Mesenchymal stem cells promote tumor angiogenesis via the action of transforming growth factor β1
Open accessAbstract
Mesenchymal stem cells (MSCs) may influence the growth and metastasis of various human malignancies, including hepatocellular carcinoma (HCC). Therefore, the underlying mechanisms via which MSCs are able to affect malignancies require investigation. In the present study, the potential role of MSC in the angiogenesis of HCC was investigated. A total of 17 nude mouse models exhibiting human HCC were used to evaluate the effects of MSC on angiogenesis. A total of 8 mice were injected with human MSCs via the tail vein, and the remaining 9 mice were injected with phosphate-buffered saline as a control. A total of 35 days subsequent to the injection of MSCs, the microvessel density (MVD) of tumors was evaluated by immunostaining, using cluster of differentiation 31 antibody. The mRNA levels of transforming growth factor (TGF)β1, Smad2 and Smad7 were detected using reverse transcription-quantitative polymerase chain reaction. Protein expression levels of TGFβ1 and vascular endothelial growth factor (VEGF) in tumor tissues were analyzed using ELISA. Compared with controls, MVD in MSC-treated mice was significantly increased (28.00±9.19 vs. 18.11±3.30; P=0.006). The levels of TGFβ1 mRNA in the MSC-treated group were 2.15-fold higher compared with the control group (1.27±0.61 vs. 0.59±0.39; P=0.033), and MVD was higher in the group exhibiting increased TGFβ1 mRNA levels compared with the control group (26.50±9.11 vs. 19.44±6.14; P=0.038). In addition, a close correlation between the expression levels of TGFβ1 and VEGF was identified. The results of the present study suggested that MSCs may be capable of enhancing the angiogenesis of HCC, which may be partly due to the involvement of TGFβ1.
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Interaction between endothelial cells and pericytes confers localized and constitutive TGF-β activation, which is required for microvascular integrity.
“and interaction between endothelial cells and pericytes confers localized and constitutive TGF-β activation, which is required for microvascular integrity274,275.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [275]
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Eljarrah, A., Gergues, M., Pobiarzyn, P. W., Sandiford, O. A., & Rameshwar, P. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-31206-0_5 · Cited by 19 · see citing works
Engineering Cell‐Based Systems for Smart Cancer Therapy
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Mesenchymal Stem Cells: Miraculous Healers or Dormant Killers?
Ghaderi, A. A., & Abtahi, S. (2018) · Stem Cell Reviews and Reports · doi:10.1007/s12015-018-9824-y · Cited by 18 · see citing works
“Tumor promoting functions of transplanted MSCs via angiogenesis has been attributed to their ability to secrete angiogenic factors such as VEGF and TGF-beta [27, 28, 43], transdifferentiation to pericytes [44, 45]/endothelial cells [46], and recruiting endothelial progenitors [47].”
Razmkhah, M., Abtahi, S., & Ghaderi, A. A. (2018) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x13666180816114809 · Cited by 18 · see citing works
Taheri, M., Tehrani, H. A., Dehghani, S., Rajabzadeh, A., Alibolandi, M., Zamani, N., Arefian, E., & Ramezani, M. (2024) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2024.01.004 · Cited by 16 · see citing works
Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells
Coccè, V., Monica, S. L., Bonelli, M. A., Alessandri, G., Alfieri, R. R., Lagrasta, C. A., Madeddu, D., Frati, C., Flammini, L., Lisini, D., et al. (2021) · Cells · doi:10.3390/cells10061427 · Cited by 15 · see citing works
“A tumor-promoting capacity of MSCs has been described as the result of paracrine activity of growth factors, exosomes and anti-apoptotic molecules secreted by MSCs [6,7].”
BackgroundMesenchymal Stem/Stromal Cells in Cancer: from Initiation to Metastasis
Zheng, Z., Li, P., Shen, F., Shi, Y., & Shao, C. (2022) · Archives of Medical Research · doi:10.1016/j.arcmed.2022.11.001 · Cited by 14 · see citing works
Ghollasi, M., Ghasembaglou, S., Rahban, D., Korani, M., Motallebnezhad, M., Asadi, M., Zarredar, H., & Salimi, A. (2021) · International Journal of Stem Cells · doi:10.15283/ijsc20146 · Cited by 13 · see citing works
“MSCs are able to regress immune responses against tumor cells (61), induce angiogenesis in tumors (62, 63), promote epithelial-to-mesenchymal transition (EMT) resulting in metastasis (64, 65), and induce a resistance in tumor cells to different therapeutics (66).”
BackgroundEffects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases
Zheng, W., Yang, Y., Sequeira, R. C., Bishop, C. E., Atala, A., Gu, Z., & Zhao, W. (2019) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x14666190308123714 · Cited by 11 · see citing works
Sorafenib and Mesenchymal Stem Cell Therapy: A Promising Approach for Treatment of HCC
Hajighasemlou, S., Nikbakht, M., Pakzad, S., Muhammadnejad, S., Gharibzadeh, S., Mirmoghtadaei, M., Zafari, F., Seyhoun, I., Ai, J., & Verdi, J. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/9602728 · Cited by 11 · see citing works
“influence tumor angiogenesis; these include VEGF and transforming growth factor (TGF) β1 [30, 31].”
BackgroundTreating Metastatic Brain Cancers With Stem Cells
Sadanandan, N., Shear, A., Brooks, B., Saft, M., Cabantan, D. A. G., Kingsbury, C., Zhang, H., Anthony, S., Wang, Z.-J., Salazar, F. E., et al. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.749716 · Cited by 10 · see citing works
“When angiogenic genes are engineered into MSCs, especially if they have EPC phenotype, their transplantation serves as a viable treatment for attenuating brain inflammation and repairing the BBB (Antonucci et al., 2011; Miloradovic et al., 2020; Pawitan et al., 2020; Castelli et al., 2021; Li et al., 2021).”
BackgroundInfluentialSelf-citationEl‐Din, S. S., Fouad, H. H., Rashed, L. A., Mahfouz, S., & Hussein, R. E. (2018) · Europe PMC (PubMed Central) · doi:10.22034/apjcp.2018.19.4.905 · Cited by 9 · see citing works
Xu, N., Meng, H., Liu, T., Feng, Y., Qi, Y., Zhang, D., & Wang, H. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01862 · Cited by 8 · see citing works
“TGF-β has a positive association with the levels of VEGF, and can enhance cellular angiogenesis (Li et al., 2016) while angiogenesis is associated with aneurysm formation (Baumann et al., 2013).”
BackgroundRoy, M.-È., Veilleux, C., & Annabi, B. (2024) · Scientific Reports · doi:10.1038/s41598-024-72862-6 · Cited by 7 · see citing works
“Alternative to angiogenesis, vasculogenic mimicry (VM) processes within tumor xenografts has been reported through cancer cells’ ability to, in part, attract MSC within primary solid tumors 11 , where their pro-angiogenic secretome is believed to contribute to tumour neovascularization 12–14 .”
BackgroundCreation of a vascular inducing device using mesenchymal stem cells to induce angiogenesis
Assis, A., Camargo, S., Margalit, R., & Mitrani, E. (2021) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2021.06.012 · Cited by 6 · see citing works
Mostafa, A., Abdelsalam, S. M., Sabbah, W. S., & Mekawy, D. M. (2022) · Asian Pacific Journal of Cancer Prevention · doi:10.31557/apjcp.2022.23.10.3309 · Cited by 5 · see citing works
“As MSCs reach the tumor niche, MSCs interact with cancer cells via direct and indirect mechanisms that affect tumor development (GC Li et al., 2016).”
BackgroundWarzycha, M., Oleksiuk, A., Suska, O., Kolanowski, T. J., & Rozwadowska, N. (2026) · Genes · doi:10.3390/genes17010108 · Cited by 4 · see citing works
Huang, X., Tan, X., Xie, X., Jiang, T., Xiao, Y., & Liu, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1321236 · Cited by 3 · see citing works
Bone Marrow Mesenchymal Stem Cells Overexpressing MicroRNA-126 to Treat Critical Limb Ischemia
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Micro-fragmented Fat Inhibits the Progression of Human Mesothelioma Xenografts in Mice
Monica, S. L., Coccè, V., Bonelli, M. A., Alessandri, G., Alfieri, R. R., Lagrasta, C. A., Frati, C., Flammini, L., Giannì, A. B., Petrella, F., et al. (2023) · Current Cancer Drug Targets · doi:10.2174/1568009623666230201092302 · Cited by 3 · see citing works
Immunogenic cell death mediated TLR3/4-activated MSCs in U87 GBM cell line
Emami Meybodi, S. M., Moradi Moraddahande, F., & Dehghani Firoozabadi, A. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e29858 · Cited by 3 · see citing works
Zhang, B., Shang, L., Zhang, Y., Li, T., & Yuan, F. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9106 · Cited by 3 · see citing works
“Previous studies have also demonstrated that TGFβ1 is associated with tumor proliferation and has different effects on liver cancer cells with high and low metastatic potentials (16), namely, the ability of BMSCs with TGFβ1 to promote MHCC97-L invasion was higher than that for MHCC97‐H (17) and MSCs may be capable of…”
ResultRay, S. K., & Mukherjee, S. (2022) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x17666220425102154 · Cited by 3 · see citing works
Liu, Y., Chen, S., Zhang, E., Xu, Y., Deng, X., Hu, Z., Nie, S., Lin, Y., & Huang, Y. (2024) · Bioscience Reports · doi:10.1042/bsr20231374 · Cited by 2 · see citing works
“TGF-β , which is linked to the development of aneurysms [40], plays a vital part in regulating the growth, specialization, and movement of different cells [41].”
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Tazetdinova, L. G., Mullagulova, A. I., Solovyeva, V. V., Chulpanova, D. S., Kitaeva, K. V., & Rizvanov, A. A. (2021) · Genes and Cells · doi:10.23868/202107003 · Cited by 1 · see citing works
Mesenchymal Stem Cells in Cancer Therapy
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Zhang, X., Kang, H., Liu, Y., Gan, C., Liu, Y., Ni, Y., Yu, C., Xia, Y., Jiang, Z., Wang, S., et al. (2026) · Stem Cells and Development · doi:10.1177/15473287251413995 · Cited by 1 · see citing works
Self-citationUnderstanding the association of stem cells in fetal development and carcinogenesis during pregnancy
Banerjee, K., Chattopadhyay, A., & Banerjee, S. (2022) · Advances in Cancer Biology - Metastasis · doi:10.1016/j.adcanc.2022.100042
[Research Progress of Mesenchymal Stem Cells and Their Exosomes on Tumors].
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Considerations for Clinical Use of Mesenchymal Stromal Cells
Hmadcha, A., Soria, B., Tejedo, J. R., Bedoya, F. J., Sempere-Ortells, J. M., & Smani, T. (2022) · Springer eBooks · doi:10.1007/978-981-16-6016-0_3-1
Considerations for Clinical Use of Mesenchymal Stromal Cells
Hmadcha, A., Soria, B., Tejedo, J. R., Bedoya, F. J., Sempere-Ortells, J. M., & Smani, T. (2022) · Springer eBooks · doi:10.1007/978-981-19-2655-6_3
Pro- and Anti-Cancer Behaviors of Mesenchymal Stem Cells
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Mesenchymal stem cell-derived extracellular vesicles in cancer immunotherapy
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- Authors
- LI, G.-C., ZHANG, H.-W., ZHAO, Q.-C., SUN, L., YANG, J.-J., HONG, L., FENG, F., & CAI, L.
- Affiliations
- Xijing Hospital (CN)
- Venue
- Oncology Letters
- Publisher
- Spandidos Publications
- Published
- 2015-12-03
- Volume
- 11
- Issue
- 2
- Pages
- 1089-1094
- ISSN
- 1792-1074 (ISSN-L)
- 1792-1082
- PMC
- PMC4733964
- OpenAlex
- W2185094661
- Cited by
- 72
- References
- 42
- Citations by year
- 2026: 6 · 2025: 1 · 2024: 10 · 2023: 6 · 2022: 12 · 2021: 11 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 2 · 2016: 2
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Oncology Letters (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fudan University
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- mesenchymal stem cells, tumor angiogenesis, hepatocellular carcinoma, TGF-β1, Smad2, Smad7, vascular endothelial growth factor, microvessel density, tumor microenvironment
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