Role of mesenchymal stem cells in growth and progression of cancer and prospective potentials in cancer therapy

authors:

avatar Farshid Zamani , avatar Saeed Oraee-Yazdani , avatar Ladan Langroudi , avatar Seyed Mahmoud Hashemi , *

Koomesh: Vol.24, issue 1; 1-25
published online: March 01, 2022
article type: issue_documents_importer
received: January 02, 2021
accepted: July 01, 2021

how to cite: Zamani F, Oraee-Yazdani S, Langroudi L, Hashemi S M. Role of mesenchymal stem cells in growth and progression of cancer and prospective potentials in cancer therapy. koomesh. 2022;24(1):e152383. 

Abstract

Introduction: Mesenchymal stem cells (MSCs) are present in most tissues of the body. These cells are involved in various biological processes, such as maintaining tissue homeostasis and wound healing. Recent studies have shown that tumor associated MSCs (TA-MSCs) are also present in tumor microenvironment (TME) of most solid tumors. MSCs have a strong tendency to migration toward tumor tissues. Once entering are TME, MSCs educated by tumor cells and other factors in the TME and become TA-MSCs. Study of the relationship between MSCs and cancer cells revealed that MSCs have a controversial role against cancer cells. Although some findings suggest that MSCs can reduce the growth of tumor cells, but most studies have shown an undeniable role of these cells in supporting of growth and progression of cancer. In this review article, we have accumulated some of the most important findings related to TA-MSCs and their interaction with cancer cells for immune system evation, metastasis, also their effects on the tumor cells behavior and other existing cells in TME. Lastly, we briefly explaine and classify some therapeutic solutions against tumors based on the features of MSCs.

References

  • 1.

    Kang SG, Shinojima N, Hossain A, Gumin J, Yong RL, Colman H, Marini F, et al. Neurosurgery 2010; 67: 711-720. https://doi.org/10.1227/01.NEU.0000377859.06219.78 PMid:20651630 PMCid:PMC3644957.

  • 2.

    Bianco P, Robey PG, Simmons PJ. Cell Stem Cell 2008; 2: 313-319. https://doi.org/10.1016/j.stem.2008.03.002 PMid:18397751 PMCid:PMC2613570.

  • 3.

    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, et al. Cytotherapy 2006; 8: 315-317. https://doi.org/10.1080/14653240600855905 PMid:16923606.

  • 4.

    Brennen WN, Chen S, Denmeade SR, John T, Stem M, Bm-mscs C. Oncotarget 2013; 4: 106-117. https://doi.org/10.18632/oncotarget.805 PMid:23362217 PMCid:PMC3702211.

  • 5.

    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Science 1999; 284: 143-147. https://doi.org/10.1126/science.284.5411.143 PMid:10102814.

  • 6.

    Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Nature 2002; 418: 41-49. https://doi.org/10.1038/nature00870 PMid:12077603.

  • 7.

    Escobar P, Bouclier C, Serret J, Biche I, Brigitte M, Caicedo A, et al. Oncotarget 2015; 6: 29034-29047. https://doi.org/10.18632/oncotarget.4732 PMid:26362269 PMCid:PMC4745709.

  • 8.

    Aravindhan S, Ejam SS, Lafta MH, Markov A, Yumashev AV, Ahmadi M. Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int 2021; 21: 1-15. https://doi.org/10.1186/s12935-021-01836-9. PMid:33685452 PMCid:PMC7938588.

  • 9.

    Tayebi Kamardi M, Pourgholaminejad A, Baghban Eslaminejad M, Sotoodehnejadnematalahi F. Mesenchymal stem cells and their application in autoimmune disease treatment. Tehran University Medical Journal, September 2014; Vol. 72, No. 6: 341-351.

  • 10.

    Mahmoudi M, Taghavi-Farahabadi M, Rezaei N, Hashemi SM. Int Immunopharmacol 2019; 74: 105689. https://doi.org/10.1016/j.intimp.2019.105689 PMid:31207404.

  • 11.

    Uccelli A, Laroni A, Brundin L, Clanet M, Fernandez O, Nabavi SM, et al. MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis. Trials 2019; 20: 1-13. https://doi.org/10.1186/s13063-019-3346-z PMid:31072380 PMCid:PMC6507027.

  • 12.

    Elgaz S, Kui Z, Kui S, Bnig H, Bader P. Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease. Transfus Med Hemotherapy 2019; 46: 27-34. https://doi.org/10.1159/000496809 PMid:31244579 PMCid:PMC6558336.

  • 13.

    Sun XY, Ding XF, Liang HY, Zhang XJ, Liu SH, Bing-Han, et al. Efficacy of mesenchymal stem cell therapy for sepsis: a meta-analysis of preclinical studies. Stem Cell Res Ther 2020; 11: 1-10. https://doi.org/10.1186/s13287-020-01730-7 PMid:32493435 PMCid:PMC7268531.

  • 14.

    Rodrguez-Fuentes DE, Fernndez-Garza LE, Samia-Meza JA, Barrera-Barrera SA, Caplan AI, Barrera-Saldaa HA. Mesenchymal stem cells current clinical applications: a systematic review. Arch Med Res 2021; 52: 93-101. https://doi.org/10.1016/j.arcmed.2020.08.006 PMid:32977984.

  • 15.

    Hill BS, Pelagalli A, Passaro N, Zannetti A. Tumor-educated mesenchymal stem cells promote pro-metastatic phenotype. Oncotarget 2017; 8: 73296-73311. https://doi.org/10.18632/oncotarget.20265 PMid:29069870 PMCid:PMC5641213.

  • 16.

    Sun Z, Wang S, Zhao RC. The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J Hematol Oncol 2014; 7: 14. https://doi.org/10.1186/1756-8722-7-14 PMid:24502410 PMCid:PMC3943443.

  • 17.

    Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 2010; 18: 884-901. https://doi.org/10.1016/j.devcel.2010.05.012 PMid:20627072 PMCid:PMC2905377.

  • 18.

    Shahar T, Rozovski U, Hess KR, Hossain A, Gumin J, Gao F, et al. Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival. Neuro Oncol 2017; 19: 660-668. https://doi.org/10.1093/neuonc/now239 PMid:28453745 PMCid:PMC5464439.

  • 19.

    Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F, et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 2011; 71: 614-624. https://doi.org/10.1158/0008-5472.CAN-10-0538 PMid:21224357 PMCid:PMC3100554.

  • 20.

    Bergfeld SA, DeClerck YA. Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metastasis Rev 2010; 29: 249-261. https://doi.org/10.1007/s10555-010-9222-7 PMid:20411303.

  • 21.

    Cuiffo BG, Karnoub AE. Mesenchymal stem cells in tumor development: emerging roles and concepts. Cell Adh Migr 2012; 6: 220-230. https://doi.org/10.4161/cam.20875 PMid:22863739 PMCid:PMC3427236.

  • 22.

    Tsai K, Yang S, Lei Y, Tsai C, Chen H, Hsu C, et al. Mesenchymal stem cells promote formation of colorectal tumors in mice. Gastroenterology 2011; 141: 1046-1056. https://doi.org/10.1053/j.gastro.2011.05.045 PMid:21699785.

  • 23.

    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557-563. https://doi.org/10.1038/nature06188 PMid:17914389.

  • 24.

    Kidd S, Spaeth E, Klopp A, Andreeff M, Hall B, Marini F. The (in) auspicious role of mesenchymal stromal cells in cancer: be it friend or foe. Cytotherapy 2008; 10: 657-667. https://doi.org/10.1080/14653240802486517 PMid:18985472.

  • 25.

    Poggi A, Musso A, Dapino I, Zocchi MR. Mechanisms of tumor escape from immune system: role of mesenchymal stromal cells. Immunol Lett 2014; 159: 55-72. https://doi.org/10.1016/j.imlet.2014.03.001 PMid:24657523.

  • 26.

    Poggi A, Varesano S, Zocchi MR. How to hit mesenchymal stromal cells and make the tumor microenvironment immunostimulant rather than immunosuppressive. Front Immunol 2018; 9: 262. https://doi.org/10.3389/fimmu.2018.01342 https://doi.org/10.3389/fimmu.2018.00262 PMid:29515580 PMCid:PMC5825917.

  • 27.

    Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 2015; 15: 669-682. https://doi.org/10.1038/nri3902 PMid:26471778.

  • 28.

    Razmkhah M, Jaberipour M, Erfani N, Habibagahi M, Talei AR, Ghaderi A. Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-1 and upregulate expression of regulatory molecules on T cells: do they protect breast cancer cells from the immune response? Cell Immunol 2011; 266: 116-122. https://doi.org/10.1016/j.cellimm.2010.09.005 PMid:20970781.

  • 29.

    Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 2006; 25: 315-322. https://doi.org/10.1007/s10555-006-9001-7 PMid:16967326.

  • 30.

    Croix BS, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, et al. Genes expressed in human tumor endothelium. Science 2000; 289: 1197-1202. https://doi.org/10.1126/science.289.5482.1197 PMid:10947988.

  • 31.

    Sneddon JB, Borowiak M, Melton DA. Self-renewal of embryonic-stem-cell-derived progenitors by organ-matched mesenchyme. Nature 2012; 491: 765-768. https://doi.org/10.1038/nature11463 PMid:23041930 PMCid:PMC6005657.

  • 32.

    Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011; 20: 370-383. https://doi.org/10.1016/j.ccr.2011.08.010 PMid:21907927.

  • 33.

    Hossain A, Gumin J, Gao F, Figueroa J, Shinojima N, Takezaki T, et al. mesenchymal stem cells isolated from human Gliomas increase proliferation and maintain stemness of Glioma stem cells through the IL-6/gp130/STAT3 pathway. Stem Cells 2015; 33: 2400-2415. https://doi.org/10.1002/stem.2053 PMid:25966666 PMCid:PMC4509942.

  • 34.

    McLean K, Gong Y, Choi Y, Deng N, Yang K, Bai S, et al. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J Clin Invest 2011; 121: 3206-3219. https://doi.org/10.1172/JCI45273 PMid:21737876 PMCid:PMC3148732.

  • 35.

    Kong BH, Shin HD, Kim SH, Mok HS, Shim JK, Lee JH, et al. Increased in vivo angiogenic effect of glioma stromal mesenchymal stem-like cells on glioma cancer stem cells from patients with glioblastoma. Int J Oncol 2013; 42: 1754-1762. https://doi.org/10.3892/ijo.2013.1856 PMid:23483121.

  • 36.

    Langroudi L, Hassan ZM, Soleimani M, Hashemi SM. Tumor associated mesenchymal stromal cells show higher immunosuppressive and angiogenic properties compared to adipose derived MSCs. Iran J Immunol 2015; 12: 226-239.

  • 37.

    Montesinos JJ, Mora-Garca MD, Mayani H, Flores-Figueroa E, Garca-Rocha R, Fajardo-Ordua GR, et al. In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. Stem Cells Dev 2013; 22: 2508-2519. https://doi.org/10.1089/scd.2013.0084 PMid:23656504 PMCid:PMC3761677.

  • 38.

    Del Papa B, Sportoletti P, Cecchini D, Rosati E, Balucani C, Baldoni S, et al. Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction. Eur J Immunol 2013; 43: 182-187. https://doi.org/10.1002/eji.201242643 PMid:23161436.

  • 39.

    Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C. A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 2002; 3: 688-694. https://doi.org/10.1093/embo-reports/kvf124 PMid:12101103 PMCid:PMC1084181.

  • 40.

    Kabashima-Niibe A, Higuchi H, Takaishi H, Masugi Y, Matsuzaki Y, Mabuchi Y, et al. Mesenchymal stem cells regulate epithelial-mesenchymal transition and tumor progression of pancreatic cancer cells. Cancer Sci 2013; 104: 157-164. https://doi.org/10.1111/cas.12059 PMid:23121112 PMCid:PMC7657182.

  • 41.

    Kamga PT, Collo GD, Cassaro A, Bazzoni R, Delfino P, Adamo A, et al. Small molecule Inhibitors of microenvironmental Wnt/-Catenin signaling enhance the chemosensitivity of acute myeloid leukemia. Cancers (Basel) 2020; 12: 1-16. https://doi.org/10.3390/cancers12092696 PMid:32967262 PMCid:PMC7565567##[42 Wu JI, Wang LH. J Biomed Sci.Emerging roles of gap junction proteins connexins in cancer metastasis, chemoresistance and clinical application 06 Biological Sciences 0601 Biochemistry and Cell Biology 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 2019; 26: 1-14. https://doi.org/10.1186/s12929-019-0497-x PMid:30642339 PMCid:PMC6332853.

  • 42.

    Mandel K, Yang Y, Schambach A, Glage S, Otte A, Hass R. Mesenchymal stem cells directly interact with breast cancer cells and promote tumor cell growth in vitro and in vivo. Stem Cells Dev 2013; 22: 3114-3127. https://doi.org/10.1089/scd.2013.0249 PMid:23895436.

  • 43.

    Caicedo A, Fritz V, Brondello JM, Ayala M, Dennemont I, Abdellaoui N, et al. MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep 2015; 5: 1-10. https://doi.org/10.1038/srep09073 PMid:25766410 PMCid:PMC4358056.

  • 44.

    Li G, Bethune MT, Wong S, Joglekar AV, Michael T, Wang JK, et al. T cell antigen discovery via trogocytosis. Nat Methods 2019; 16: 183-190. https://doi.org/10.1038/s41592-018-0305-7 PMid:30700903 PMCid:PMC6719556.

  • 45.

    Rafii A, Mirshahi P, Poupot M, Faussat AM, Simon A, Ducros E, et al. Oncologic trogocytosis of an original stromal cells induces chemoresistance of ovarian tumours. PLoS One 2008; 3: e3894. https://doi.org/10.1371/journal.pone.0003894 PMid:19079610 PMCid:PMC2597737.

  • 46.

    Castells M, Milhas D, Gandy C, Thibault B, Rafii A, Delord JP, Couderc B. Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation. Cell Death Dis 2013; 4: e887-889. https://doi.org/10.1038/cddis.2013.384 PMid:24176845 PMCid:PMC3824693.

  • 47.

    Melzer C, Ohe J Von Der, Luo T, Hass R. Spontaneous fusion of MSC with breast cancer cells can generate tumor dormancy. Int J Mol Sci 2021; 22: 5930. https://doi.org/10.3390/ijms22115930 PMid:34072967 PMCid:PMC8198754.

  • 48.

    Melzer C, von der Ohe J, Hass R. In vivo cell fusion between mesenchymal stroma/stem-like cells and breast cancer cells. Cancers (Basel). 2019; 11. https://doi.org/10.3390/cancers11020185 PMid:30764554 PMCid:PMC6406489.

  • 49.

    Hass R, Ohe J Von Der, Ungefroren H. Potential role of msc/cancer cell fusion and emt for breast cancer stem cell formation Cancers (Basel) 2019; 11: 1-15. https://doi.org/10.3390/cancers11101432 PMid:31557960 PMCid:PMC6826868.

  • 50.

    Oliveira Rodini C, Benites Gonalves da Silva P, Faria Assoni A, Melechco Carvalho V, Keith Okamoto O. Mesenchymal stem cells enhance tumorigenic properties of human glioblastoma through independent cell-cell communication mechanisms. Oncotarget 2018; 9: 24766-24777. https://doi.org/10.18632/oncotarget.25346 PMid:29872504 PMCid:PMC5973871.

  • 51.

    Chaturvedi P, Gilkes DM, Wong CC, Kshitiz, Luo W, Zhang H, et al. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest 2013; 123: 189-205. https://doi.org/10.1172/JCI69244 PMid:23318994 PMCid:PMC3674862.

  • 52.

    Crisostomo PR, Wang Y, Markel TA, Wang M, Lahm T, Meldrum DR. Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism. Am J Physiol Cell Physiol 2008; 294: 675-682. https://doi.org/10.1152/ajpcell.00437.2007 PMid:18234850.

  • 53.

    Zhukareva V, Obrocka M, Houle JD, Fischer I, Neuhuber B. Secretion profile of human bone marrow stromal cells: donor variability and response to inflammatory stimuli. Cytokine 2010; 50: 317-321. https://doi.org/10.1016/j.cyto.2010.01.004 PMid:20185331.

  • 54.

    Kantolati K, Ciettos C. Numerical analysis of a mechanotransduction dynamical model reveals homoclinic bifurcations of extracellular matrix mediated oscillations of the mesenchymal stem cell fate. arXiv preprint arXiv:1902.01481 (2019). https://doi.org/10.1016/j.ijnonlinmec.2019.04.001.

  • 55.

    English K, Mahon BP. Allogeneic mesenchymal stem cells: agents of immune modulation. J Cell Biochem 2011; 112: 1963-1968. https://doi.org/10.1002/jcb.23119 PMid:21445861.

  • 56.

    Hendijani F, Javanmard SH, Rafiee L, Sadeghi-Aliabadi H. Effect of human Wharton's jelly mesenchymal stem cell secretome on proliferation, apoptosis and drug resistance of lung cancer cells. Res Pharm Sci 2015; 10: 134.

  • 57.

    Zhou K, Xia M, Tang B, Yang D, Liu N, Tang D, et al. Isolation and comparison of mesenchymal stem cell like cells derived from human gastric cancer tissues and corresponding ovarian metastases. Mol Med Rep 2016; 13: 1788-1794. https://doi.org/10.3892/mmr.2015.4735 PMid:26718033.

  • 58.

    Velletri T, Xie N, Wang Y, Huang Y, Yang Q, Chen X, et al. P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development. Cell Death Dis 2016; 7: e2015-e2015. https://doi.org/10.1038/cddis.2015.367 PMid:26775693 PMCid:PMC4816167.

  • 59.

    Nishimura K, Semba S, Aoyagi K, Sasaki H, Yokozaki H. Mesenchymal stem cells provide an advantageous tumor microenvironment for the restoration of cancer stem cells. Pathobiology 2012; 79: 290-306. https://doi.org/10.1159/000337296 PMid:22688186.

  • 60.

    Roorda BD, ter Elst A, Kamps WA, de Bont ES. Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells. Crit Rev Oncol Hematol 2009; 69: 187-198. https://doi.org/10.1016/j.critrevonc.2008.06.004 PMid:18675551.

  • 61.

    Shi Y, Du L, Lin L, Wang Y. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat Rev Drug Discov 2016; 16: 35-52. https://doi.org/10.1038/nrd.2016.193 PMid:27811929.

  • 62.

    Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315: 1650-1659. https://doi.org/10.1056/NEJM198612253152606 PMid:3537791.

  • 63.

    Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004; 4: 540-550. https://doi.org/10.1038/nrc1388 PMid:15229479.

  • 64.

    Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 2008; 15: 730-738. https://doi.org/10.1038/gt.2008.39 PMid:18401438.

  • 65.

    Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002; 62: 3603-3608.

  • 66.

    Son B, MarquezCurtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 2006; 24: 1254-1264. https://doi.org/10.1634/stemcells.2005-0271 PMid:16410389.

  • 67.

    Xie C, Yang Z, Suo Y, Chen Q, Wei D, Weng X, et al. Systemically infused mesenchymal stem cells show different homing profiles in healthy and tumor mouse models. Stem Cells Transl Med 2017; 6: 1120-1131. https://doi.org/10.1002/sctm.16-0204 PMid:28205428 PMCid:PMC5442841.

  • 68.

    Svensson A, Ramos-Moreno T, Eberstl S, Scheding S, Bengzon J. Identification of two distinct mesenchymal stromal cell populations in human malignant glioma. J Neurooncol 2017; 131: 245-254. https://doi.org/10.1007/s11060-016-2302-y PMid:27757723 PMCid:PMC5306185.

  • 69.

    Ahmadian Kia N, Bahrami AR, Ebrahimi M, Matin MM, Neshati Z, Almohaddesin MR, et al. Comparative analysis of chemokine receptor's expression in mesenchymal stem cells derived from human bone marrow and adipose tissue. J Mol Neurosci 2011; 44: 178-185. https://doi.org/10.1007/s12031-010-9446-6 PMid:20938756.

  • 70.

    Guo HT, Cai CQ, Schroeder RA, Kuo PC. Nitric oxide is necessary for CC-class chemokine expression in endotoxin-stimulated ANA-1 murine macrophages. Immunol Lett 2002; 80: 21-26. https://doi.org/10.1016/S0165-2478(01)00284-X.

  • 71.

    Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293: 1118-1128. https://doi.org/10.1152/ajpendo.00435.2007 PMid:17666485.

  • 72.

    Winner M, Koong A, Rendon B, Zundel W, Mitchell R. Amplification of Tumor Hypoxic Responses by Macrophage Migration Inhibitory Factor-Dependent Hypoxia-Inducible Factor Stabilization. Cancer Res. 2007 January 1; 67(1): 186-193. https://doi.org/10.1158/0008-5472.CAN-06-3292 PMid:17210698 PMCid:PMC2941512.

  • 73.

    Lazennec G, Lam PY. Recent discoveries concerning the tumor - mesenchymal stem cell interactions. Biochim Biophys Acta 2016; 1866: 290-299. https://doi.org/10.1016/j.bbcan.2016.10.004 PMid:27750042.

  • 74.

    Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest 2011; 121: 3804-3809. https://doi.org/10.1172/JCI57099 PMid:21965337 PMCid:PMC3223613.

  • 75.

    Yan XL, Jia YL, Chen L, Zeng Q, Zhou JN, Fu CJ, et al. Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis. Hepatology 2013; 57: 2274-2286. https://doi.org/10.1002/hep.26257 PMid:23316018.

  • 76.

    Guilloton F, Caron G, Mnard C, Pangault C, Am-Thomas P, Dulong J, et al. Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes. Blood 2012; 119: 2556-2567. https://doi.org/10.1182/blood-2011-08-370908 PMid:22289889.

  • 77.

    Behnan J, Isakson P, Joel M, Cilio C, Langmoen IA, Vik-Mo EO, Badn W. Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells 2014; 32: 1110-1123. https://doi.org/10.1002/stem.1614 PMid:24302539.

  • 78.

    Klopp AH, Zhang Y, Solley T, Amaya-Manzanares F, Marini F, Andreeff M, et al. Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors. Clin Cancer Res 2012; 18: 771-782. https://doi.org/10.1158/1078-432.CCR-11-1916 PMid:22167410 PMCid:PMC3481843.

  • 79.

    Bayo J, Fiore E, Aquino JB, Malvicini M, Rizzo M, Peixoto E, et al. Increased migration of human mesenchymal stromal cells by autocrine motility factor (AMF) resulted in enhanced recruitment towards hepatocellular carcinoma. PLoS One 2014; 9: e95171. https://doi.org/10.1371/journal.pone.0095171 PMid:24736611 PMCid:PMC3988162.

  • 80.

    Zhang T, Lee YW, Rui YF, Cheng TY, Jiang XH, Li G. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors. Stem Cell Res Ther 2013; 4: 70. https://doi.org/10.1186/scrt221 PMid:23763837 PMCid:PMC3707041.

  • 81.

    Wang M, Zhao X, Qiu R, Gong Z, Huang F, Yu W, et al. Lymph node metastasis-derived gastric cancer cells educate bone marrow-derived mesenchymal stem cells via YAP signaling activation by exosomal Wnt5a. Oncogene 2021; 40: 2296-2308. https://doi.org/10.1038/s41388-021-01722-8 PMid:33654199 PMCid:PMC7994201.

  • 82.

    Yang Y, Bucan V, Baehre H, Von Der Ohe J, Otte A, Hass R. Acquisition of new tumor cell properties by MSC-derived exosomes. Int J Oncol 2015; 47: 244-252. https://doi.org/10.3892/ijo.2015.3001 PMid:25963929.

  • 83.

    Figueroa J, Phillips LM, Shahar T, Hossain A, Gumin J, Kim H, et al. Exosomes from Glioma-Associated mesenchymal stem cells increase the tumorigenicity of Glioma stem-like cells via transfer of miR-1587. Cancer Res 2017; 77: 5808-5819. https://doi.org/10.1158/0008-5472.CAN-16-2524 PMid:28855213 PMCid:PMC5668150.

  • 84.

    Qiao L, Xu Z, Zhao T, Zhao Z, Shi M, Zhao RC, et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res 2008; 18: 500-507. https://doi.org/10.1038/cr.2008.40 PMid:18364678.

  • 85.

    Mirabdollahi M, Sadeghi-Aliabadi H, Javanmard SH. Human Wharton's jelly mesenchymal stem cells-derived secretome could inhibit breast cancer growth in vitro and in vivo. Iran J Basic Med Sci 2020; 23: 945-953.

  • 86.

    Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 2006; 203: 1235-1247. https://doi.org/10.1084/jem.20051921 PMid:16636132 PMCid:PMC2121206.

  • 87.

    Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H, et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 2004; 11: 1155-1164. https://doi.org/10.1038/sj.gt.3302276 PMid:15141157.

  • 88.

    Ohlsson LB, Varas L, Kjellman C, Edvardsen K, Lindvall M. Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix. Exp Mol Pathol 2003; 75: 248-255. https://doi.org/10.1016/j.yexmp.2003.06.001 PMid:14611816.

  • 89.

    Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One 2013; 8: e84256. https://doi.org/10.1371/journal.pone.0084256 PMid:24391924 PMCid:PMC3877259.

  • 90.

    Yu B, Zhang X, Li X. Acquisition of new tumor cell properties by MSC-derived exosomes. Int. J. Mol. Sci. 2014; 15: 4142- 4157. https://doi.org/10.3390/ijms15034142 PMid:24608926 PMCid:PMC3975389.

  • 91.

    Del Fattore A, Luciano R, Saracino R, Battafarano G, Rizzo C, Pascucci L, et al. Differential effects of extracellular vesicles secreted by mesenchymal stem cells from different sources on glioblastoma cells. Expert Opin Biol Ther 2015; 15: 495-504. https://doi.org/10.1517/14712598.2015.997706 PMid:25539575.

  • 92.

    Rivera-Cruz CM, Shearer JJ, Figueiredo Neto M, Figueiredo ML. The immunomodulatory effects of mesenchymal stem cell polarization within the tumor microenvironment niche. Stem Cells Int 2017; 2017: 4015039. https://doi.org/10.1155/2017/4015039 PMid:29181035 PMCid:PMC5664329.

  • 93.

    Sasser AK, Mundy BL, Smith KM, Studebaker AW, Axel AE, Haidet AM, et al. Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor environments. Cancer Lett 2007; 254: 255-264. https://doi.org/10.1016/j.canlet.2007.03.012 PMid:17467167.

  • 94.

    Li, Wei, Ying Zhou, Jin Yang, Xu Zhang, Huanhuan Zhang, Ting Zhang, Shaolin Zhao, Ping Zheng, Juan Huo, Huiyi Wu. Gastric cancer-derived mesenchymal stem cells prompt gastric cancer progression through secretion of interleukin-8. Journal of Experimental & Clinical Cancer Research 34, no. 1 (2015): 1-15. https://doi.org/10.1186/s13046-015-0172-3 PMid:25986392 PMCid:PMC4443537.

  • 95.

    Bruno S, Collino F, Iavello A, Camussi G. Effects of mesenchymal stromal cell-derived extracellular vesicles on tumor growth. Front Immunol 2014; 5: 382. https://doi.org/10.3389/fimmu.2014.00382 PMid:25157253 PMCid:PMC4127796.

  • 96.

    Yan XL, Fu CJ, Chen L, Qin JH, Zeng Q, Yuan HF, et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat 2012; 132: 153-164. https://doi.org/10.1007/s10549-011-1577-0 PMid:21584665.

  • 97.

    Melincovici CS, Boca AB, uman S, Mrginean M, Mihu C, Istrate M, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 2018; 59: 455-467.

  • 98.

    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-676. https://doi.org/10.1038/nm0603-669 PMid:12778165.

  • 99.

    Detmar M, Yeo KT, Nagy JA, Van de Water L, Brown LF, Berse B, et al. Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J Invest Dermatol 1995; 105: 44-50. https://doi.org/10.1111/1523-1747.ep12312542 PMid:7615975.

  • 100.

    Eming SA, Krieg T. Molecular mechanisms of VEGF-A action during tissue repair. J Investig Dermatology Symp Proc 2006; 11: 79-86. https://doi.org/10.1038/sj.jidsymp.5650016 PMid:17069014.

  • 101.

    Galiano RD, Tepper OM, Pelo CR, Bhatt KA, Callaghan M, Bastidas N, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol 2004; 164: 1935-1947. https://doi.org/10.1016/S0002-9440(10)63754-6.

  • 102.

    Frank S, Hbner G, Breier G, Longaker MT, Greenhalgh DG, Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem 1995; 270: 12607-12613. https://doi.org/10.1074/jbc.270.21.12607 PMid:7759509.

  • 103.

    Romano Di Peppe S, Mangoni A, Zambruno G, Spinetti G, Melillo G, Napolitano M, Capogrossi MC. Adenovirus-mediated VEGF(165) gene transfer enhances wound healing by promoting angiogenesis in CD1 diabetic mice. Gene Ther 2002; 9: 1271-1277. https://doi.org/10.1038/sj.gt.3301798 PMid:12224009.

  • 104.

    Howdieshell TR, Callaway D, Webb WL, Gaines MD, Procter CDJ, Sathyanarayana, et al. Antibody neutralization of vascular endothelial growth factor inhibits wound granulation tissue formation. J Surg Res 2001; 96: 173-182. https://doi.org/10.1006/jsre.2001.6089 PMid:11266270.

  • 105.

    Javan MR, Khosrojerdi A, Moazzeni SM. New insights into implementation of mesenchymal stem cells in cancer therapy: prospects for anti-angiogenesis treatment. Front Oncol 2019; 9: 1-17. https://doi.org/10.3389/fonc.2019.00840 PMid:31555593 PMCid:PMC6722482.

  • 106.

    Khoury CC, Ziyadeh FN. Angiogenic factors. Contrib Nephrol 2011; 170: 83-92. https://doi.org/10.1159/000324950 PMid:21659761.

  • 107.

    Yin J, Zeng F, Wu N, Kang K, Yang Z, Yang H. Interleukin-8 promotes human ovarian cancer cell migration by epithelial-mesenchymal transition induction in vitro. Clin Transl Oncol 2015; 17: 365-370. https://doi.org/10.1007/s12094-014-1240-4 PMid:25373532.

  • 108.

    Ucuzian AA, Gassman AA, East AT, Greisler HP. Molecular mediators of angiogenesis. J Burn Care Res 2010; 31: 158-175. https://doi.org/10.1097/BCR.0b013e3181c7ed82 PMid:20061852 PMCid:PMC2818794.

  • 109.

    Ocana A, Nieto-Jimnez C, Pandiella A, Templeton AJ. Neutrophils in cancer: prognostic role and therapeutic strategies. Mol Cancer 2017; 16: 1-7. https://doi.org/10.1186/s12943-017-0707-7 PMid:28810877 PMCid:PMC5558711.

  • 110.

    Tevis KM, Cecchi RJ, Colson YL, Grinstaff MW. Mimicking the tumor microenvironment to regulate macrophage phenotype and assessing chemotherapeutic efficacy in embedded cancer cell/macrophage spheroid models. Acta Biomater. 2017;50:271-279. doi:10.1016/j.actbio.2016.12.037. https://doi.org/10.1016/j.actbio.2016.12.037 PMid:28011141 PMCid:PMC5316313.

  • 111.

    Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309-322. https://doi.org/10.1016/j.ccr.2012.02.022 PMid:22439926.

  • 112.

    Liu Y, Han ZP, Zhang SS, Jing YY, Bu XX, Wang CY, et al. Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer. J Biol Chem 2011; 286: 25007-25015. https://doi.org/10.1074/jbc.M110.213108 PMid:21592963 PMCid:PMC3137074.

  • 113.

    Lee KE, Khoi PN, Xia Y, Park JS, Joo YE, Kim KK, et al. Helicobacter pylori and interleukin-8 in gastric cancer. World J Gastroenterol 2013; 19: 8192. https://doi.org/10.3748/wjg.v19.i45.8192 PMid:24363509 PMCid:PMC3857441.

  • 114.

    Kim JH, Frantz AM, Anderson KL, Graef AJ, Scott MC, Robinson S, et al. Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment. Exp Cell Res 2014; 323: 155-164. https://doi.org/10.1016/j.yexcr.2014.02.020 PMid:24582862 PMCid:PMC4256199.

  • 115.

    Komaki M, Numata Y, Morioka C, Honda I, Tooi M, Yokoyama N, et al. Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis. Stem Cell Res Ther 2017; 8: 1-12. https://doi.org/10.1186/s13287-017-0660-9 PMid:28974256 PMCid:PMC5627451##[117 Ren W, Hou J, Yang C, Wang H, Wu S, Wu Y, Zhao X, Lu C. 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: 1-14. https://doi.org/10.1186/s13046-019-1027-0 PMid:30736829 PMCid:PMC6367822.

  • 116.

    Zitvogel L, Apetoh L, Ghiringhelli F, Andr F, Tesniere A, Kroemer G. The anticancer immune response: indispensable for therapeutic success? J Clin Invest 2008; 118: 1991-2001. https://doi.org/10.1172/JCI35180 PMid:18523649 PMCid:PMC2396905.

  • 117.

    Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, Seliger B. Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 2005; 11: 2552-2560. https://doi.org/10.1158/1078-0432.CCR-04-2146 PMid:15814633.

  • 118.

    Shevach EM. Fatal attraction: tumors beckon regulatory T cells. Nat Med 2004; 10: 900-901. https://doi.org/10.1038/nm0904-900 PMid:15340410.

  • 119.

    Bogen B. Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma. Eur J Immunol 1996; 26: 2671-2679. https://doi.org/10.1002/eji.1830261119 PMid:8921954.

  • 120.

    Wu SZ, Roden DL, Wang C, Holliday H, Harvey K, Cazet AS, et al. Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J 2020; 39: e104063. https://doi.org/10.15252/embj.2019104063.

  • 121.

    Berger L, Shamai Y, Skorecki KL, Tzukerman M. Tumor specific recruitment and reprogramming of mesenchymal stem cells in tumorigenesis. Stem Cells 2016; 34: 1011-1026. https://doi.org/10.1002/stem.2269 PMid:26676563.

  • 122.

    Ren G, Zhao X, Wang Y, Zhang X, Chen X, Xu C, et al. CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNF. Cell Stem Cell 2012; 11: 812-824. https://doi.org/10.1016/j.stem.2012.08.013 PMid:23168163 PMCid:PMC3518598.

  • 123.

    Poggi A, Giuliani M. Mesenchymal stromal cells can regulate the immune response in the tumor microenvironment. Vaccines 2016; 4: 1-21. https://doi.org/10.3390/vaccines4040041 PMid:27834810 PMCid:PMC5192361.

  • 124.

    Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 2013; 13: 392-402. https://doi.org/10.1016/j.stem.2013.09.006 PMid:24094322.

  • 125.

    Giallongo C, Romano A, Parrinello NL, La Cava P, Brundo MV, Bramanti V, et al. Mesenchymal stem cells (MSC) regulate activation of granulocyte-like myeloid derived suppressor cells (G-MDSC) in chronic myeloid leukemia patients. PLoS One 2016; 11: e0158392. https://doi.org/10.1371/journal.pone.0158392 PMid:27391078 PMCid:PMC4938578.

  • 126.

    Giallongo C, Tibullo D, Parrinello NL, La Cava P, Di Rosa M, Bramanti V, et al. Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC). Oncotarget 2016; 7: 85764. https://doi.org/10.18632/oncotarget.7969 PMid:26967390 PMCid:PMC5349872.

  • 127.

    Galland S, Vuille J, Martin P, Letovanec I, Caignard A, Fregni G, Stamenkovic I. Tumor-derived mesenchymal stem cells use distinct mechanisms to block the activity of natural killer cell subsets. Cell Rep 2017; 20: 2891-2905. https://doi.org/10.1016/j.celrep.2017.08.089 PMid:28930684.

  • 128.

    Liotta F, Querci V, Mannelli G, Santarlasci V, Maggi L, Capone M, et al. Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation. Br J Cancer 2015; 112: 745-754. https://doi.org/10.1038/bjc.2015.15 PMid:25647013 PMCid:PMC4333504.

  • 129.

    Pelizzo G, Veschi V, Mantelli M, Croce S, Di Benedetto V, et al. Microenvironment in neuroblastoma: isolation and characterization of tumor-derived mesenchymal stromal cells. BMC Cancer 2018; 18: 1-12. https://doi.org/10.1186/s12885-018-5082-2 PMid:30482160 PMCid:PMC6260687.

  • 130.

    Arnulf B, Lecourt S, Soulier J, Ternaux B, Lacassagne MN, Crinquette A, et al. Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma. Leukemia 2007; 21: 158-163. https://doi.org/10.1038/sj.leu.2404466 PMid:17096013.

  • 131.

    Wang M, Chen B, Sun XX, Zhao XD, Zhao YY, Sun L, et al. Gastric cancer tissue-derived mesenchymal stem cells impact peripheral blood mononuclear cells via disruption of Treg/Th17 balance to promote gastric cancer progression. Exp Cell Res 2017; 361: 19-29. https://doi.org/10.1016/j.yexcr.2017.09.036 PMid:28964780.

  • 132.

    Cao W, Cao K, Cao J, Wang Y, Shi Y. Mesenchymal stem cells and adaptive immune responses. Immunol Lett 2015; 168: 147-153. https://doi.org/10.1016/j.imlet.2015.06.003 PMid:26073566.

  • 133.

    Ghannam S, Pne J, Torcy-Moquet G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 2010; 185: 302-312. https://doi.org/10.4049/jimmunol.0902007 PMid:20511548.

  • 134.

    Liu X, Ren S, Qu X, Ge C, Cheng K, Zhao RC. Mesenchymal stem cells inhibit Th17 cells differentiation via IFN--mediated SOCS3 activation. Immunol Res 2015; 61: 219-229. https://doi.org/10.1007/s12026-014-8612-2 PMid:25588866.

  • 135.

    Tumangelova-Yuzeir K, Naydenov E, Ivanova-Todorova E, Krasimirova E, Vasilev G, Nachev S, Kyurkchiev D. Mesenchymal stem cells derived and cultured from glioblastoma multiforme increase tregs, downregulate Th17, and induce the tolerogenic phenotype of monocyte-derived cells. Stem Cells Int 2019; 2019: 1-15. https://doi.org/10.1155/2019/6904638 PMid:31191680 PMCid:PMC6525812.

  • 136.

    Ghosh T, Barik S, Bhuniya A, Dhar J, Dasgupta S, Ghosh S, et al. Tumor-associated mesenchymal stem cells inhibit nave T cell expansion by blocking cysteine export from dendritic cells. Int J Cancer 2016; 139: 2068-2081. https://doi.org/10.1002/ijc.30265 PMid:27405489.

  • 137.

    Sineh Sepehr K, Razavi A, Hassan ZM, Fazel A, Abdollahpour-Alitappeh M, Mossahebi-Mohammadi M, et al. Comparative immunomodulatory properties of mesenchymal stem cells derived from human breast tumor and normal breast adipose tissue. Cancer Immunol Immunother 2020; 69: 1841-1854. https://doi.org/10.1007/s00262-020-02567-y PMid:32350594.

  • 138.

    Bergers G, Fendt SM. The metabolism of cancer cells during metastasis. Nat Rev Cancer 2021; 21: 162-180. https://doi.org/10.1038/s41568-020-00320-2 PMid:33462499.

  • 139.

    Osmani F, Rasekhi A, Hajizadeh E, Akbari ME. Simultaneous modeling of multiple recurrences in breast cancer patients. Koomesh. 2020 Apr 10;22(2):359-64. https://doi.org/10.29252/koomesh.22.2.359.

  • 140.

    Komoda H, Okura H, Lee CM, Sougawa N, Iwayama T, Hashikawa T, Saga A, Yamamoto-Kakuta A, Ichinose A, Murakami S, Sawa Y, Matsuyama A. Reduction of N-glycolylneuraminic acid xenoantigen on human adipose tissue-derived stromal cells/mesenchymal stem cells leads to safer and more useful cell sources for various stem cell therapies. Tissue Eng Part A. 2010 Apr;16(4):1143-55. https://doi.org/10.1089/ten.tea.2009.0386 PMid:19863253.

  • 141.

    Lim EJ, Suh Y, Kim S, Kang SG, Lee SJ. Force-mediated proinvasive matrix remodeling driven by tumor-associated mesenchymal stem-like cells in glioblastoma. BMB Rep 2018; 51: 182-187. https://doi.org/10.5483/BMBRep.2018.51.4.185 PMid:29301607 PMCid:PMC5933213.

  • 142.

    Lim EJ, Suh Y, Yoo KC, Lee JH, Kim IG, Kim MJ, et al. Tumor-associated mesenchymal stem-like cells provide extracellular signaling cue for invasiveness of glioblastoma cells. Oncotarget 2017; 8: 1438-1448. https://doi.org/10.18632/oncotarget.13638 PMid:27903965 PMCid:PMC5352067.

  • 143.

    Turley EA, Noble PW, Bourguignon LY. Signaling properties of hyaluronan receptors. J Biol Chem 2002; 277: 4589-4592. https://doi.org/10.1074/jbc.R100038200 PMid:11717317.

  • 144.

    Toole BP. Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities. Clin Cancer Res 2009; 15: 7462-7468. https://doi.org/10.1158/1078-0432.CCR-09-0479 PMid:20008845 PMCid:PMC2796593.

  • 145.

    Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 2004; 4: 528-539. https://doi.org/10.1038/nrc1391 PMid:15229478.

  • 146.

    Zhang X, Hu F, Li G, Li G, Yang X, Liu L, Zhang R, Zhang B, Feng Y. Human colorectal cancer-derived mesenchymal stem cells promote colorectal cancer progression through IL-6/JAK2/STAT3 signaling. Cell death & disease. 2018 Jan 18;9(2):1-3. https://doi.org/10.1038/s41419-017-0176-3 PMid:29348540 PMCid:PMC5833830.

  • 147.

    Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics 2010; 73: 1907-1920. https://doi.org/10.1016/j.jprot.2010.06.006 PMid:20601276.

  • 148.

    Heidari N, Abbasi H, Namaki S, Hashemi SM. Application of extracellular vesicles in the treatment of inflammatory bowel disease. Koomesh. 2020 Apr 10;22(2):209-19. https://doi.org/10.29252/koomesh.22.2.209.

  • 149.

    Skog J, Wrdinger T, Van Rijn S, Meijer DH, Gainche L, Curry WT, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10: 1470-1476. https://doi.org/10.1038/ncb1800 PMid:19011622 PMCid:PMC3423894.

  • 150.

    Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 2012; 151: 1542-1556. https://doi.org/10.1016/j.cell.2012.11.024 PMid:23260141.

  • 151.

    Wang M, Zhao C, Shi H, Zhang B, Zhang L, Zhang X, et al. Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer. Br J Cancer 2014; 110: 1199-1210. https://doi.org/10.1038/bjc.2014.14 PMid:24473397 PMCid:PMC3950864.

  • 152.

    Roccaro AM, Scadden DT, Ghobrial IM, Roccaro AM, Sacco A, Maiso P, et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest 2013; 123: 1542-1555. https://doi.org/10.1172/JCI66517 PMid:23454749 PMCid:PMC3613927.

  • 153.

    Nakata R, Shimada H, Fernandez GE, Fanter R, Fabbri M, Malvar J, et al. Contribution of neuroblastoma-derived exosomes to the production of pro-tumorigenic signals by bone marrow mesenchymal stromal cells. J Extracell vesicles 2017; 6: 1332941. https://doi.org/10.1080/20013078.2017.1332941 PMid:28717423 PMCid:PMC5505006.

  • 154.

    Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: Cancer-associated fibroblasts and their markers. Int J Cancer 2020; 146: 895-905. https://doi.org/10.1002/ijc.32193 PMid:30734283 PMCid:PMC6972582.

  • 155.

    Tommelein J, Verset L, Boterberg T, Demetter P, Bracke M, De Wever O. Cancer-associated fibroblasts connect metastasis-promoting communication in colorectal cancer. Front Oncol 2015; 5: 1-11. https://doi.org/10.3389/fonc.2015.00063 PMid:25853091 PMCid:PMC4369728.

  • 156.

    Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 2020; 20: 174-186. https://doi.org/10.1038/s41568-019-0238-1 PMid:31980749 PMCid:PMC7046529.

  • 157.

    Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014; 159: 80-93. https://doi.org/10.1016/j.cell.2014.08.007 PMid:25259922 PMCid:PMC4177038.

  • 158.

    Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-Dependent manner. Cancer Cell 2010; 17: 135-147. https://doi.org/10.1016/j.ccr.2010.04.018 https://doi.org/10.1016/j.ccr.2009.12.041 PMid:20138012.

  • 159.

    Paunescu V, Bojin FM, Tatu CA, Gavriliuc OI, Rosca A, Gruia AT, et al. Tumour-associated fibroblasts and mesenchymal stem cells: more similarities than differences. J Cell Mol Med 2011; 15: 635-646. https://doi.org/10.1111/j.1582-4934.2010.01044.x PMid:20184663 PMCid:PMC3922385.

  • 160.

    Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Kodama M, Higashi Y, et al. Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer 2010; 127: 2323-2333. https://doi.org/10.1002/ijc.25440 PMid:20473928.

  • 161.

    Madar S, Goldstein I, Rotter V. 'Cancer associated fibroblasts'--more than meets the eye. Trends Mol Med 2013; 19: 447-453. https://doi.org/10.1016/j.molmed.2013.05.004 PMid:23769623.

  • 162.

    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006; 6: 392-401. https://doi.org/10.1038/nrc1877 PMid:16572188.

  • 163.

    Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 2011; 19: 257-272. https://doi.org/10.1016/j.ccr.2011.01.020 PMid:21316604 PMCid:PMC3060401.

  • 164.

    Tirino V, Desiderio V, Paino F, De Rosa A, Papaccio F, Fazioli F, et al. Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo. FASEB J 2011; 25: 2022-2030. https://doi.org/10.1096/fj.10-179036 PMid:21385990.

  • 165.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674. https://doi.org/10.1016/j.cell.2011.02.013 PMid:21376230.

  • 166.

    Ren F, Sheng WQ, Du X. CD133: a cancer stem cells marker, is used in colorectal cancers. World J Gastroenterol 2013; 19: 2603-2611. https://doi.org/10.3748/wjg.v19.i17.2603 PMid:23674867 PMCid:PMC3645378.

  • 167.

    Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 2008; 118: 2111-2120. https://doi.org/10.1172/JCI34401 PMid:18497886 PMCid:PMC2391278.

  • 168.

    Diaz-Cano SJ. Tumor heterogeneity: mechanisms and bases for a reliable application of molecular marker design. Int J Mol Sci 2012; 13: 1951-2011. https://doi.org/10.3390/ijms13021951 PMid:22408433 PMCid:PMC3292002.

  • 169.

    Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F, et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 2011; 71: 614-624. https://doi.org/10.1158/0008-5472.CAN-10-0538 PMid:21224357 PMCid:PMC3100554.

  • 170.

    Wu XB, Liu Y, Wang GH, Xu X, Cai Y, Wang HY, et al. Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-B activation. Sci Rep 2016; 6: 1-12. https://doi.org/10.1038/srep21420 PMid:26892992 PMCid:PMC4759824.

  • 171.

    Luo J, Lee SO, Cui Y, Yang R, Li L, Chang C. Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2/androgen receptor signals. Oncotarget 2015; 6: 27555-27565. https://doi.org/10.18632/oncotarget.4515 PMid:26342197 PMCid:PMC4695008.

  • 172.

    van der Zee M, Sacchetti A, Cansoy M, Joosten R, Teeuwssen M, Heijmans-Antonissen C, et al. IL6/JAK1/STAT3 signaling blockade in endometrial cancer affects the ALDHhi/CD126+ stem-like component and reduces tumor burden. Cancer Res 2015; 75: 3608-3622. https://doi.org/10.1158/0008-5472.CAN-14-2498 PMid:26130650.

  • 173.

    Caplan AI. Mesenchymal stem cells. J Orthop Res 1991; 9: 641-650. https://doi.org/10.1002/jor.1100090504 PMid:1870029##.

  • 174.

    Orbay H, Tobita M, Mizuno H. Mesenchymal stem cells isolated from adipose and other tissues: basic biological properties and clinical applications. Stem Cells Int 2012; 2012. https://doi.org/10.1155/2012/461718 PMid:22666271 PMCid:PMC3361347.

  • 175.

    Ciavarella S, Dominici M, Dammacco F, Silvestris F. Mesenchymal stem cells: a new promise in anticancer therapy. Stem Cells Dev 2011; 20: 1-10. https://doi.org/10.1089/scd.2010.0223 PMid:20670160.

  • 176.

    Dai LJ, Moniri MR, Zeng ZR, Zhou JX, Rayat J, Warnock GL. Potential implications of mesenchymal stem cells in cancer therapy. Cancer Lett 2011; 305: 8-20. https://doi.org/10.1016/j.canlet.2011.02.012 PMid:21396770.

  • 177.

    Shahrabi S, Mansournezhad S, Azizidoost S, Jorfi F, Saki N. Challenges for treatment of cardiovascular diseases based on stem cells. Koomesh. 2019 Jun 10;21(3):395-407.

  • 178.

    Chang KA, Lee JH, Suh YH. Therapeutic potential of human adipose-derived stem cells in neurological disorders. J Pharmacol Sci 2014; 126: 293-301. https://doi.org/10.1254/jphs.14R10CP PMid:25409785.

  • 179.

    Kamalabadi-Farahani M, Vasei M, Ahmadbeigi N, Ebrahimi-Barough S, Soleimani M, Roozafzoon R. Anti-tumour effects of TRAIL-expressing human placental derived mesenchymal stem cells with curcumin-loaded chitosan nanoparticles in a mice model of triple negative breast cancer. Artif Cells Nanomedicine Biotechnol 2018; 46: S1011-S1021. https://doi.org/10.1080/21691401.2018.1527345 PMid:30580635.

  • 180.

    Bahman Soufiani K, Pourfathollah AA, Nikougoftar Zarifi M, Arefian E. Tumor microenvironment changing through application of microRNA-34a related mesenchymal stem cells conditioned medium: modulation of breast cancer cells toward non-aggressive behavior. Iran J Allergy Asthma Immunol 2021; 20: 221-232. https://doi.org/10.18502/ijaai.v20i2.6055 PMid:33904680.

  • 181.

    Hombach AA, Geumann U, Gnther C, Hermann FG, Abken H. IL7-IL12 engineered mesenchymal stem cells (MSCs) improve A CAR T cell attack against colorectal cancer cells. Cells 2020; 9: 873. https://doi.org/10.3390/cells9040873 PMid:32260097 PMCid:PMC7226757##.

  • 182.

    Babajani A, Soltani P, Jamshidi E, Farjoo MH, Niknejad H. Recent advances on drug-loaded mesenchymal stem cells with anti-neoplastic agents for targeted treatment of cancer. Front Bioeng Biotechnol 2020; 8: 1-19. https://doi.org/10.3389/fbioe.2020.00748 PMid:32793565 PMCid:PMC7390947.

  • 183.

    Moradian Tehrani R, Verdi J, Noureddini M, Salehi R, Salarinia R, Mosalaei M, et al. Mesenchymal stem cells: A new platform for targeting suicide genes in cancer. J Cell Physiol 2018; 233: 3831-3845. https://doi.org/10.1002/jcp.26094 PMid:28703313.

  • 184.

    Sabet MN, Esfeh MK, Nasrabadi N, Shakarami M, Alani B, Alimolaie A, et al. Mesenchymal stem cells as professional actors in gastrointestinal cancer therapy: From Nave to genetically modified. Iran J Basic Med Sci 2021; 24: 561-576.

  • 185.

    Torsvik A, Bjerkvig R. Mesenchymal stem cell signaling in cancer progression. Cancer Treat Rev 2013; 39: 180-188. https://doi.org/10.1016/j.ctrv.2012.03.005 PMid:22494966.

  • 186.

    Xu H, Zhou Y, Li W, Zhang B, Zhang H, Zhao S, et al. Tumor-derived mesenchymal-stem-cell-secreted IL-6 enhances resistance to cisplatin via the STAT3 pathway in breast cancer. Oncol Lett 2018; 15: 9142-9150. https://doi.org/10.3892/ol.2018.8463 PMid:29844821 PMCid:PMC5958889##.

  • 187.

    Ren T, Shan J, Qing Y, Qian C, Li Q, Lu G, et al. Sequential treatment with AT-101 enhances cisplatin chemosensitivity in human non-small cell lung cancer cells through inhibition of apurinic/apyrimidinic endonuclease 1-activated IL-6/STAT3 signaling pathway. Drug Des Devel Ther 2014; 8: 2517-2529. https://doi.org/10.2147/DDDT.S71432 PMid:25548514 PMCid:PMC4271790.

  • 188.

    Rodriguez-Barrueco R, Yu J, Saucedo-Cuevas LP, Olivan M, Llobet-Navas D, Putcha P, et al. Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers. Genes Dev 2015; 29: 1631-1648. https://doi.org/10.1101/gad.262642.115 PMid:26227964 PMCid:PMC4536311.

  • 189.

    Lee HY, Hong IS. Double-edged sword of mesenchymal stem cells: Cancer-promoting versus therapeutic potential. Cancer Sci 2017; 108: 1939-1946. https://doi.org/10.1111/cas.13334 PMid:28756624 PMCid:PMC5623746.

  • 190.

    Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005; 7: 513-520. https://doi.org/10.1016/j.ccr.2005.05.024 PMid:15950901.

  • 191.

    Li P, Gong Z, Shultz LD, Ren G. Mesenchymal stem cells: From regeneration to cancer. Pharmacol Ther 2019; 200: 42-54.##https://doi.org/10.1016/j.pharmthera.2019.04.005 PMid:30998940 PMCid:PMC6626571.