Contribution of multipotent mesenchymal stromal cells in the tumor microenvironment and carcinogenesis

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Carcinogenesis is a complex and dynamic process, an important part of which is the formation of the tumor microenvironment, which is an integral part of malignant tumors and plays an important role in their progression. To maintain the growth and development of a tumor, constant contact and cross exchange of various trophic factors and cytokines with the cell of microenvironment, such as endothelial, immune, stromal cells, are essential. Multipotent mesenchymal stromal cells are an integral component of the tumor microenvironment, but their role in carcinogenesis is highly controversial. It has been described that multipotent mesenchymal stromal cells are able to stimulate tumor growth by differentiation into tumor-associated fibroblasts, immunosuppression, stimulation of angiogen-esis, participation in the epithelial-mesenchymal transition, inhibition of apoptosis, and maintenance of the metastatic potential of the tumor. However, other studies show that multipotent mesenchymal stromal cells suppress tumor growth by increasing inflammatory infiltration, inhibiting angiogenesis, suppressing WNT and AKT signals, and by directly inducing apoptosis of tumor cells. This review discusses the role of multipotent mesenchymal stromal cells in carcinogenesis, as well as the mechanisms responsible for the pro- and antitumor effects of multipotent mesenchymal stromal cells.

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About the authors

L. G Tazetdinova

Kazan Federal University

A. I Mullagulova

Kazan Federal University

V. V Solovyeva

Kazan Federal University

D. S Chulpanova

Kazan Federal University

K. V Kitaeva

Kazan Federal University

A. A Rizvanov

Kazan Federal University



  1. Kitaeva K.V., Rutland C.S., Rizvanov A.A. et al. Cell culture based in vitro test systems for anticancer drug screening. Front. Bioeng. Biotechnol. 2020; 8: 322.
  2. Gilazieva Z.E., Tazetdinova L.G., Arkhipova S.S. et al. Effect of cisplatin on ultrastructure and viability of adipose-derived mesenchymal stem cells. BioNanoSci. 2016; 6: 534-9.
  3. Brennen W.N., Chen S., Denmeade S.R. et al. Quantification of mesenchymal stem cells (MSCs) at sites of human prostate cancer. Oncotarget 2013; 4(1): 106-17.
  4. Solovyeva V.V., Salafutdinov 1.1., Tazetdinova L.G. et al. Genetic modification of adipose derived stem cells with recombinant plasmid DNA pBUD-VEGF-FGF2 results in increased of IL-8 and MCP-1 secretion. Journal of Pure and Applied Microbiol. 2014; 8: 523-8.
  5. Tropel P., Platet N., Platel J.C. et al. Functional neuronal differentiation of bone marrow-derived mesenchymal stem cells. Stem cells 2006; 24(12): 2868-76.
  6. Mortada I., Mortada R. Epigenetic changes in mesenchymal stem cells differentiation. Eur. J. Med. Genet. 2018; 61(2): 114-8.
  7. Melzer C., Yang Y., Hass R.Interaction of MSC with tumor cells. Cell Commun. Signal. 2016; 14(1): 20.
  8. Nakamizo A., Marini F., Amano T. et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 2005; 65(8): 3307-18.
  9. Sonabend A.M., Ulasov I.V., Tyler M.A. et al. Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells 2008; 26(3): 831-41.
  10. Kalimuthu S., Zhu L., Oh J.M. et al. Migration of mesenchymal stem cells to tumor xenograft models and in vitro drug delivery by doxorubicin.Int. J. Med. Sci. 2018; 15(10): 1051-61.
  11. Whiteside T.L. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008; 27: 5904-12.
  12. Соловьева В.В., Блатт Н.Л., Шафигуллина А.К. и др. Исследование эндогенной секреции сосудистого эндотелиального фактора роста мультипотентными мезенхимными стромальными клетками из зачатков третьих моляров человека. Клеточная трансплантология и тканевая инженерия 2012; 7(3): 155-8.
  13. Kim S.M., Oh J.H., Park S.A. et al. Irradiation enhances the tumor tropism and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand-secreting human umbilical cord blood-derived mesenchymal stem cells in glioma therapy. Stem Cells 2010; 28(12): 2217-28.
  14. Klopp A.H., Spaeth E.L., Dembinski J.L. et al. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res. 2007; 67(24): 11687-95.
  15. Jotzu C., Alt E., Welte G. et al. Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors. Cell. Oncol. (Dordr) 2011; 34(1): 55-67.
  16. Maccario R., Podesta M., Moretta A. et al.Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 2005; 90(4): 516-25.
  17. O'Malley G., Heijltjes M., Houston A.M. et al. Mesenchymal stromal cells (MSCs) and colorectal cancer: a troublesome twosome for the antitumour immune response? Oncotarget 2016; 7(37): 60752-74.
  18. Kansy B.A., Dissmann P.A., Hemeda H. et al. The bidirectional tumor--mesenchymal stromal cell interaction promotes the progression of head and neck cancer. Stem Cell Res. Ther. 2014; 5(4): 95.
  19. Chen D., Liu S., Ma H. et al. Paracrine factors from adipose-mesenchymal stem cells enhance metastatic capacity through wnt signaling pathway in a colon cancer cell co-culture model. Cancer Cell Int. 2015; 15: 42.
  20. Madrigal M., Rao K.S., Riordan N.H. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J. Transl. Med. 2014; 12: 260.
  21. Sun B., Roh K.H., Park J.R. et al. Therapeutic potential of mesenchymal stromal cells in a mouse breast cancer metastasis model. Cytotherapy 2009; 11(3): 289-98.
  22. Lin L., Hu X., Zhang H. et al. Tertiary lymphoid organs in cancer immunology: mechanisms and the new strategy for immunotherapy. Front. Immunol. 2019; 10: 1398.
  23. Lu Y.R., Yuan Y., Wang X.J. et al. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol. Ther. 2008; 7(2): 245-51.
  24. Rhee K.J., Lee J.I., Eom Y.W. Mesenchymal stem cell-mediated effects of tumor support or suppression.Int. J. Mol. Sci. 2015; 16(12): 30015-33.
  25. Dvorak H.F. Tumors: wounds that do not heal-redux. Cancer Immunol. Res. 2015; 3(1): 1-11.
  26. Pietras K., Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 2010; 316(8): 1324-31.
  27. Balkwill F. Cancer and the chemokine network. Nat. Rev. Cancer 2004; 4(7): 540-50.
  28. Spaeth E., Klopp A., Dembinski J. et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 2008; 15(10): 730-8.
  29. Escobar P., Bouclier C., Serret J. et al. IL-1beta produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production. Oncotarget 2015; 6(30): 29034-47.
  30. Dwyer R.M., Potter-Beirne S.M., Harrington K.A. et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin. Cancer Res. 2007; 13(17): 5020-7.
  31. Lejmi E., Perriraz N., Clement S. et al. Inflammatory chemokines MIP-1delta and MIP-3alpha are involved in the migration of multipotent mesenchymal stromal cells induced by hepatoma cells. Stem Cells Dev. 2015; 24(10): 1223-35.
  32. Egea V., von Baumgarten L., Schichor C. et al. TNF-alpha respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma. Cell Death Differ. 2011; 18(5): 853-63.
  33. Li Y., Yu X., Lin S. et al. Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells. Biochem. Biophys. Res.Commun. 2007; 356(3): 780-4.
  34. Tomchuck S.L., Zwezdaryk K.J., Coffelt S.B. et al. Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodu-lating responses. Stem Cells 2008; 26(1): 99-107.
  35. Ridge S.M., Sullivan F.J., Glynn S.A. Mesenchymal stem cells: key players in cancer progression. Mol. Cancer 2017; 16(1): 31.
  36. Lee H.Y., Hong I.S. Double-edged sword of mesenchymal stem cells: cancer-promoting versus therapeutic potential. Cancer Sci. 2017; 108(10): 1939-46.
  37. Webber J., Steadman R., Mason M.D. et al. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010; 70(23): 9621-30.
  38. Xing F., Saidou J., Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front. Biosci. (Landmark Ed.) 2010; 15: 166-79.
  39. Bhowmick N.A., Neilson E.G., Moses H.L. Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432(7015): 332-7.
  40. Sullivan R., Maresh G., Zhang X. et al. The emerging roles of extracellular vesicles as communication vehicles within the tumor microenvironment and beyond. Front. Endocrinol. (Lausanne) 2017; 8: 194.
  41. Peddareddigari V.G., Wang D., Dubois R.N. The tumor microenvironment in colorectal carcinogenesis. Cancer Microenviron. 2010; 3(1): 149-66.
  42. Borriello L., Nakata R., Sheard M.A. et al. Cancer-associated fibroblasts share characteristics and protumorigenic activity with mesenchymal stromal cells. Cancer Res. 2017; 77(18): 5142-57.
  43. Nakagawa H., Liyanarachchi S., Davuluri R.V. et al. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene 2004; 23(44): 7366-77.
  44. Sugimoto H., Mundel T.M., Kieran M.W. et al. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 2006; 5(12): 1640-6.
  45. Ostman A., Pietras K.Introduction to tumor-stroma interactions. Exp. Cell Res. 2013; 319(11): 1595.
  46. Ostman A., Augsten M. Cancer-associated fibroblasts and tumor growth--bystanders turning into key players. Curr. Opin. Genet. Dev. 2009; 19(1): 67-73.
  47. Anderberg C., Pietras K. On the origin of cancer-associated fibroblasts. Cell Cycle 2009; 8(10): 1461-2.
  48. Bassi E.J., Aita C.A., Camara N.O. Immune regulatory properties of multipotent mesenchymal stromal cells: where do we stand? World J. Stem Cells 2011; 3(1): 1-8.
  49. Di Nicola M., Carlo-Stella C., Magni M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99(10): 3838-43.
  50. Plumas J., Chaperot L., Richard M.J. et al. Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia 2005; 19(9): 1597-604.
  51. Sheng H., Wang Y., Jin Y. et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 2008; 18(8): 846-57.
  52. Nasef A., Zhang Y.Z., Mazurier C. et al. Selected STRO-1-enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferation.Int. J. Lab. Hematol. 2009; 31(1): 9-19.
  53. Puissant B., Barreau C., Bourin P. et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br.J. Haematol. 2005; 129(1): 118-29.
  54. Zhou C., Yang B., Tian Y. et al. Immunomodulatory effect of human umbilical cord Wharton's jelly-derived mesenchymal stem cells on lymphocytes. Cell. Immunol. 2011; 272(1): 33-8.
  55. Djouad F., Plence P., Bony C. et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003; 102(10): 3837-44.
  56. Le Blanc K., Rasmusson I., Sundberg B. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363(9419): 1439-41.
  57. Ning H., Yang F., Jiang M. et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 2008; 22(3): 593-9.
  58. Lugano R., Ramachandran M., Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell. Mol. Life Sci. 2020; 77(9): 1745-70.
  59. Lin L., Sun W., Wang L. Effects of mesenchymal stem cells on angiogenesis of cervical cancer HeLa cancer cell line HeLa in vivo. Zhonghua Yi Xue Za Zhi 2015; 95(15): 1175-8.
  60. Zhang T., Lee Y.W., Rui Y.F. et al. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors. Stem Cell Res. Ther. 2013; 4(3): 70.
  61. Li G.C., Zhang H.W., Zhao Q.C. et al. Mesenchymal stem cells promote tumor angiogenesis via the action of transforming growth factor beta1. Oncol. Lett. 2016; 11(2): 1089-94.
  62. Batlle R., Andres E., Gonzalez L. et al. Regulation of tumor angiogenesis and mesenchymal-endothelial transition by p38 alpha through TGF-beta and JNK signaling. Nat.Commun. 2019; 10(1): 3071.
  63. Christodoulou I., Goulielmaki M., Devetzi M. et al. Mesenchymal stem cells in preclinical cancer cytotherapy: a systematic review. Stem Cell Res. Ther. 2018; 9(1): 336.
  64. Karnoub A.E., Dash A.B., Vo A.P. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449(7162): 557-63.
  65. Chen Y., He Y., Wang X. et al. Adipose-derived mesenchymal stem cells exhibit tumor tropism and promote tumorsphere formation of breast cancer cells. Oncol. Rep. 2019; 41(4): 2126-36.
  66. Prantl L., Muehlberg F., Navone N.M. et al. Adipose tissue-derived stem cells promote prostate tumor growth. Prostate 2010; 70(15): 1709-15.
  67. Ye H., Cheng J., Tang Y. et al. Human bone marrow-derived mesenchymal stem cells produced TGFbeta contributes to progression and metastasis of prostate cancer. Cancer Invest. 2012; 30(7): 513-8.
  68. Costanza B., Umelo I.A., Bellier J. et al. Stromal modulators of TGFbeta in cancer. J. din. Med. 2017; 6(1): 7.
  69. Lacerda L., Debeb B.G., Smith D. et al. Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model. Breast Cancer Res. 2015; 17(1): 42.
  70. Atsuta I., Liu S., Miura Y. et al. Mesenchymal stem cells inhibit multiple myeloma cells via the Fas/Fas ligand pathway. Stem Cell Res. Ther. 2013; 4(5): 111.
  71. Chai L., Bai L., Li L. et al. Biological functions of lung cancer cells are suppressed in co-culture with mesenchymal stem cells isolated from umbilical cord. Exp. Ther. Med. 2018; 15(1): 1076-80.
  72. Wang W., Li L., Chen F. et al. Umbilical cordderived mesenchymal stem cells can inhibit the biological functions of melanoma A375 cells. Oncol. Rep. 2018; 40(1): 511-7.
  73. Li X., Li Z. Effects of human umbilical cord mesenchymal stem cells on co-cultured ovarian carcinoma cells. Microsc. Res. Tech. 2019; 82(6): 898-902.
  74. Alshareeda A.T., Alsowayan B., Almubarak A. et al. Exploring the potential of mesenchymal stem cell sheet on the development of hepatocellular carcinoma in vivo. J. Vis. Exp. 2018; 139: 57805.
  75. Khalil C., Moussa M., Azar A. et al. Anti-proliferative effects of mesenchymal stem cells (MSCs) derived from multiple sources on ovarian cancer cell lines: an in-vitro experimental study. J. Ovarian Res. 2019; 12(1): 70.
  76. Ryu H., Oh J.E., Rhee K.J. et al. Adipose tissue-derived mesenchymal stem cells cultured at high density express IFN-beta and suppress the growth of MCF-7 human breast cancer cells. Cancer Lett. 2014; 352(2): 220-7.
  77. Khakoo A.Y., Pati S., Anderson S.A. et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J. Exp. Med. 2006; 203(5): 1235-47.
  78. Dasari V.R., Kaur K., Velpula K.K. et al. Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway. PLoS One 2010; 5(4): e10350.
  79. Qiao L., Xu Z., Zhao T. et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res. 2008; 18(4): 500-7.
  80. Qiao L., Xu Z.L., Zhao T.J. et al. Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of wnt signalling. Cancer Lett. 2008; 269(1): 67-77.
  81. Zhu Y., Sun Z., Han Q. et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009; 23(5): 925-33.
  82. Glennie S., Soeiro I., Dyson P.J. et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105(7): 2821-7.
  83. Ramasamy R., Lam E.W., Soeiro I. et al. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia 2007; 21(2): 304-10.
  84. Fathi E., Farahzadi R., Valipour B. et al. Cytokines secreted from bone marrow derived mesenchymal stem cells promote apoptosis and change cell cycle distribution of K562 cell line as clinical agent in cell transplantation. PLoS One 2019; 14(4): e0215678.
  85. Fonseka M., Ramasamy R., Tan B.C. et al. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) inhibit the proliferation of K562 (human erythromyeloblastoid leukaemic cell line). Cell Biol.Int. 2012; 36(9): 793-801.
  86. Ohlsson L.B., Varas L., Kjellman C. et al. Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix. Exp. Mol. Pathol. 2003; 75(3): 248-55.
  87. Chulpanova D.S., Gilazieva Z.E., Kletukhina S.K. et al. Cytochalasin B-induced membrane vesicles from human mesenchymal stem cells overexpressing IL2 are able to stimulate CD8+ T-killers to kill human triple negative breast cancer cells. Biology 2021; 10(2): 141.
  88. Zhou X., Li T., Chen Y. et al. Mesenchymal stem cell-derived extracellular vesicles promote the in vitro proliferation and migration of breast cancer cells through the activation of the ERK pathway.Int. J. Oncol. 2019; 54(5): 1843-52.
  89. Zhu W., Huang L., Li Y. et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett. 2012; 315(1): 28-37.
  90. Ren W., Hou J., Yang C. et al. Extracellular vesicles secreted by hypoxia pre-challenged mesenchymal stem cells promote non-small cell lung cancer cell growth and mobility as well as macrophage M2 polarization via miR-21-5p delivery. J. Exp. Clin. Cancer Res. 2019; 38(1): 62.

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