BMI1 expression in a large CCA cohort. We demonstrated that BMI1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of BMI1 promoted CCA proliferation, migration, and invasion. And BMI1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain BMI1 proteins, which can transfer BMI1 between CCA cells. The unique BMI1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that BMI1 inhibits CD8+T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells.
    CONCLUSIONS: BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA.
    Keywords:  Antitumor immunity; BMI1; Cholangiocarcinoma; Exosomes; Progression; prognosis
    DOI:  https://doi.org/10.1007/s00018-022-04500-1
  8. J Extracell Vesicles. 2022 Jul;11(8): e12245
    Characterization of protein complexes in extracellular vesicles by intact extracellular vesicle crosslinking mass spectrometry (iEVXL).
    Julia Bauzá-Martinez, Gad Armony, Matti F Pronker, Wei Wu.
      Extracellular vesicles (EVs) are blood-borne messengers that coordinate signalling between different tissues and organs in the body. The specificity of such crosstalk is determined by preferential EV docking to target sites, as mediated through protein-protein interactions. As such, the need to structurally characterize the EV surface precedes further understanding of docking selectivity and recipient-cell uptake mechanisms. Here, we describe an intact extracellular vesicle crosslinking mass spectrometry (iEVXL) method that can be applied for structural characterization of protein complexes in EVs. By using a partially membrane-permeable disuccinimidyl suberate crosslinker, proteins on the EV outer-surface and inside EVs can be immobilized together with their interacting partners. This not only provides covalent stabilization of protein complexes before extraction from the membrane-enclosed environment, but also generates a set of crosslinking distance restraints that can be used for structural modelling and comparative screening of changes in EV protein assemblies. Here we demonstrate iEVXL as a powerful approach to reveal high-resolution information, about protein determinants that govern EV docking and signalling, and as a crucial aid in modelling docking interactions.
    DOI:  https://doi.org/10.1002/jev2.12245
  9. J Biomed Sci. 2022 Aug 05. 29(1): 56
    Recent advances in conventional and unconventional vesicular secretion pathways in the tumor microenvironment.
    I-Ying Kuo, Chih-Hsiung Hsieh, Wan-Ting Kuo, Chih-Peng Chang, Yi-Ching Wang.
      All cells in the changing tumor microenvironment (TME) need a class of checkpoints to regulate the balance among exocytosis, endocytosis, recycling and degradation. The vesicular trafficking and secretion pathways regulated by the small Rab GTPases and their effectors convey cell growth and migration signals and function as meditators of intercellular communication and molecular transfer. Recent advances suggest that Rab proteins govern conventional and unconventional vesicular secretion pathways by trafficking widely diverse cargoes and substrates in remodeling TME. The mechanisms underlying the regulation of conventional and unconventional vesicular secretion pathways, their action modes and impacts on the cancer and stromal cells have been the focus of much attention for the past two decades. In this review, we discuss the current understanding of vesicular secretion pathways in TME. We begin with an overview of the structure, regulation, substrate recognition and subcellular localization of vesicular secretion pathways. We then systematically discuss how the three fundamental vesicular secretion processes respond to extracellular cues in TME. These processes are the conventional protein secretion via the endoplasmic reticulum-Golgi apparatus route and two types of unconventional protein secretion via extracellular vesicles and secretory autophagy. The latest advances and future directions in vesicular secretion-involved interplays between tumor cells, stromal cell and host immunity are also described.
    Keywords:  Exocytosis; Extracellular vesicle; Rab GTPase; Secretory autophagy; Tumor microenvironment; Vesicle trafficking
    DOI:  https://doi.org/10.1186/s12929-022-00837-8
  10. Mol Cell Proteomics. 2022 Jul 30. pii: S1535-9476(22)00081-0. [Epub ahead of print] 100273
    Quantitative proteomics identifies proteins enriched in large and small extracellular vesicles.
    Anna Lischnig, Markus Bergqvist, Takahiro Ochiya, Cecilia Lässer.
      There is a long-held consensus that several proteins are unique to small extracellular vesicles (EVs), such as exosomes. However, recent studies have shown that several of these markers can also be present in other subpopulations of EVs to a similar degree. Furthermore, few markers have been identified as enriched or uniquely present in larger EVs, such as microvesicles. The aim of this study was to address these issues by conducting an in-depth comparison of the proteome of large and small EVs. Large (16,500 × g) and small EVs (118,000 × g) were isolated from three cell lines using a combination of differential ultracentrifugation and a density cushion and quantitative mass spectrometry (TMT-LC-MS/MS) was used to identify differently-enriched proteins in large and small EVs. In total, 6493 proteins were quantified, with 818 and 1567 proteins significantly enriched in small and large EVs, respectively. Tetraspanins, ADAMs and ESCRT proteins, as well as SNAREs and Rab proteins associated with endosomes were enriched in small EVs compared to large EVs, whereas ribosomal, mitochondrial and nuclear proteins, as well as proteins involved in cytokinesis, were enriched in large EVs compared to small EVs. However, Flotillin-1 was not differently expressed in large and small EVs. In conclusion, our study shows that the proteome of large and small EVs are substantially dissimilar. We validated several proteins previously suggested to be enriched in either small or large EVs (e.g. ADAM10 and Mitofilin, respectively), and we suggest several additional novel protein markers.
    Keywords:  LC-MS/MS; exosomes; microvesicles; subpopulations; tandem mass tag
    DOI:  https://doi.org/10.1016/j.mcpro.2022.100273
  11. Int J Med Sci. 2022 ;19(7): 1205-1215
    Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43.
    Zhang-Jian Yang, Qiu-Chen Bi, Li-Jun Gan, Le-Ling Zhang, Min-Jun Wei, Tao Hong, Rong Liu, Cheng-Lin Qiu, Xiao-Jian Han, Li-Ping Jiang.
      Glioblastoma multiform (GBM) is a highly aggressive primary brain tumor. Exosomes derived from glioma cells under a hypoxic microenvironment play an important role in tumor biology including metastasis, angiogenesis and chemoresistance. However, the underlying mechanisms remain to be elucidated. In this study, we aimed to explore the role of connexin 43 on exosomal uptake and angiogenesis in glioma under hypoxia. U251 cells were exposed to 3% oxygen to achieve hypoxia, and the expression levels of HIF-1α and Cx43, involved in the colony formation and proliferation of cells were assessed. Exosomes were isolated by differential velocity centrifugation from U251 cells under normoxia and hypoxia (Nor-Exos and Hypo-Exos), respectively. Immunofluorescence staining, along with assays for CCK-8, tube formation and wound healing along with a transwell assay were conducted to profile exosomal uptake, proliferation, tube formation, migration and invasion of HUVECs, respectively. Our results revealed that Hypoxia significantly up-regulated the expression of HIF-1α in U251 cells as well as promoting proliferation and colony number. Hypoxia also increased the level of Cx43 in U251 cells and in the exosomes secreted. The uptake of Dio-stained Hypo-Exos by HUVECs was greater than that of Nor-Exos, and inhibition of Cx43 by 37,43gap27 or lenti-Cx43-shRNA efficiently prevented the uptake of Hypo-Exos by recipient endothelial cells. In addition, the proliferation and total loops of HUVECs were remarkably increased at 24 h, 48 h, and 10 h after Hypo-Exos, respectively. Notably, 37,43gap27, a specific Cx-mimetic peptide blocker of Cx37 and Cx43, efficiently alleviated Hypo-Exos-induced proliferation and tube formation by HUVECs. Finally, 37,43gap27 also significantly attenuated Hypo-Exos-induced migration and invasion of HUVECs. These findings demonstrate that exosomal Cx43 contributes to glioma angiogenesis mediated by Hypo-Exos, and suggests that exosomal Cx43 might serve as a potential therapeutic target for glioblastoma.
    Keywords:  angiogenesis; connexin 43; exosome; glioma; hypoxia
    DOI:  https://doi.org/10.7150/ijms.71912
  12. Cell Death Discov. 2022 Aug 03. 8(1): 346
    Cancer-associated fibroblasts-derived extracellular vesicles carrying lncRNA SNHG3 facilitate colorectal cancer cell proliferation via the miR-34b-5p/HuR/HOXC6 axis.
    Jiangning Zhao, Huanrong Lin, Kunsong Huang, Shen Li.
      Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) can mediate tumorigenesis. Long noncoding RNA (LncRNA) SNHG3 is implicated in colorectal cancer (CRC) progression. The current study sought to clarify the role of CAFs-EVs carrying SNHG3 in CRC cell proliferation. Firstly, CAFs and normal fibroblasts (NFs) were cultured and identified, followed by isolation and characterization of CAFs-EVs and NFs-EVs. CRC cells were cultured with CAFs-EVs or CAFs-EVs overexpressing SNHG3. The effects of SNHG3 on CRC cell proliferation was evaluated using CCK-8, colony formation, and EdU staining assays. The binding relationships among SNHG3, miR-34b-5p, and HuR were validated, in addition to analyzing the binding between HuR and HOXC6. Lastly, xenograft tumor model was established to verify the role of CAFs-EVs carrying SNHG3 in vivo. SNHG3 was highly expressed in CRC cells and CAFs-EVs, whereas CAFs-EVs facilitated CRC cell proliferation. Mechanically, CAFs-EVs carried SNHG3 into CRC cells to upregulate HuR expression by competitively binding to miR-34b-5p, promote the binding of HuR and HOXC6, and enhance HOXC6 transcription. miR-34b-5p over-expression or HOXC6 silencing annulled the effect of CAFs-EVs. SNHG3 carried by CAFs-EVs facilitated CRC proliferation via the miR-34b-5p/HuR/HOXC6 axis in vivo. Collectively, our findings indicated that CAFs-EVs carried SNHG3 into CRC cells to upregulate HuR expression by sponging miR-34b-5p and finally enhance HOXC6 transcription, thereby facilitating CRC cell proliferation.
    DOI:  https://doi.org/10.1038/s41420-022-01116-z
  13. Cancer Lett. 2022 Jul 31. pii: S0304-3835(22)00325-1. [Epub ahead of print] 215841
    Melanoma-derived small extracellular vesicles remodel the systemic onco-immunity via disrupting hematopoietic stem cell proliferation and differentiation.
    Zhimin Du, Yueyuan Feng, Hui Zhang, Jinbao Liu, Jinheng Wang.
      Hematopoiesis and the immune system beyond the tumor microenvironment are typically dysregulated in cancer. Tumor-derived small extracellular vesicles (sEVs) containing exosomes are emerging contributors to tumor progression and immunomodulation. However, a comprehensive definition of how tumor-derived sEVs impacts systemic immunity is lacking. In this study, we used mass cytometry with extensive antibody panels to determine the expression of 24 immune cell markers, eight intracellular proteins, and seven immune checkpoint proteins in systemic immune cell lineages. The systemic immune landscape in response to tumor-derived sEVs across three immune organs in a melanoma mouse model was then characterized. Melanoma-derived sEVs significantly and extensively influenced the composition and intracellular pathways of immune lineage and T cells. An immunosuppressive immune system with decreased natural killer and CD8 T cells in the spleen and bone marrow (BM), increased regulatory T cells in lymph nodes, and increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the BM, was induced by melanoma-derived sEVs. Additionally, melanoma-derived sEVs significantly enhanced the PD-1/PD-L1 axis in CD4 T cells and myeloid cell subsets. These sEVs largely promoted the proliferation of multiple hematopoietic stem and progenitor cell subsets and accelerated their differentiation towards MDSCs in naive mice and mice undergoing hematopoietic reconstruction. Moreover, melanoma-derived sEVs directly promoted the survival and activation of MDSCs in vitro. Collectively, our work examines the effects of tumor-derived sEVs on the systemic onco-immune macroenvironments and highlights the contribution of these sEVs to the dysregulation of hematopoiesis and systemic immune landscape in cancer.
    Keywords:  Exosomes; Hematopoietic dysregulation; Mass cytometry; Myeloid-derived suppressor cells; Systemic immune landscape
    DOI:  https://doi.org/10.1016/j.canlet.2022.215841
  14. Anal Biochem. 2022 Jul 31. pii: S0003-2697(22)00291-3. [Epub ahead of print]654 114831
    Ultrasensitive ELISA detection of proteins in separated lumen and membrane fractions of cancer cell exosomes.
    Kanako Iha, Naoko Tsurusawa, Hsin-Yi Tsai, Ming-Wei Lin, Hikaru Sonoda, Satoshi Watabe, Teruki Yoshimura, Etsuro Ito.
      Exosomes transfer molecules horizontally to surrounding cells and therefore have a key role in cancer progression. To clarify the role of exosomes in cancer progression, trace amounts of proteins in their lumen and membrane fractions should be analyzed separately. For this purpose, an adequate and easy-to-use method of separating the lumen and membrane fractions of exosomes must be developed. Further, because exosomes contain only trace amounts of proteins, an ultrasensitive protein detection method is necessary. To develop an adequate and easy-to-use lumen and membrane fraction separation method, we applied a commercially available kit originally developed for cells to exosomes and examined the validity of the results compared with those obtained using a conventional, complicated Na2CO3 method. To develop an ultrasensitive protein detection method, we designated GRP78, which is upregulated in cancer cells and contributes to cancer progression, as the target protein and detected it at the subattomolar level using an ultrasensitive ELISA combined with thio-NAD cycling. By applying these methods together, GRP78 was successfully quantified in both the lumen and membrane fractions of exosomes obtained from cultured cancer cells. The present results will facilitate studies to broaden our understanding of the tumor microenvironment.
    Keywords:  Exosome; GRP78; Lumen-membrane separation; Thio-NAD cycling; Ultrasensitive ELISA
    DOI:  https://doi.org/10.1016/j.ab.2022.114831
  15. Front Cell Dev Biol. 2022 ;10 891281
    Extracellular vimentin is expressed at the rear of activated macrophage-like cells: Potential role in enhancement of migration and phagocytosis.
    Divyendu Goud Thalla, Ashish Chand Rajwar, Annalena Maria Laurent, Johanna Elisabeth Becher, Lucina Kainka, Franziska Lautenschläger.
      Macrophages have a vital role in the immune system through elimination of cell debris and microorganisms by phagocytosis. The activation of macrophages by tumour necrosis factor-α induces expression of extracellular cell-surface vimentin and promotes release of this vimentin into the extracellular environment. Vimentin is a cytoskeletal protein that is primarily located in the cytoplasm of cells. However, under circumstances like injury, stress, senescence and activation, vimentin can be expressed on the extracellular cell surface, or it can be released into the extracellular space. The characteristics of this extracellular vimentin, and its implications for the functional role of macrophages and the mechanism of secretion remain unclear. Here, we demonstrate that vimentin is released mainly from the back of macrophage-like cells. This polarisation is strongly enhanced upon macrophage activation. One-dimensional patterned lines showed that extracellular cell-surface vimentin is localised primarily at the back of activated macrophage-like cells. Through two-dimensional migration and phagocytosis assays, we show that this extracellular vimentin enhances migration and phagocytosis of macrophage-like cells. We further show that this extracellular vimentin forms agglomerates on the cell surface, in contrast to its intracellular filamentous form, and that it is released into the extracellular space in the form of small fragments. Taken together, we provide new insights into the release of extracellular cell-surface vimentin and its implications for macrophage functionality.
    Keywords:  activation; extracellular vimentin; macrophages; migration; phagocytosis; polarisation; vimentin secretion
    DOI:  https://doi.org/10.3389/fcell.2022.891281
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