Therapeutic potential of mesenchymal stem cell exosomes for tumors in the digestive system: From bench to bedside

Abstract

Exosomes are small, bilayer lipid vesicles with diameters ranging from approximately 40-160 nm. These vesicles carry a diverse array of molecular cargo, including DNA, RNA, lipids, and proteins, which play a critical role in intercellular communication. Among the various cell types, mesenchymal stem cells (MSCs) are recognized as highly efficient producers of exosomes. MSC-derived exosomes (MSC-exo) have been demonstrated to play dual roles in cancer progression, either promoting or inhibiting tumor growth, depending on the specific context. This unique ability positions MSC-exo as a promising tool for cancer therapy. This review examines the multifaceted roles of MSC-exo in various types of digestive system tumors. It highlights the exosomes’ potential to modulate tumor microenvironments, influence immune responses, and deliver therapeutic molecules, thereby offering new avenues for targeted cancer treatment. In addition, the review explores the clinical application value of MSC-exo as anti-tumor agents, emphasizing the exosomes’ potential for drug delivery and personalized medicine. However, despite the exosomes’ therapeutic potential, several challenges must be addressed before MSC-exo can be widely adopted in clinical settings. These include issues related to large-scale production, standardization, safety, and regulatory approval. By addressing these challenges, MSC-exo could emerge as a transformative approach in cancer treatment, offering innovative solutions for precision medicine and improved patient outcomes. This review underscores the importance of continued research to fully realize the potential of MSC-exo in oncology.

Keywords

Mesenchymal stem cells / Exosomes / Mesenchymal stem cell-derived exosomes / Intercellular communication regulators / Anti-tumor / Drug delivery

Funding

None.

Conflict of interest

Ying Liu is an employee of the Sinocelltech Ltd. company. This has not influenced the content of the manuscript. No reference to the author’s company is made, but it is declared for full transparency. Other authors declare no conflict of interest.

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74:229-263. doi: 10.3322/caac.21834

[2] Huppert L, Gumusay O, Idossa D, Rugo HS. Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer. CA Cancer J Clin. 2023; 73:480-515. doi: 10.3322/caac.21777

[3] Zhang T, Lin R, Wu H, Jiang X, Gao J. Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev. 2022; 185(0):137001. doi: 10.1016/j.addr.2022.114300

[4] Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: A matter of timing. Physiol Rev. 2023; 104:659-725. doi: 10.1152/physrev.00009.2023

[5] Li C, Sun Y, Xu W, Chang F, Wang Y, Ding J. Mesenchymal stem cells-involved strategies for rheumatoid arthritis therapy. Adv Sci (Weinh). 2024;11:e2305116. doi: 10.1002/advs.202305116

[6] Arya S, Collie S, Parent CA. The ins-and-outs of exosome biogenesis, secretion, and internalization. Trends Cell Biol. 2024; 34:90-108. doi: 10.1016/j.tcb.2023.06.006

[7] Minetti G, Achilli C, Perotti C, Ciana A. Continuous change in membrane and membrane-skeleton organization during development from proerythroblast to senescent red blood cell. Front Physiol. 2018;9:286. doi: 10.3389/fphys.2018.00286

[8] Welsh J, Goberdhan D, O’Driscoll L, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles. 2024;13:e12404. doi: 10.1080/20013078.2018.1535750

[9] Lai J, Chau Z, Chen S, et al. Exosome processing and characterization approaches for research and technology development. Adv Sci (Weinh). 2022;9:e2103222. doi: 10.1002/advs.202103222

[10] Jeppesen D, Fenix A, Franklin J, et al. Reassessment of exosome composition. Cell. 2019; 177:428-445.e418. doi: 10.1016/j.cell.2019.02.029

[11] Zhang Y, Bi J, Huang J, et al. Exosome: A review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int J Nanomedicine. 2020; 15:6917-6934. doi: 10.2147/IJN.S264498

[12] Lee K, Seo E, Lee J, Kim HJ, Hwangbo C. The multifunctional protein syntenin-1: Regulator of exosome biogenesis, cellular function, and tumor progression. Int J Mol Sci. 2023;24:9418. doi: 10.3390/ijms24119418

[13] Han Q, Li W, Hu K, et al. Exosome biogenesis: Machinery, regulation, and therapeutic implications in cancer. Mol Cancer. 2022;21:207. doi: 10.1186/s12943-022-01671-0

[14] Zhu L, Sun H, Wang S, et al. Isolation and characterization of exosomes for cancer research. J Hematol Oncol. 2020;13:152. doi: 10.1186/s13045-020-00987-y

[15] Elhanani O, Ben-Uri R, Keren L. Spatial profiling technologies illuminate the tumor microenvironment. Cancer Cell. 2023; 41:404-420. doi: 10.1016/j.ccell.2023.01.010

[16] Wang J, Hendrix A, Hernot S, et al. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood. 2014;124:555-566. doi: 10.1182/blood-2014-03-562439

[17] Deng M, Yuan H, Liu S, et al. Exosome-transmitted LINC00461 promotes multiple myeloma cell proliferation and suppresses apoptosis by modulating microRNA/BCL-2 expression. Cytotherapy. 2019; 21:96-106. doi: 10.1016/j.jcyt.2018.10.006

[18] Zhang F, Lu Y, Wang M, et al. Exosomes derived from human bone marrow mesenchymal stem cells transfer miR- 222-3p to suppress acute myeloid leukemia cell proliferation by targeting IRF2/INPP4B. Mol Cell Probes. 2020;51:101513. doi: 10.1016/j.mcp.2020.101513

[19] Liu X, Li Y, Zhou W, et al. Chinese multidisciplinary expert consensus on immune checkpoint inhibitor-based combination therapy for hepatocellular carcinoma (2023 edition). Liver Cancer. 2024;13:355-375. doi: 10.1159/000535496

[20] Ma YS, Liu JB, Lin L, et al. Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4. Cell Death Discov. 2021;7:224. doi: 10.1038/s41420-021-00611-z

[21] ElBadre HM, El-Deek SEM, Ramadan HK, et al. Potential role of human umbilical cord stem cells-derived exosomes as novel molecular inhibitors of hepatocellular carcinoma growth. Apoptosis. 2023; 28:1346-1356. doi: 10.1007/s10495-023-01863-z

[22] Xu Y, Lai Y, Cao L, et al. Human umbilical cord mesenchymal stem cells-derived exosomal microRNA-451a represses epithelial-mesenchymal transition of hepatocellular carcinoma cells by inhibiting ADAM10. RNA Biol. 2020;18:1408-1423. doi: 10.1080/15476286.2020.1851540

[23] Xu G, Ban K, Mu H, Wang B. Human umbilical cord mesenchymal stem cells-derived exosomal lncrna fam99b represses hepatocellular carcinoma cell malignancy. Mol Biotechnol. 2023; 66:1389-1401. doi: 10.1007/s12033-023-00795-y

[24] Gu H, Yu C, Wang H, et al. Mesenchymal stem cell-derived exosomes block malignant behaviors of hepatocellular carcinoma stem cells through a lncRNA C5orf66-AS1/ microRNA-127-3p/DUSP1/ERK axis. Hum Cell. 2021;34:1812-1829. doi: 10.1007/s13577-021-00599-9

[25] Li M, Zhai P, Mu X, et al. Hypoxic BMSC-derived exosomal miR-652-3p promotes proliferation and metastasis of hepatocarcinoma cancer cells via targeting TNRC6A. Aging (Albany NY). 2023; 15:12780-12793. doi: 10.18632/aging.205025

[26] Wang Y, Wang B, Xiao S, et al. miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90. J Cell Biochem. 2018; 120:3046-3055. doi: 10.1002/jcb.27436

[27] Lou G, Chen L, Xia C, et al. MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway. Exp Clin Cancer. 2020;39:4. doi: 10.1186/s13046-019-1512-5

[28] Li YH, Lv MF, Lu M, Bi JP. Bone marrow mesenchymal stem cell-derived exosomal MiR-338-3p represses progression of hepatocellular carcinoma by targeting ETS1. J Biol Regul Homeost Agents. 2021; 35:617-627. doi: 10.23812/20-638-a

[29] Dong B, Liu W, Fan W, Pan J. Exosomal miR-374c-5p derived from mesenchymal stem cells suppresses epithelial-mesenchymal transition of hepatocellular carcinoma via the LIMK1-Wnt/β- catenin axis. Environ Toxicol. 2023; 38:1038-1052. doi: 10.1002/tox.23746

[30] Liang L, Zhao L, Wang Y, Wang Y. Treatment for hepatocellular carcinoma is enhanced when norcantharidin is encapsulated in exosomes derived from bone marrow mesenchymal stem cells. Mol Pharm. 2021; 18:1003-1013. doi: 10.1021/acs.molpharmaceut.0c00976

[31] Li H, Yang C, Shi Y, Zhao L. Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma. J Nanobiotechnology. 2018;16:103. doi: 10.1186/s12951-018-0429-z

[32] Liu G, Cenador MBG, Si S, Wang H, Yang Q. Influences of umbilical cord mesenchymal stem cells and their exosomes on tumor cell phenotypes. Am J Cancer Res. 2024;13: 6270-6279.

[33] Mirzaei S, Gholami M, Aghdaei HA, et al. Exosome-mediated miR-200a delivery into TGF-β-treated AGS cells abolished epithelial-mesenchymal transition with normalization of ZEB1, vimentin and Snail1 expression. Environ Res. 2023;231:116115. doi: 10.1016/j.envres.2023.116115

[34] Chang L, Gao H, Wang L, et al. Exosomes derived from miR-1228 overexpressing bone marrow-mesenchymal stem cells promote growth of gastric cancer cells. Aging (Albany NY). 2021; 13:11808-11821. doi: 10.18632/aging.202878

[35] Sun W, Chen W, Li N, et al. Oxaliplatin-induced upregulation of exosomal miR-424-3p derived from human bone marrow mesenchymal stem cells attenuates progression of gastric cancer cells. Sci Rep. 2024;14:17812. doi: 10.1038/s41598-024-68922-6

[36] Jin R, Zhang B, Zhang X, et al. Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer. Cell Cycle. 2015; 14(15):2473-2483. doi: 10.1080/15384101.2015.1005530

[37] Mao J, Liang Z, Zhang B, et al. UBR2 enriched in p53 deficient mouse bone marrow mesenchymal stem cell-exosome promoted gastric cancer progression via Wnt/β- catenin pathway. Stem Cells. 2017; 35(11):2267-2279. doi: 10.1002/stem.2702

[38] Ji R, Lin J, Gu H, Ma J, Fu M, Zhang X. Gastric cancer derived mesenchymal stem cells promote the migration of gastric cancer cells through miR-374a-5p. Cell Death Dis. 2022;18:918. doi: 10.2174/1574888X18666221124145847

[39] Ma M, Chen S, Liu Z, et al. miRNA-221 of exosomes originating from bone marrow mesenchymal stem cells promotes oncogenic activity in gastric cancer. Onco Targets Ther. 2017; 10:4161-4171. doi: 10.2147/OTT.S143315

[40] Qi J, Zhou Y, Jiao Z, et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway. Cell Physiol Biochem. 2017; 42(6):2242-2254. doi: 10.1159/000479998

[41] Mansourabadi AH, Aghamajidi A, Faraji F, et al. Mesenchymal stem cells-derived exosomes inhibit the expression of Aquaporin-5 and EGFR in HCT-116 human colorectal carcinoma cell line. BMC Mol Cell Biol. 2022;23:40. doi: 10.1186/s12860-022-00439-0

[42] Jahangiri B, Khalaj-Kondori M, Asadollahi E, Purrafee Dizaj L, Sadeghizadeh M. MSC-Derived exosomes suppress colorectal cancer cell proliferation and metastasis via miR- 100/mTOR/miR-143 pathway. Int J Pharm. 2022;627:122214. doi: 10.1016/j.ijpharm.2022.122214

[43] Chen J, Li Z, Yue C, et al. Human umbilical cord mesenchymal stem cell-derived exosomes carrying miR- 1827 downregulate SUCNR1 to inhibit macrophage M2 polarization and prevent colorectal liver metastasis. Apoptosis. 2023; 28:549-565. doi: 10.1007/s10495-022-01798-x

[44] Xu Y, Shen L, Li F, Yang J, Wan X, Ouyang M. microRNA-16-5p-containing exosomes derived from bone marrow-derived mesenchymal stem cells inhibit proliferation, migration, and invasion, while promoting apoptosis of colorectal cancer cells by downregulating ITGA2. J Cell Physiol. 2019; 234:21380-21394. doi: 10.1002/jcp.28747

[45] Xue C, Gao Y, Li X, et al. Mesenchymal stem cells derived from adipose accelerate the progression of colon cancer by inducing a MT-CAFs phenotype via TRPC3/NF-KB axis. Stem Cell Res Ther. 2022;13:335. doi: 10.1186/s13287-022-03017-5

[46] Qu M, Li J, Hong Z, Jia F, He Y, Yuan L. The role of human umbilical cord mesenchymal stem cells-derived exosomal microRNA-431- p in survival and prognosis of colorectal cancer patients. Mutagenesis. 2022;37:164-171. doi: 10.1093/mutage/geac007

[47] Chen HL, Li JJ, Jiang F, Shi WJ, Chang GY. MicroRNA-4461 derived from bone marrow mesenchymal stem cell exosomes inhibits tumorigenesis by downregulating COPB2 expression in colorectal cancer. Biosci Biotechnol Biochem. 2019;84:338-346. doi: 10.1080/09168451.2019.1677452

[48] Pishavar E, Yazdian-Robati R, Abnous K, et al. Aptamer-functionalized mesenchymal stem cells-derived exosomes for targeted delivery of SN38 to colon cancer cells. Iran J Basic Med Sci. 2023; 26:388-394. doi: 10.22038/IJBMS.2023.68039.14873

[49] Bagheri E, Abnous K, Farzad SA, Taghdisi SM, Ramezani M, Alibolandi M. Targeted doxorubicin-loaded mesenchymal stem cells-derived exosomes as a versatile platform for fighting against colorectal cancer. Life Sci. 2020;261:118369. doi: 10.1016/j.lfs.2020.118369

[50] Han S, Li G, Jia M, et al. Delivery of anti-miRNA-221 for colorectal carcinoma therapy using modified cord blood mesenchymal stem cells-derived exosomes. Front Mol Biosci. 2021;8:743013. doi: 10.3389/fmolb.2021.743013

[51] Ding Y, Mei W, Zheng Z, et al. Exosomes secreted from human umbilical cord mesenchymal stem cells promote pancreatic ductal adenocarcinoma growth by transferring miR-100-5p. Tissue Cell. 2021;73:101623. doi: 10.1016/j.tice.2021.101623

[52] Ding Y, Cao F, Sun H, et al. Exosomes derived from human umbilical cord mesenchymal stromal cells deliver exogenous miR-145-5p to inhibit pancreatic ductal adenocarcinoma progression. Cancer Lett. 2018; 442:351-361. doi: 10.1016/j.canlet.2018.10.039

[53] Shang S, Wang J, Chen S, et al. Exosomal miRNA-1231 derived from bone marrow mesenchymal stem cells inhibits the activity of pancreatic cancer. Cancer Med. 2019;8:7728-7740. doi: 10.1002/cam4.2633

[54] Sherman MH, Beatty GL. Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance. Annu Rev Pathol. 2022;18:123-148. doi: 10.1146/annurev-pathmechdis-031621-024600

[55] Kumarasamy V, Wang J, Frangou C, et al. The extracellular niche and tumor microenvironment enhance KRAS inhibitor efficacy in pancreatic cancer. Cancer Res. 2024;84:1115-1132. doi: 10.1158/0008-5472.CAN-23-2504

[56] Parte S, Kaur AB, Nimmakayala RK, et al. Cancer-associated fibroblast induces acinar-to-ductal cell transdifferentiation and pancreatic cancer initiation Via LAMA5/ITGA4 axis. Gastroenterology. 2023; 166:842-858.e5. doi: 10.1053/j.gastro.2023.12.018

[57] Zhou Y, Zhou W, Chen X, et al. Bone marrow mesenchymal stem cells-derived exosomes for penetrating and targeted chemotherapy of pancreatic cancer. Acta Pharm Sin B. 2020; 10:1563-1575. doi: 10.1016/j.apsb.2019.11.013

[58] Zhou W, Zhou Y, Chen X, et al. Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment. Biomaterials. 2020;268:120546. doi: 10.1016/j.biomaterials.2020.120546

[59] He Z, Li W, Zheng T, Liu D, Zhao S. Human umbilical cord mesenchymal stem cells-derived exosomes deliver microRNA-375 to downregulate ENAH and thus retard esophageal squamous cell carcinoma progression. J Exp Clin Cancer Res. 2020;39:59. doi: 10.1186/s13046-020-01631-w

[60] Li N, Wang B. Suppressive effects of umbilical cord mesenchymal stem cell-derived exosomal miR-15a-5p on the progression of cholangiocarcinoma by inhibiting CHEK1 expression. Cell Death Discov. 2022;8:205. doi: 10.1038/s41420-022-00932-7

[61] Zou J, Yang W, Cui W, et al. Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon-bone healing. J Nanobiotechnol. 2023;21:14. doi: 10.1186/s12951-023-01778-6

[62] Popowski K, Lutz H, Hu S, et al. Exosome therapeutics for lung regenerative medicine. J Extracell Vesicles. 2020;9:1785161. doi: 10.1080/20013078.2020.1785161

[63] Huang R, Bo Jia 2 Dandan Su, et al. Plant exosomes fused with engineered mesenchymal stem cell-derived nanovesicles for synergistic therapy of autoimmune skin disorders. J Extracell Vesicles. 2023;12:e12361. doi: 10.1002/jev2.12361

[64] Levy D, Jeyaram A, Born LJ, et al. Impact of storage conditions and duration on function of native and cargo-loaded mesenchymal stromal cell extracellular vesicles. Cytotherapy. 2022; 25:502-509. doi: 10.1016/j.jcyt.2022.11.006

[65] Wang S, Leu B, Zhang E, et al. Targeted therapy for inflammatory diseases with mesenchymal stem cells and their derived exosomes: from basic to clinics. Int J Nanomedicine. 2022; 17:1757-1781. doi: 10.2147/IJN.S355366

[66] Zhang L, Ma XJ, Fei YY, et al. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther. 2021;232:108004. doi: 10.1016/j.pharmthera.2021.108004

[67] Zhang J, Guan J, Niu X, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015;13:49. doi: 10.1186/s12967-015-0417-0

[68] Kim S, Lee SK, Kim H, Kim TM. Exosomes secreted from induced pluripotent stem cell-derived mesenchymal stem cells accelerate skin cell proliferation. Int J Mol Sci. 2018;19:3119. doi: 10.3390/ijms19103119

[69] Wei Y, Hou H, Zhang L, et al. JNKi-and DAC-programmed mesenchymal stem/stromal cells from hESCs facilitate hematopoiesis and alleviate hind limb ischemia. Stem Cell Res Ther. 2019;10:186. doi: 10.1186/s13287-019-1302-1

[70] Zhou H, Zhu L, Song J, et al. Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer. Mol Cancer. 2022;21:86. doi: 10.1186/s12943-022-01556-2

[71] Xia Y, Sun Y, Liu Y, et al. Targeted delivery of RGD-CD146(+) CD271(+) human umbilical cord mesenchymal stem cell-derived exosomes promotes blood-spinal cord barrier repair after spinal cord injury. ACS Nano. 2023; 17:18008-18024. doi: 10.1021/acsnano.3c04423

[72] Phan J, Kumar P, Hao D, Gao K, Farmer D, Wang A. Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy. J Extracell Vesicles. 2018; 7(1):1522236. doi: 10.1080/20013078.2018.1522236