Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells
Abstract
1. Introduction
2. Plasmid-Based Genetic Modification of Mesenchymal Stem Cells
3. Exosomes
4. Use and Applications of Viral Vectors by Modifying MSCs against Tumor Cells
5. Clinical Trials and Combination of Treatments
6. Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Function | Target Therapy | Therapeutic Approach | References | |
---|---|---|---|---|
Cancer Type | ||||
Breast cancer | TNF-α, IL-1β, IL-6, IL-8, IFN-γ | Cytokines regulate immune system | [11] | |
PI3k/AKT MYC-Max * inhibitors RTK inhibitors Anti-HER2 Anti-EGFR | Signaling pathways | [12] [13] [14] [15] [16] | ||
Anti-PARP | DNA repair pathway | [17] | ||
CPT1A/2 CYP2B6TM-RED Genes CDK4/6, | Suicide gene | [18] [19] | ||
Colon cancer | BMP4, IL7-IL12 CX3CL NK4 Inhibitor MDM2 | Immune regulatory networks | [20] [21] [22] | |
TRAIL | Apoptotic proteins | [23] | ||
MDM2 | Negative regulator of p53 | [22] | ||
Lung cancer | PD1/PDL-1 CXCL12 CXCR4 | Immune regulatory networks | [24] [25,26] | |
Oncolytic virus | Elimination directly | [27] | ||
Gastric cancer | Anti-HER2 Anti-EGFR Anti-VEGF TKIs Anti-mTOR Anti-HFG/MET | Key signaling pathways | [28] [29] [30] [28] | |
Anti-PARP | DNA repair pathway | [31] | ||
Prostate |
Anti-VEGFR PI3K ERK | Key signaling pathways | [32] | |
Anti-CTLA-4 | Immune regulatory networks | [33] | ||
Anti-PARP | DNA repair pathway | [34,35] | ||
Pancreatic |
HDAC inhibitors TKIs RAS-RAF-MEK-ERK PI3K-AKT-mTOR TP53 | Key signaling pathways | [36] [37] [38] [39] [40] | |
PARP inhibitors ATM inhibitors Checkpoint kinase 1 (CHK1) and CHK2 | DNA repair pathway | [41,42] [43] [44] | ||
Enhance dependency on BCL-2 and/or MCL-1 inhibition) | Anti-apoptosis | [39] | ||
Hepatocellular | Anti-HER2 GPC-3 IL-12 VEGFR GM-CSF | Key signaling pathways | [45] [46] [47] [48] [49] | |
MDM2 | Negative regulator of p53 | [50] | ||
TRAIL | Apoptosis protein | [51] |
Source | Tumor Type | Approach | Reference |
---|---|---|---|
Umbilical cord MSC | Colorectal cancer | Exosomes loaded with Anti-miR—146b-5p ASO (PMO-146b) | [87] |
Non-specified MSC | Cancer cell lines (lung, renal, breast and neuroblastoma) | Exosomes loaded with TRAIL (TNFa-Related Apoptosis Inducing Ligand). | [88] |
Non-specified MSC | Gastric cancer | Exosomes loaded with lipocalin-type prostaglandin D2 synthetase (L-PGDS). | [89] |
Adipose tissue MSC | Prostate cancer | Exosomes loaded with cytosine deaminase:uracil phosphoribosyl transferase along with 5-flucytosine treatment (enzyme and substrate-prodrug to synthesize 5-FU) | [90] |
Adipose tissue MSC | Glioblastoma | Exosomes loaded with herpes simplex virus thymidine kinase (HSV-TK) along with ganciclovir treatment (enzyme and substrate prodrug to synthesize GCV-triphosphate) | [91] |
Umbilical cord MSC | Breast cancer | Exosomes loaded with taxol. | [83] |
Non-specified MSC | Breast cancer | Exosomes carrying DARPins (Designed Ankyrin Repeated Proteins) to enhance HER2+ cell uptake. Exosomes loaded with doxorubicin. | [92] |
Bone marrow MSC | Castration-resistant prostate cancer | Exosomes loaded with miR-let-7c | [93] |
Umbilical cord MSC | Acute myeloid leukemia | Exosomes overexpressing Lamp2b-IL3 to improve their targeting system against leukemia stem cells. Exosomes loaded with miR-34c-5p to eliminate malignant cells. | [94] |
Non-specified MSC | Oral squamous cell carcinoma | Exosomes loaded with TRAIL and cabazitaxel. | [95] |
Bone marrow MSC | Osteosarcoma | Exosomes loaded with doxorubicin. | [96] |
Virus | Ad | AVV | Lentivirus |
---|---|---|---|
Advantages | Low pathogenicity Safety Well-tolerated Large transgene-carrying capacity (8–36 kb) Transduce-dividing and non-dividing cells Do not integrate their genome into the host genome and remain extrachromosomal. The most common viral vectors for MSC transduction | High efficiency, safety, and lowest risk (non-inflammatory and non-pathogenic) Transgene-carrying capacity 5 kb Transduce-dividing and non-dividing cells Genome episomal (>90%) site-specific integration (<10%) | Low pathogenicity Safety Well-tolerated transgene-carrying capacity (8 kb) Transduce-dividing and non-dividing cells Integration genome High infectivity Capability of stable gene transferring |
Disadvantages | Inflammatory effect | Small packaging capacity Requiring helper AdV for replication-associated difficulty producing pure viral stocks Application of these vectors has been limited due to their low aptitude for MSC transduction. Improve the efficiency of transgene delivery of Ad vectors in MSC modifications done on the viral capsid and fibers. | Transgene integration might result in oncogenesis. Next-generation lentivirus block integration into the host cell genome, and a few mutations in viral integrase coding sequence are enough to inactivate the integrase function while preserving its role in transgene expression. |
References | [99,100,101,102] | [103,104,105,106] | [106,107,108] |
Author | Vector | Transgene | Cancer Model | Results’ Relevance | Reference |
---|---|---|---|---|---|
Proteins | |||||
Michael R. Loebinger, 2009 | Lentivirus | TRAIL | Breast cancer Lung cancer | TRAIL-MSCs reduce tumor and metastasis. | [134] |
Quiroz-Reyes, 2023 | Lentivirus | TRAIL | Colorectal cancer | Oxaliplatin increases the sensibility of cancer cells to soluble TRAIL apoptosis. | [120] |
Shahrokhi, S., 2014 | Lentivirus | TNF-α and CD40L | Breast cancer | Increased mouse survival, optimized antitumor immunity response | [122] |
Yan, C, 2016. | Lentivirus | ISZ-sTRAIL | Lung cancer | Apoptosis induction and tumor growth reduction in xenograft murine model | [123] |
Harati, M.D, 2015 | Lentivirus | Lipocalin 2 | Colon cancer | Reduction of liver metastasis by downregulation of VEGF | [124] |
Du, J., 2015. | Lentivirus | Apoptin | Lung cancer | Apoptosis via caspase-3 activation | [125] |
Studeny, M., 2004 | Adenovirus | IFN-β | Breast cancer | In situ inhibition of proliferation | [118] |
Ling, X, 2010. | Lentivirus | IFN-β | Breast cancer | Inactivation of Stat3, Src, and Akt; downregulation of cMyc and MMP2 expression | [127] |
Yang, X, 2014 | Lentivirus | IFN-γ | Lung cancerBreast cancer | Activation of apoptosis by TRAIL-mediated caspase-3. Suppress tumor growth on a lung carcinoma xenograft. | [128]. |
Li, X., 2015 | Lentivirus | IL-12 | Lung cancer | Prevent tumor growth and invasion of A549 carcinoma cells | [131] |
Zhang, X, 2012. | Lentivirus | IL-24 | Lung cancer | Inhibit A549 cell growth in vitro and in vivo tumor xenograft. | [132]. |
Suzuki, T., 2014. | Adenovirus AdF35 | IL-28A | Lung cancer | Reduction of OBA-LK1 viability. | [133]. |
Yin, P. et al., 2020 | Lentivirus | CXCL9/OX40L | Colon cancer | Increase CD8+ T and NK cells in tumors and improve PD-1 response. | [126] |
Oncolytic Virus | |||||
Hoyos, V. et al., 2015 | Oncolytic adenovirus | ICOVIR15 and Ad.iC9 | Lung cancer | Increase overall survival and tumor control | [135] |
Stoff-Khalili, M.A., 2007 | Oncolytic adenovirus Ad5/3 | CXCR4 | Breast cancer | Oncolysis in MDA-MB-231 cells and reduction of lung metastasis | [113]. |
Guo, Y. et al., 2019 | Oncolytic adenovirus | ICOVIR5 | Lung cancer | Activation of T cell immunity and migration | [136] |
Modification | MSC Delivering | Conventional Therapy | Model | Reference |
---|---|---|---|---|
Unmodified MSC | microRNA-1236 | Cisplatin | In vitro | [137] |
SDF-1α/CXCR4 | 5-FU and doxorubicin | In vitro | [138] | |
Nanoparticles | Manganese oxide (MnO2) nanoparticles | Ce6 | In vivo | [139] |
Nanoparticles | 5-Fluorouracil (FU) and folinic acid (FA) | In vitro | [140] | |
Nanoparticles | Paclitaxel | In vitro and in vivo | [141] | |
Lentiviral | TRAIL | Oxaliplatin | In vitro | [120] |
Adenoviral | sFlt-1 | Doxorubicin | In vitro and in vivo | [142] |
Oncolytic virus | Delta-24-RGD | Chemotherapy and radiotherapy | In vivo | [143] |
AF2.CD-TK | 5-FC and GCV | In vitro and in vivo | [144] |
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Garza Treviño, E.N.; Quiroz Reyes, A.G.; Delgado Gonzalez, P.; Rojas Murillo, J.A.; Islas, J.F.; Alonso, S.S.; Gonzalez Villarreal, C.A. Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells. Int. J. Mol. Sci. 2024, 25, 7791. https://doi.org/10.3390/ijms25147791
Garza Treviño EN, Quiroz Reyes AG, Delgado Gonzalez P, Rojas Murillo JA, Islas JF, Alonso SS, Gonzalez Villarreal CA. Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells. International Journal of Molecular Sciences. 2024; 25(14):7791. https://doi.org/10.3390/ijms25147791
Chicago/Turabian StyleGarza Treviño, Elsa N., Adriana G. Quiroz Reyes, Paulina Delgado Gonzalez, Juan Antonio Rojas Murillo, Jose Francisco Islas, Santiago Saavedra Alonso, and Carlos A. Gonzalez Villarreal. 2024. "Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells" International Journal of Molecular Sciences 25, no. 14: 7791. https://doi.org/10.3390/ijms25147791
APA StyleGarza Treviño, E. N., Quiroz Reyes, A. G., Delgado Gonzalez, P., Rojas Murillo, J. A., Islas, J. F., Alonso, S. S., & Gonzalez Villarreal, C. A. (2024). Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells. International Journal of Molecular Sciences, 25(14), 7791. https://doi.org/10.3390/ijms25147791