Influences of umbilical cord mesenchymal stem cells and their exosomes on tumor cell phenotypes

  1. Guoqing Liu 1
  2. María Begoña García Cenador 1
  3. Shupeng Si 2
  4. Heng Wang 3
  5. Qiu Yang 3
  1. 1 Department of Surgery, School of Medicine, University of Salamanca
  2. 2 Department of Traditional Chinese Medicine, Zibo Maternal and Child Health Care Hospital
  3. 3 Department of Oncology, The General Hospital of Western Theater Command, Chengdu
Revista:
American Journal of Cancer Research

ISSN: 2156-6976

Año de publicación: 2023

Volumen: 13

Número: 12

Páginas: 6270-6279

Tipo: Artículo

Otras publicaciones en: American Journal of Cancer Research

Resumen

Mesenchymal stem cells (MSCs), extensively utilized in contemporary stem cell research, hold significant potential in the treatment of neoplastic diseases. This study aims to investigate the influences of umbilical cord mesenchymal stem cells (UMSCs) and their exosomes (UMSCs-exos) on tumor cell phenotypes. UMSCs and UMSCs-exos, isolated from human umbilical cord tissue, were validated for isolation efficiency and differentiation capacity using flow cytometry, electron microscopy, and cell staining. MDA-MB-231, BGC-823, A549, and LN-229, which are human breast (BC), gastric (GC), lung carcinoma (LC) cells and glioma cells, respectively, were treated with UMSCs and UMSCs-exos. Cell counting kit-8 (CCK-8), cell scratch-wound, and Transwell assays were performed on treated cultures to observe the phenotypic changes induced by UMSCs- and UMSCs-exos-treated cancer cells. The results demonstrated that UMSCs highly express PE-labeled positive surface antigens and exhibit low expression of FITC-labeled negative surface antigens, alongside possessing osteogenic and adipogenic differentiation potentials. Electron microscopy revealed UMSCs-exos to be approximately 30-150 nm in diameter, averaging 126.62±1.64 nm, and displaying increased Tsg101, CD9, and CD63 protein expression. Moreover, MDA-MB-231 and BGC-823 cells exhibited enhanced proliferation, invasion, and migration upon UMSCs and UMSCs-exos treatment. In contrast, A549 cells showed minimal alteration to invasiveness but a marked increase in proliferation and migration capabilities, while LN-229 cells displayed a phenotype indicative of suppressed activity. In conclusion, UMSCs and UMSCs-exos effectively promote the growth of BC and LC cells and inhibit the activity of GC and glioma cells, presenting promising avenues for future neoplastic disease treatments.

Referencias bibliográficas

  • 1. Yamanaka S. Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell. 2020;27:523–531. [PubMed] [Google Scholar]
  • 2. Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther. 2017;8:111. [PMC free article] [PubMed] [Google Scholar]
  • 3. Müller P, Lemcke H, David R. Stem cell therapy in heart diseases - cell types, mechanisms and improvement strategies. Cell Physiol Biochem. 2018;48:2607–2655. [PubMed] [Google Scholar]
  • 4. Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10:68. [PMC free article] [PubMed] [Google Scholar]
  • 5. Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017;74:2345–2360. [PubMed] [Google Scholar]
  • 6. Fu X, Liu G, Halim A, Ju Y, Luo Q, Song AG. Mesenchymal stem cell migration and tissue repair. Cells. 2019;8:784. [PMC free article] [PubMed] [Google Scholar]
  • 7. Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med. 2017;6:2173–2185. [PMC free article] [PubMed] [Google Scholar]
  • 8. Lin W, Huang L, Li Y, Fang B, Li G, Chen L, Xu L. Mesenchymal stem cells and cancer: clinical challenges and opportunities. Biomed Res Int. 2019;2019:2820853. [PMC free article] [PubMed] [Google Scholar]
  • 9. Solares I, Viñal D, Morales-Conejo M, Rodriguez-Salas N, Feliu J. Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. ESMO Open. 2021;6:100223. [PMC free article] [PubMed] [Google Scholar]
  • 10. Wang JJ, Lei KF, Han F. Tumor microenvironment: recent advances in various cancer treatments. Eur Rev Med Pharmacol Sci. 2018;22:3855–3864. [PubMed] [Google Scholar]
  • 11. Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, Yoshida M, Tsuda H, Tamura K, Ochiya T. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal. 2014;7:ra63. [PubMed] [Google Scholar]
  • 12. Shojaei S, Hashemi SM, Ghanbarian H, Salehi M, Mohammadi-Yeganeh S. Effect of mesenchymal stem cells-derived exosomes on tumor microenvironment: tumor progression versus tumor suppression. J Cell Physiol. 2019;234:3394–3409. [PubMed] [Google Scholar]
  • 13. Ding DC, Chang YH, Shyu WC, Lin SZ. Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant. 2015;24:339–347. [PubMed] [Google Scholar]
  • 14. Mullard A. Addressing cancer’s grand challenges. Nat Rev Drug Discov. 2020;19:825–826. [PubMed] [Google Scholar]
  • 15. Roy PS, Saikia BJ. Cancer and cure: a critical analysis. Indian J Cancer. 2016;53:441–442. [PubMed] [Google Scholar]
  • 16. Yang S, Liang X, Song J, Li C, Liu A, Luo Y, Ma H, Tan Y, Zhang X. A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6. Stem Cell Res Ther. 2021;12:315. [PMC free article] [PubMed] [Google Scholar]
  • 17. Naseri Z, Oskuee RK, Jaafari MR, Forouzandeh Moghadam M. Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo. Int J Nanomedicine. 2018;13:7727–7747. [PMC free article] [PubMed] [Google Scholar]
  • 18. Cheng C, Chen X, Wang Y, Cheng W, Zuo X, Tang W, Huang W. MSCs-derived exosomes attenuate ischemia-reperfusion brain injury and inhibit microglia apoptosis might via exosomal miR-26a-5p mediated suppression of CDK6. Mol Med. 2021;27:67. [PMC free article] [PubMed] [Google Scholar]
  • 19. Tang J, Jin L, Liu Y, Li L, Ma Y, Lu L, Ma J, Ding P, Yang X, Liu J, Yang J. Exosomes derived from mesenchymal stem cells protect the myocardium against ischemia/reperfusion injury through inhibiting pyroptosis. Drug Des Devel Ther. 2020;14:3765–3775. [PMC free article] [PubMed] [Google Scholar]
  • 20. Xu M, Shaw G, Murphy M, Barry F. Induced pluripotent stem cell-derived mesenchymal stromal cells are functionally and genetically different from bone marrow-derived mesenchymal stromal cells. Stem Cells. 2019;37:754–765. [PMC free article] [PubMed] [Google Scholar]
  • 21. Li KD, Wang Y, Sun Q, Li MS, Chen JL, Liu L. Rabbit umbilical cord mesenchymal stem cells: a new option for tissue engineering. J Gene Med. 2021;23:e3282. [PubMed] [Google Scholar]
  • 22. Zhang L, Yu D. Exosomes in cancer development, metastasis, and immunity. Biochim Biophys Acta Rev Cancer. 2019;1871:455–468. [PMC free article] [PubMed] [Google Scholar]
  • 23. Batrakova EV, Kim MS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release. 2015;219:396–405. [PMC free article] [PubMed] [Google Scholar]
  • 24. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977. [PMC free article] [PubMed] [Google Scholar]
  • 25. Li P, Lu M, Shi J, Gong Z, Hua L, Li Q, Lim B, Zhang XH, Chen X, Li S, Shultz LD, Ren G. Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis. Nat Immunol. 2020;21:1444–1455. [PMC free article] [PubMed] [Google Scholar]
  • 26. Wang S, Su X, Xu M, Xiao X, Li X, Li H, Keating A, Zhao RC. Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway. Stem Cell Res Ther. 2019;10:117. [PMC free article] [PubMed] [Google Scholar]
  • 27. Chang L, Gao H, Wang L, Wang N, Zhang S, Zhou X, Yang H. Exosomes derived from miR-1228 overexpressing bone marrow-mesenchymal stem cells promote growth of gastric cancer cells. Aging (Albany NY) 2021;13:11808–11821. [PMC free article] [PubMed] [Google Scholar]
  • 28. Bie Q, Zhang B, Sun C, Ji X, Barnie PA, Qi C, Peng J, Zhang D, Zheng D, Su Z, Wang S, Xu H. IL-17B activated mesenchymal stem cells enhance proliferation and migration of gastric cancer cells. Oncotarget. 2017;8:18914–18923. [PMC free article] [PubMed] [Google Scholar]
  • 29. Wu F, Wang L, Zhou C. Lung cancer in China: current and prospect. Curr Opin Oncol. 2021;33:40–46. [PubMed] [Google Scholar]
  • 30. Wu H, Mu X, Liu L, Wu H, Hu X, Chen L, Liu J, Mu Y, Yuan F, Liu W, Zhao Y. Bone marrow mesenchymal stem cells-derived exosomal microRNA-193a reduces cisplatin resistance of non-small cell lung cancer cells via targeting LRRC1. Cell Death Dis. 2020;11:801. [PMC free article] [PubMed] [Google Scholar]
  • 31. Yu L, Gui S, Liu Y, Qiu X, Zhang G, Zhang X, Pan J, Fan J, Qi S, Qiu B. Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2. Aging (Albany NY) 2019;11:5300–5318. [PMC free article] [PubMed] [Google Scholar]
  • 32. Li Q, Wang C, Cai L, Lu J, Zhu Z, Wang C, Su Z, Lu X. miR-34a derived from mesenchymal stem cells stimulates senescence in glioma cells by inducing DNA damage. Mol Med Rep. 2019;19:1849–1857. [PubMed] [Google Scholar]