Immunopathology of Extracellular Vesicles in Macrophage and Glioma Cross-Talk
Abstract
:1. Introduction
2. Macrophage/Microglial Polarization in GBM Pathology
3. EVs as Biological Mediators of Intercellular Communication
4. Impact of GBM-Derived EVs on Macrophage Function
5. Impact of Macrophage-Derived EVs on GBM Immunopathology
6. Approaches to Target GBM/Macrophage EV Crosstalk
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Thakkar, J.P.; Dolecek, T.A.; Horbinski, C.; Ostrom, Q.T.; Lightner, D.D.; Barnholtz-Sloan, J.S.; Villano, J.L. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol. Biomark. Prev. 2014, 23, 1985–1996. [Google Scholar] [CrossRef] [PubMed]
- Burster, T.; Traut, R.; Yermekkyzy, Z.; Mayer, K.; Westhoff, M.-A.; Bischof, J.; Knippschild, U. Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells. Front. Cell Dev. Biol. 2021, 9, 695325. [Google Scholar] [CrossRef] [PubMed]
- Sun, R.; Kim, A.H. The multifaceted mechanisms of malignant glioblastoma progression and clinical implications. Cancer Metastasis Rev. 2022, 41, 871–898. [Google Scholar] [CrossRef] [PubMed]
- Vilar, J.B.; Christmann, M.; Tomicic, M.T. Alterations in Molecular Profiles Affecting Glioblastoma Resistance to Radiochemotherapy: Where Does the Good Go? Cancers 2022, 14, 2416. [Google Scholar] [CrossRef]
- Fabro, F.; Lamfers, M.L.M.; Leenstra, S. Advancements, Challenges, and Future Directions in Tackling Glioblastoma Resistance to Small Kinase Inhibitors. Cancers 2022, 14, 600. [Google Scholar] [CrossRef]
- Charles, N.A.; Holland, E.C.; Gilbertson, R.; Glass, R.; Kettenmann, H. The brain tumor microenvironment. Glia 2011, 59, 1169–1180. [Google Scholar] [CrossRef]
- Badie, B.; Schartner, J.M. Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery 2000, 46, 957–962. [Google Scholar] [PubMed]
- Basheer, A.S.; Abas, F.; Othman, I.; Naidu, R. Role of Inflammatory Mediators, Macrophages, and Neutrophils in Glioma Maintenance and Progression: Mechanistic Understanding and Potential Therapeutic Applications. Cancers 2021, 13, 4226. [Google Scholar] [CrossRef]
- Annovazzi, L.; Mellai, M.; Bovio, E.; Mazzetti, S.; Pollo, B.; Schiffer, D. Microglia immunophenotyping in gliomas. Oncol. Lett. 2018, 15, 998–1006. [Google Scholar] [CrossRef]
- Wu, S.-Y.; Watabe, K. The roles of microglia/macrophages in tumor progression of brain cancer and metastatic disease. Front. Biosci. 2017, 22, 1805–1829. [Google Scholar] [CrossRef]
- Andersen, J.K.; Miletic, H.; Hossain, J.A. Tumor-Associated Macrophages in Gliomas-Basic Insights and Treatment Opportunities. Cancers 2022, 14, 1319. [Google Scholar] [CrossRef] [PubMed]
- Yekula, A.; Yekula, A.; Muralidharan, K.; Kang, K.; Carter, B.S.; Balaj, L. Extracellular Vesicles in Glioblastoma Tumor Microenvironment. Front. Immunol. 2019, 10, 3137. [Google Scholar] [CrossRef] [PubMed]
- Ma, J.; Chen, C.C.; Li, M. Macrophages/Microglia in the Glioblastoma Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 5775. [Google Scholar] [CrossRef] [PubMed]
- Buzas, E.I. The roles of extracellular vesicles in the immune system. Nat. Rev. Immunol. 2022, 23, 236–250. [Google Scholar] [CrossRef]
- Shetty, A.K.; Upadhya, R. Extracellular Vesicles in Health and Disease. Aging Dis. 2021, 12, 1358–1362. [Google Scholar] [CrossRef] [PubMed]
- Parham, P. The Immune System; Garland Science: New York, NY, USA, 2009. [Google Scholar]
- Wang, G.; Zhong, K.; Wang, Z.; Zhang, Z.; Tang, X.; Tong, A.; Zhou, L. Tumor-associated microglia and macrophages in glioblastoma: From basic insights to therapeutic opportunities. Front. Immunol. 2022, 13, 964898. [Google Scholar] [CrossRef]
- Kotwal, G.J.; Chien, S. Macrophage Differentiation in Normal and Accelerated Wound Healing. Results Probl. Cell Differ. 2017, 62, 353–364. [Google Scholar]
- Chang, R.B.; Beatty, G.L. The interplay between innate and adaptive immunity in cancer shapes the productivity of cancer immunosurveillance. J. Leukoc. Biol. 2020, 108, 363–376. [Google Scholar] [CrossRef]
- Chitadze, G.; Kabelitz, D. Immune surveillance in glioblastoma: Role of the NKG2D system and novel cell-based therapeutic approaches. Scand. J. Immunol. 2022, 96, e13201. [Google Scholar] [CrossRef]
- Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969. [Google Scholar] [CrossRef]
- Xue, J.; Schmidt, S.V.; Sander, J.; Draffehn, A.; Krebs, W.; Quester, I.; De Nardo, D.; Gohel, T.D.; Emde, M.; Schmidleithner, L.; et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014, 40, 274–288. [Google Scholar] [CrossRef] [PubMed]
- Arango Duque, G.; Descoteaux, A. Macrophage Cytokines: Involvement in Immunity and Infectious Diseases. Front. Immunol. 2014, 5, 491. [Google Scholar] [CrossRef]
- Lichtnekert, J.; Kawakami, T.; Parks, W.C.; Duffield, J.S. Changes in macrophage phenotype as the immune response evolves. Curr. Opin. Pharmacol. 2013, 13, 555–564. [Google Scholar] [CrossRef]
- Buonfiglioli, A.; Hambardzumyan, D. Macrophages and microglia: The cerberus of glioblastoma. Acta Neuropathol. Commun. 2021, 9, 54. [Google Scholar] [CrossRef]
- Liu, J.; Geng, X.; Hou, J.; Wu, G. New insights into M1/M2 macrophages: Key modulators in cancer progression. Cancer Cell Int. 2021, 21, 389. [Google Scholar] [CrossRef]
- Zhao, Y.-L.; Tian, P.-X.; Han, F.; Zheng, J.; Xia, X.-X.; Xue, W.-J.; Ding, X.-M.; Ding, C.-G. Comparison of the characteristics of macrophages derived from murine spleen, peritoneal cavity, and bone marrow. J. Zhejiang Univ. Sci. B 2017, 18, 1055–1063. [Google Scholar] [CrossRef]
- Wang, N.; Liang, H.; Zen, K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front. Immunol. 2014, 5, 614. [Google Scholar] [CrossRef]
- Haydar, D.; Cory, T.J.; Birket, S.E.; Murphy, B.S.; Pennypacker, K.R.; Sinai, A.P.; Feola, D.J. Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-κB Signaling Pathways. J. Immunol. 2019, 203, 1021–1030. [Google Scholar] [CrossRef]
- Kopper, T.J.; Zhang, B.; Bailey, W.M.; Bethel, K.E.; Gensel, J.C. The effects of myelin on macrophage activation are phenotypic specific via cPLA 2 in the context of spinal cord injury inflammation. Sci. Rep. 2021, 11, 6341. [Google Scholar] [CrossRef]
- Gensel, J.C.; Kopper, T.J.; Zhang, B.; Orr, M.B.; Bailey, W.M. Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment. Sci. Rep. 2017, 7, 40144. [Google Scholar] [CrossRef]
- Kopper, T.J.; Gensel, J.C. Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury. J. Neurosci. Res. 2017, 21, 1831–1839. [Google Scholar] [CrossRef] [PubMed]
- Garofalo, S.; Porzia, A.; Mainiero, F.; Di Angelantonio, S.; Cortese, B.; Basilico, B.; Pagani, F.; Cignitti, G.; Chece, G.; Maggio, R.; et al. Environmental stimuli shape microglial plasticity in glioma. Elife 2017, 6, e33415. [Google Scholar] [CrossRef] [PubMed]
- Khan, F.; Pang, L.; Dunterman, M.; Lesniak, M.S.; Heimberger, A.B.; Chen, P. Macrophages and microglia in glioblastoma: Heterogeneity, plasticity, and therapy. J. Clin. Investig. 2023, 133, e163446. [Google Scholar] [CrossRef] [PubMed]
- DeNardo, D.G.; Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 2019, 19, 369–382. [Google Scholar] [CrossRef]
- Duan, Z.; Luo, Y. Targeting macrophages in cancer immunotherapy. Signal Transduct. Target. Ther. 2021, 6, 127. [Google Scholar] [CrossRef]
- Yin, J.; Valin, K.L.; Dixon, M.L.; Leavenworth, J.W. The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer. J. Immunol. Res. 2017, 2017, 5150678. [Google Scholar] [CrossRef]
- Doyle, L.M.; Wang, M.Z. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019, 8, 727. [Google Scholar] [CrossRef]
- Di Bella, M.A. Overview and Update on Extracellular Vesicles: Considerations on Exosomes and Their Application in Modern Medicine. Biology 2022, 11, 804. [Google Scholar] [CrossRef]
- Bazzan, E.; Tinè, M.; Casara, A.; Biondini, D.; Semenzato, U.; Cocconcelli, E.; Balestro, E.; Damin, M.; Radu, C.M.; Turato, G.; et al. Critical Review of the Evolution of Extracellular Vesicles’ Knowledge: From 1946 to Today. Int. J. Mol. Sci. 2021, 22, 6417. [Google Scholar] [CrossRef]
- Cauvi, D.M.; Hawisher, D.; Dores-Silva, P.R.; Lizardo, R.E.; De Maio, A. Macrophage reprogramming by negatively charged membrane phospholipids controls infection. FASEB J. 2019, 33, 2995–3009. [Google Scholar] [CrossRef]
- Battistelli, M.; Falcieri, E. Apoptotic Bodies: Particular Extracellular Vesicles Involved in Intercellular Communication. Biology 2020, 9, 21. [Google Scholar] [CrossRef]
- Théry, C.; Witwer, K.W.; Aikawa, E.; Alcaraz, M.J.; Anderson, J.D.; Andriantsitohaina, R.; Antoniou, A.; Arab, T.; Archer, F.; Atkin-Smith, G.K.; et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 2018, 7, 1535750. [Google Scholar] [CrossRef]
- Graner, M.W. Roles of Extracellular Vesicles in High-Grade Gliomas: Tiny Particles with Outsized Influence. Annu. Rev. Genom. Hum. Genet. 2019, 20, 331–357. [Google Scholar] [CrossRef]
- van Niel, G.; D’Angelo, G.; Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 2018, 19, 213–228. [Google Scholar] [CrossRef]
- Hallal, S.; Mallawaaratchy, D.M.; Wei, H.; Ebrahimkhani, S.; Stringer, B.W.; Day, B.W.; Boyd, A.W.; Guillemin, G.J.; Buckland, M.E.; Kaufman, K.L. Extracellular Vesicles Released by Glioblastoma Cells Stimulate Normal Astrocytes to Acquire a Tumor-Supportive Phenotype Via p53 and MYC Signaling Pathways. Mol. Neurobiol. 2019, 56, 4566–4581. [Google Scholar] [CrossRef]
- Andre, F.; Schartz, N.E.C.; Movassagh, M.; Flament, C.; Pautier, P.; Morice, P.; Pomel, C.; Lhomme, C.; Escudier, B.; Le Chevalier, T.; et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 2002, 360, 295–305. [Google Scholar] [CrossRef]
- de Vrij, J.; Maas, S.L.N.; Kwappenberg, K.M.C.; Schnoor, R.; Kleijn, A.; Dekker, L.; Luider, T.M.; de Witte, L.D.; Litjens, M.; van Strien, M.E.; et al. Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int. J. Cancer 2015, 137, 1630–1642. [Google Scholar] [CrossRef]
- Gabrusiewicz, K.; Li, X.; Wei, J.; Hashimoto, Y.; Marisetty, A.L.; Ott, M.; Wang, F.; Hawke, D.; Yu, J.; Healy, L.M.; et al. Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes. Oncoimmunology 2018, 7, e1412909. [Google Scholar] [CrossRef]
- Zhao, G.; Yu, H.; Ding, L.; Wang, W.; Wang, H.; Hu, Y.; Qin, L.; Deng, G.; Xie, B.; Li, G.; et al. microRNA-27a-3p delivered by extracellular vesicles from glioblastoma cells induces M2 macrophage polarization via the EZH1/KDM3A/CTGF axis. Cell. Death Discov. 2022, 8, 260. [Google Scholar] [CrossRef]
- Abels, E.R.; Maas, S.L.N.; Nieland, L.; Wei, Z.; Cheah, P.S.; Tai, E.; Kolsteeg, C.-J.; Dusoswa, S.A.; Ting, D.T.; Hickman, S.; et al. Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21. Cell. Rep. 2019, 28, 3105–3119.e7. [Google Scholar] [CrossRef]
- Yang, J.-K.; Liu, H.-J.; Wang, Y.; Li, C.; Yang, J.-P.; Yang, L.; Qi, X.-J.; Zhao, Y.-L.; Shi, X.-F.; Li, J.-C.; et al. Exosomal miR-214-5p Released from Glioblastoma Cells Modulates Inflammatory Response of Microglia after Lipopolysaccharide Stimulation through Targeting CXCR5. CNS Neurol. Disord. Drug. Targets 2019, 18, 78–87. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.; Zhang, J.; Zhang, Z.; Gao, Z.; Qi, Y.; Qiu, W.; Pan, Z.; Guo, Q.; Li, B.; Zhao, S.; et al. Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction. Cell. Death Dis. 2021, 12, 373. [Google Scholar] [CrossRef] [PubMed]
- Serpe, C.; Monaco, L.; Relucenti, M.; Iovino, L.; Familiari, P.; Scavizzi, F.; Raspa, M.; Familiari, G.; Civiero, L.; D’Agnano, I.; et al. Microglia-Derived Small Extracellular Vesicles Reduce Glioma Growth by Modifying Tumor Cell Metabolism and Enhancing Glutamate Clearance through miR-124. Cells 2021, 10, 2066. [Google Scholar] [CrossRef]
- Zhang, Z.; Xu, J.; Chen, Z.; Wang, H.; Xue, H.; Yang, C.; Guo, Q.; Qi, Y.; Guo, X.; Qian, M.; et al. Transfer of MicroRNA via Macrophage-Derived Extracellular Vesicles Promotes Proneural-to-Mesenchymal Transition in Glioma Stem Cells. Cancer Immunol. Res. 2020, 8, 966–981. [Google Scholar] [CrossRef] [PubMed]
- Zhao, G.; Ding, L.; Yu, H.; Wang, W.; Wang, H.; Hu, Y.; Qin, L.; Deng, G.; Xie, B.; Li, G.; et al. M2-like tumor-associated macrophages transmit exosomal miR-27b-3p and maintain glioblastoma stem-like cell properties. Cell Death Discov. 2022, 8, 350. [Google Scholar] [CrossRef]
- Jiang, Y.; Zhao, J.; Xu, J.; Zhang, H.; Zhou, J.; Li, H.; Zhang, G.; Xu, K.; Jing, Z. Glioblastoma-associated microglia-derived exosomal circKIF18A promotes angiogenesis by targeting FOXC2. Oncogene 2022, 41, 3461–3473. [Google Scholar] [CrossRef] [PubMed]
- Azambuja, J.H.; Ludwig, N.; Yerneni, S.S.; Braganhol, E.; Whiteside, T.L. Arginase-1+ Exosomes from Reprogrammed Macrophages Promote Glioblastoma Progression. Int. J. Mol. Sci. 2020, 21, 3990. [Google Scholar] [CrossRef]
- Low, J.J.W.; Sulaiman, S.A.; Johdi, N.A.; Abu, N. Immunomodulatory effects of extracellular vesicles in glioblastoma. Front. Cell Dev. Biol. 2022, 10, 996805. [Google Scholar] [CrossRef]
- De Leo, A.; Ugolini, A.; Veglia, F. Myeloid Cells in Glioblastoma Microenvironment. Cells 2020, 10, 18. [Google Scholar] [CrossRef]
- Geribaldi-Doldán, N.; Fernández-Ponce, C.; Quiroz, R.N.; Sánchez-Gomar, I.; Escorcia, L.G.; Velásquez, E.P.; Quiroz, E.N. The Role of Microglia in Glioblastoma. Front. Oncol. 2020, 10, 603495. [Google Scholar] [CrossRef]
- Sasaki, A.; Ishiuchi, S.; Kanda, T.; Hasegawa, M.; Nakazato, Y. Analysis of interleukin-6 gene expression in primary human gliomas, glioblastoma xenografts, and glioblastoma cell lines. Brain Tumor Pathol. 2001, 18, 13–21. [Google Scholar] [CrossRef] [PubMed]
- Wei, Q.; Singh, O.; Ekinci, C.; Gill, J.; Li, M.; Mamatjan, Y.; Karimi, S.; Bunda, S.; Mansouri, S.; Aldape, K.; et al. TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy. Acta Neuropathol. Commun. 2021, 9, 67. [Google Scholar] [CrossRef] [PubMed]
- Fabbri, M.; Paone, A.; Calore, F.; Galli, R.; Gaudio, E.; Santhanam, R.; Lovat, F.; Fadda, P.; Mao, C.; Nuovo, G.J.; et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl. Acad. Sci. USA 2012, 109, E2110–E2116. [Google Scholar] [CrossRef] [PubMed]
- van der Vos, K.E.; Abels, E.R.; Zhang, X.; Lai, C.; Carrizosa, E.; Oakley, D.; Prabhakar, S.; Mardini, O.; Crommentuijn, M.H.W.; Skog, J.; et al. Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. Neuro. Oncol. 2016, 18, 58–69. [Google Scholar] [CrossRef] [PubMed]
- Jia, X.; Xu, H.; Miron, R.J.; Yin, C.; Zhang, X.; Wu, M.; Zhang, Y. EZH1 Is Associated with TCP-Induced Bone Regeneration through Macrophage Polarization. Stem Cells Int. 2018, 2018, 6310560. [Google Scholar] [CrossRef]
- Munder, M. Arginase: An emerging key player in the mammalian immune system. Br. J. Pharmacol. 2009, 158, 638–651. [Google Scholar] [CrossRef]
- Mallawaaratchy, D.M.; Hallal, S.; Russell, B.; Ly, L.; Ebrahimkhani, S.; Wei, H.; Christopherson, R.I.; Buckland, M.E.; Kaufman, K.L. Comprehensive proteome profiling of glioblastoma-derived extracellular vesicles identifies markers for more aggressive disease. J. Neurooncol. 2017, 131, 233–244. [Google Scholar] [CrossRef]
- Tugal, D.; Liao, X.; Jain, M.K. Transcriptional control of macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 1135–1144. [Google Scholar] [CrossRef]
- Kazanietz, M.G.; Durando, M.; Cooke, M. CXCL13 and Its Receptor CXCR5 in Cancer: Inflammation, Immune Response, and Beyond. Front. Endocrinol. (Lausanne) 2019, 10, 471. [Google Scholar] [CrossRef]
- Hu, H.M.; Baer, M.; Williams, S.C.; Johnson, P.F.; Schwartz, R.C. Redundancy of C/EBP alpha, -beta, and -delta in supporting the lipopolysaccharide-induced transcription of IL-6 and monocyte chemoattractant protein-1. J. Immunol. 1998, 160, 2334–2342. [Google Scholar] [CrossRef]
- de Groot, J.; Sontheimer, H. Glutamate and the biology of gliomas. Glia 2011, 59, 1181–1189. [Google Scholar] [CrossRef] [PubMed]
- Bhaskaran, V.; Nowicki, M.O.; Idriss, M.; Jimenez, M.A.; Lugli, G.; Hayes, J.L.; Mahmoud, A.B.; Zane, R.E.; Passaro, C.; Ligon, K.L.; et al. The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma. Nat. Commun. 2019, 10, 442. [Google Scholar] [CrossRef] [PubMed]
- Silber, J.; Lim, D.A.; Petritsch, C.; Persson, A.I.; Maunakea, A.K.; Yu, M.; Vandenberg, S.R.; Ginzinger, D.G.; James, C.D.; Costello, J.F.; et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008, 6, 14–17. [Google Scholar] [CrossRef] [PubMed]
- Fedele, M.; Cerchia, L.; Pegoraro, S.; Sgarra, R.; Manfioletti, G. Proneural-Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma. Int. J. Mol. Sci. 2019, 20, 2746. [Google Scholar] [CrossRef]
- Bhat, K.P.L.; Balasubramaniyan, V.; Vaillant, B.; Ezhilarasan, R.; Hummelink, K.; Hollingsworth, F.; Wani, K.; Heathcock, L.; James, J.D.; Goodman, L.D.; et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 2013, 24, 331–346. [Google Scholar] [CrossRef]
- Grégoire, H.; Roncali, L.; Rousseau, A.; Chérel, M.; Delneste, Y.; Jeannin, P.; Hindré, F.; Garcion, E. Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma. Front. Pharmacol. 2020, 11, 368. [Google Scholar] [CrossRef]
- Gutmann, D.H.; Kettenmann, H. Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology. Neuron 2019, 104, 442–449. [Google Scholar] [CrossRef]
- Andersen, R.S.; Anand, A.; Harwood, D.S.L.; Kristensen, B.W. Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and Their Implications for Therapy. Cancers 2021, 13, 4255. [Google Scholar] [CrossRef]
- Hayashi, H.; Kume, T. Foxc2 transcription factor as a regulator of angiogenesis via induction of integrin beta3 expression. Cell Adhes. Migr. 2009, 3, 24–26. [Google Scholar] [CrossRef]
- Yang, Z.; Ming, X.-F. Functions of arginase isoforms in macrophage inflammatory responses: Impact on cardiovascular diseases and metabolic disorders. Front. Immunol. 2014, 5, 533. [Google Scholar] [CrossRef]
- Szefel, J.; Danielak, A.; Kruszewski, W.J. Metabolic pathways of L-arginine and therapeutic consequences in tumors. Adv. Med. Sci. 2019, 64, 104–110. [Google Scholar] [CrossRef] [PubMed]
- Grzywa, T.M.; Sosnowska, A.; Matryba, P.; Rydzynska, Z.; Jasinski, M.; Nowis, D.; Golab, J. Myeloid Cell-Derived Arginase in Cancer Immune Response. Front. Immunol. 2020, 11, 938. [Google Scholar] [CrossRef] [PubMed]
- Niu, F.; Yu, Y.; Li, Z.; Ren, Y.; Li, Z.; Ye, Q.; Liu, P.; Ji, C.; Qian, L.; Xiong, Y. Arginase: An emerging and promising therapeutic target for cancer treatment. Biomed. Pharm. 2022, 149, 112840. [Google Scholar] [CrossRef] [PubMed]
- Zhou, W.; Craft, J.; Ojemann, A.; Bergen, L.; Graner, A.; Gonzales, A.; He, Q.; Kopper, T.; Smith, M.; Graner, M.W.; et al. Glioblastoma Extracellular Vesicle-Specific Peptides Inhibit EV-Induced Neuronal Cytotoxicity. Int. J. Mol. Sci. 2022, 23, 7200. [Google Scholar] [CrossRef] [PubMed]
- Chiocca, E.A.; Yu, J.S.; Lukas, R.V.; Solomon, I.H.; Ligon, K.L.; Nakashima, H.; Triggs, D.A.; Reardon, D.A.; Wen, P.; Stopa, B.M.; et al. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. Sci. Transl. Med. 2019, 11, eaaw5680. [Google Scholar] [CrossRef]
- Bai, L.; Liu, Y.; Guo, K.; Zhang, K.; Liu, Q.; Wang, P.; Wang, X. Ultrasound Facilitates Naturally Equipped Exosomes Derived from Macrophages and Blood Serum for Orthotopic Glioma Treatment. ACS Appl. Mater. Interfaces 2019, 11, 14576–14587. [Google Scholar] [CrossRef]
- Guth, A.M.; Hafeman, S.D.; Elmslie, R.E.; Dow, S.W. Liposomal clodronate treatment for tumour macrophage depletion in dogs with soft-tissue sarcoma. Vet. Comp. Oncol. 2013, 11, 296–305. [Google Scholar] [CrossRef]
- Luo, Y.; Han, R.; Evanoff, D.P.; Chen, X. Interleukin-10 inhibits Mycobacterium bovis bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against bladder cancer cells. Clin. Exp. Immunol. 2010, 160, 359–368. [Google Scholar] [CrossRef]
- Banerjee, S.; Halder, K.; Ghosh, S.; Bose, A.; Majumdar, S. The combination of a novel immunomodulator with a regulatory T cell suppressing antibody (DTA-1) regress advanced stage B16F10 solid tumor by repolarizing tumor associated macrophages in situ. Oncoimmunology 2015, 4, e995559. [Google Scholar] [CrossRef]
- Zhou, J.; Tang, Z.; Gao, S.; Li, C.; Feng, Y.; Zhou, X. Tumor-Associated Macrophages: Recent Insights and Therapies. Front. Oncol. 2020, 10, 188. [Google Scholar] [CrossRef]
- Grimaldi, A.; Serpe, C.; Chece, G.; Nigro, V.; Sarra, A.; Ruzicka, B.; Relucenti, M.; Familiari, G.; Ruocco, G.; Pascucci, G.R.; et al. Microglia-Derived Microvesicles Affect Microglia Phenotype in Glioma. Front. Cell. Neurosci. 2019, 13, 41. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Ding, H.; Li, Z.; Peng, Y.; Tan, H.; Wang, C.; Huang, G.; Li, W.; Ma, G.; Wei, W. Exploration and functionalization of M1-macrophage extracellular vesicles for effective accumulation in glioblastoma and strong synergistic therapeutic effects. Signal Transduct. Target. Ther. 2022, 7, 74. [Google Scholar] [CrossRef] [PubMed]
- Mulcahy, L.A.; Pink, R.C.; Carter, D.R.F. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 2014, 3, 24641. [Google Scholar] [CrossRef] [PubMed]
- Matias, D.; Balça-Silva, J.; da Graça, G.C.; Wanjiru, C.M.; Macharia, L.W.; Nascimento, C.P.; Roque, N.R.; Coelho-Aguiar, J.M.; Pereira, C.M.; Dos Santos, M.F.; et al. Microglia/Astrocytes-Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors. Front. Cell. Neurosci. 2018, 12, 235. [Google Scholar] [CrossRef]
- Pancholi, S.; Tripathi, A.; Bhan, A.; Acharya, M.M.; Pillai, P. Emerging Concepts on the Role of Extracellular Vesicles and Its Cargo Contents in Glioblastoma-Microglial Crosstalk. Mol. Neurobiol. 2022, 59, 2822–2837. [Google Scholar] [CrossRef]
- Hong, S.; You, J.Y.; Paek, K.; Park, J.; Kang, S.J.; Han, E.H.; Choi, N.; Chung, S.; Rhee, W.J.; Kim, J.A. Inhibition of tumor progression and M2 microglial polarization by extracellular vesicle-mediated microRNA-124 in a 3D microfluidic glioblastoma microenvironment. Theranostics 2021, 11, 9687–9704. [Google Scholar] [CrossRef]
- Bier, A.; Hong, X.; Cazacu, S.; Goldstein, H.; Rand, D.; Xiang, C.; Jiang, W.; Ben-Asher, H.W.; Attia, M.; Brodie, A.; et al. miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles. Cell Death Dis. 2020, 11, 899. [Google Scholar] [CrossRef]
- Li, Z.; Meng, X.; Wu, P.; Zha, C.; Han, B.; Li, L.; Sun, N.; Qi, T.; Qin, J.; Zhang, Y.; et al. Glioblastoma Cell-Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance. Cancer Immunol. Res. 2021, 9, 1383–1399. [Google Scholar] [CrossRef]
- Reed, T.; Schorey, J.; D’Souza-Schorey, C. Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment. Front. Cell Dev. Biol. 2021, 9, 746432. [Google Scholar] [CrossRef]
- Graner, M.W.; Schnell, S.; Olin, M.R. Tumor-derived exosomes, microRNAs, and cancer immune suppression. Semin. Immunopathol. 2018, 40, 505–515. [Google Scholar] [CrossRef]
- Graner, M.W. Extracellular vesicles in cancer immune responses: Roles of purinergic receptors. Semin. Immunopathol. 2018, 40, 465–475. [Google Scholar] [CrossRef] [PubMed]
Author | Biological Mediator in EVs | Key Findings |
---|---|---|
de Vrij et al., 2015 [48] | Small RNA molecules | GBM-derived sEVs induced monocyte-derived macrophages towards an M2 pro-tumor phenotype. The macrophages produced increased levels of VEGF and IL-6. |
Zhao et al., 2022 [50] | microRNA-27a-3p | Here, the authors demonstrated that microRNA-27a-3p inhibits enhancer of zeste homologue 1 (EZH1), thereby promoting M2 macrophage polarization. microRNA-27a-3p-treated macrophages had elevated levels of Arginase-1 (M2 phenotypic marker) and reduced iNOS (M1 phenotypic marker). |
Abels et al., 2019 [51] | microRNA-21 | The authors found that tumor-derived EVs deliver miR-21 to microglia. This resulted in a shift in numerous gene targets, notably the downregulation of Pdcd4 and Btg2, causing increased microglial proliferation. |
Gabrusiewicz et al., 2018 [49] | Stat3 | GBM stem-cell-derived sEVs applied to monocytes induced a shift in monocyte-derived macrophage polarization state towards a tumor-supportive M2 phenotype. This was evidenced through flow cytometry analysis, indicating reduced expression of M1 indicators (MHCII and CD80) and increased M2 indicators (CD163 and CD206). The sEVs contained the transcription factor STAT3, which is associated with M2 polarization. |
Yang et al., 2019 [52] | microRNA-214-5p | GMB EV microRNA miR-214-5p was associated with poor clinical prognosis and targeted microglial CXCR5 transcripts, and thus reduced CXCR5 protein expression. |
Xu et al., 2021 [53] | Stat3, IL-6, and microRNA-155-3p | GBM-derived sEVs were isolated under hypoxic conditions, common in the GBM microenvironment. These EVs induce macrophages towards an M2 state through an induction of autophagy pathways. These results were greatly subdued in EVs derived from normoxic glioma cells. |
Serpe et al., 2021 [54] | microRNA-124 | Cultured microglia were stimulated with LPS and IFNγ (M1 activation). sEVs isolated from these microglia were applied intracranially via a cannula infusion into tumor-bearing mice. The application of these microglia-derived EVs resulted in prolonged survival and reduced tumor mass. These effects were attributed to microRNA-124-induced modulation of tumor metabolism. |
Zhang et al., 2020 [55] | microRNA-27a-3p, microRNA-22-3p, and microRNA-221-3p | The authors found that tumor-associated macrophages produce sEVs that trigger a proneural-to-mesenchymal transition in glioma stem cells. This is believed to be tumor-supportive as it leads to increased resistance to various therapeutic modalities, including radiotherapy. This was attributed to EV cargo, particularly microRNA-27a-3p, microRNA-22-3p, and microRNA-221-3p. |
Zhao, G et al., 2022 [56] | microRNA-27b-3p | The authors isolated glioblastoma stem cells and tumor-associated macrophages from GMB tissue specimens. Macrophage sEVs were applied to the GBM stem cells where they maintained some of the stem cell properties of the GBM stem cells. They implicated microRNA-27b-3p for the increase in the tumorigenicity of the GBM stem cells. This process was found to be mediated through the MLL4/PRDM1/IL-33 cell signaling axis. |
Jiang e al. 2022 [57] | Circular RNA circKIF18A | Here, a human microglial cell line was treated with GBM-conditioned media to induce an M2 phenotype. sEVs from these treated microglia then transferred circular RNA circKIF18A from microglia. circKIF18A enhances the FOXC2 transcription factor activity, leading to increased angiogenesis in the tumor microenvironment. |
Azambuja et al., 2020 [58] | Arginase-1 | Using an in vitro model of GBM/macrophage crosstalk, the authors found that macrophage EVs promote glioma cell proliferation and migration in vitro. Using chemical inhibitors, they identified Arginase-1 on the surface of these EVs as a primary mediator. Arginase-1 is strongly associated with M2 macrophages. |
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Kopper, T.J.; Yu, X.; Graner, M.W. Immunopathology of Extracellular Vesicles in Macrophage and Glioma Cross-Talk. J. Clin. Med. 2023, 12, 3430. https://doi.org/10.3390/jcm12103430
Kopper TJ, Yu X, Graner MW. Immunopathology of Extracellular Vesicles in Macrophage and Glioma Cross-Talk. Journal of Clinical Medicine. 2023; 12(10):3430. https://doi.org/10.3390/jcm12103430
Chicago/Turabian StyleKopper, Timothy J., Xiaoli Yu, and Michael W. Graner. 2023. "Immunopathology of Extracellular Vesicles in Macrophage and Glioma Cross-Talk" Journal of Clinical Medicine 12, no. 10: 3430. https://doi.org/10.3390/jcm12103430
APA StyleKopper, T. J., Yu, X., & Graner, M. W. (2023). Immunopathology of Extracellular Vesicles in Macrophage and Glioma Cross-Talk. Journal of Clinical Medicine, 12(10), 3430. https://doi.org/10.3390/jcm12103430