Role of the mesenchymal stem cells derived from adipose tissue in changing the rate of breast cancer cell proliferation and autophagy, in vitro and in vivo

Document Type : Original Article


1 Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

3 Department of Immunology, Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran

4 Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

5 Abadan Faculty of Medical Science, Abadan, Iran


Objective(s): Autophagy is an intracellular degradation system of damaged proteins and organelles; however, the role of autophagy in the progression of cancer remains unclear. In recent years, mesenchymal stem cell (MSC)-based approaches have attracted considerable attention for anti-cancer therapy. The present study aimed to examine the interaction of MSCs with the breast cancer cells under autophagy-induced conditions.
Materials and Methods: In this study, MSCs isolated from human adipose tissue were co-cultured with MDA-MB 231, a breast cancer cell line, and the autophagy process was induced by tunicamycin treatment. The cell viability was monitored by the MTT assay, and the cells were recovered at different time intervals (24 or 48 hours) to determine autophagy markers such as Beclin, mTOR and the ratio of LC3II/I expression. Additionally, the animal study was conducted using a mouse model of breast cancer treated with isogenic adipose-derived MSCs, and the expression of Beclin and Ki67 was determined using immunohistochemistry in breast tumor tissue.
Results: In cancer cells co-cultured with MSCs, the cell proliferation was increased, the Beclin expression and the LC3II/I protein ratio were decreased, and the mTOR expression was increased in MDA-MB 231 upon co-cultured with MSCs. Direct injection of MSCs to a mouse model of breast cancer showed an increase in tumor volume, an increase in the accumulation of Ki67 and a decrease in the Beclin expression in tumor tissues.
Conclusion: The data may suggest that suppressed autophagy in breast cancer cells is probably a mechanism by which MSCs can induce cancer cell proliferation.


1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
2. Turashvili G, Brogi E. Tumor heterogeneity in breast cancer. Front Med 2017;4:227-237.
3. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA 2019;321:288-300.
4. Timaner M, Tsai K, Shaked Y, editors. The multifaceted role of mesenchymal stem cells in cancer. Semin Cancer Biol 2019: Elsevier.
5. Cheng S, Nethi SK, Rathi S, Layek B, Prabha S. Engineered mesenchymal stem cells for targeting solid tumors: therapeutic potential beyond regenerative therapy. J Pharmacol Exp Ther 2019;370:231-241.
6. Martin F, Dwyer RM, Kelly J, Khan S, Murphy J, Curran C, et al. Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res Treat 2010;124:317-326.
7. Ohta N, Ishiguro S, Kawabata A, Uppalapati D, Pyle M, Troyer D, et al. Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes. PLoS One 10:e0123756.
8.    Maurya DK, Doi C, Kawabata A, Pyle MM, King C, Wu Z, et al. Therapy with un-engineered naive rat umbilical cord matrix stem cells markedly inhibits growth of murine lung adenocarcinoma. BMC cancer 2010;10:590-599.
9.    Kamdje AHN, Etet PFS, Lukong KE. Mesenchymal stem cell therapy for breast cancer: Challenges remaining. Int J Biomed Sci 2015;2:129-141.
10.    Adelipour M, Allameh A, Tavangar S, Hassan Z, Soleimani M. Inhibition of breast tumor growth and abnormal angiogenesis in mice treated with endothelial cells and their progenitor mesenchymal stem cells derived from bone marrow. Neoplasma 2016;6:911-924.
11.    Maycotte P, Thorburn A. Targeting autophagy in breast cancer. World J Clin Oncol 2014;5:224-240.
12.    Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer 2017;17:528-542.
13.    Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008;451:1069-1075.
14.    YANG Yp, LIANG Zq, GU Zl, QIN Zh. Molecular mechanism and regulation of autophagy 1. Acta Pharmacol Sin 2005;26:1421-1434.
15.    Jung CH, Ro S-H, Cao J, Otto NM, Kim D-H. mTOR regulation of autophagy. FEBS Lett 2010;584:1287-1295.
16.    Easton J, Houghton PJ. mTOR and cancer therapy. Oncogene 2006;25:6436-6446.
17.    Wang C-W, Klionsky DJ. The molecular mechanism of autophagy. Mol Med 2003;9:65-76.
18.    He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93.
19.    Kazemnejad S, Allameh A, Soleimani M, Gharehbaghian A, Mohammadi Y, Amirizadeh N, et al. Biochemical and molecular characterization of hepatocyte‐like cells derived from human bone marrow mesenchymal stem cells on a novel three‐dimensional biocompatible nanofibrous scaffold. J Gastroenterol Hepatol 2009;24:278-287.
20.    Ho IA, Toh HC, Ng WH, Teo YL, Guo CM, Hui KM, et al. Human bone marrow‐derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. Stem Cells 2013;31:146-155.
21.    Fritz V, Jorgensen C. Mesenchymal stem cells: an emerging tool for cancer targeting and therapy. Curr Stem Cell Res Ther 2008;3:32-42.
22.    Cho JA, Park H, Kim HK, Lim EH, Seo SW, Choi JS, et al. Hyperthermia‐treated mesenchymal stem cells exert antitumor effects on human carcinoma cell line. Cancer 2009;115:311-323.
23.    Li L, Pan J, Cai X, Gong E, Xu C, Zheng H, et al. Human umbilical cord mesenchymal stem cells suppress lung cancer via TLR4/NF-κB signalling pathway. Biotechnol Biotechnol Equip 2020;34:24-29.
24.    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.
25.    Yu JM, Jun ES, Bae YC, Jung JS. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo. Stem Cells Dev 2008;17:463-474.
26.    Hung S-P, Yang M-H, Tseng K-F, Lee OK. Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant 2013;22:1869-1882.
27.    Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, et al. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. Cell Death Dis 2019;10:1-13.
28.    Zhao Q, Ren H, Han Z. Mesenchymal stem cells: Immunomodulatory capability and clinical potential in immune diseases. J Cell Immunother 2016;2:3-20.
29.    Gunawardena TNA, Rahman MT, Abdullah BJJ, Abu Kasim NH. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. J Tissue Eng Regen Med 2019;13:569-586.
30.    Maffey A, Storini C, Diceglie C, Martelli C, Sironi L, Calzarossa C, et al. Mesenchymal stem cells from tumor microenvironment favour breast cancer stem cell proliferation, cancerogenic and metastatic potential, via ionotropic purinergic signalling. Sci Rep 2017;7:1-9.
31.    Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2012;45:487-498.
32.    Debnath J, Baehrecke EH, Kroemer G. Does autophagy contribute to cell death? Autophagy 2005;1:66-74.
33.    Chang S-J, Ou-Yang F, Tu H-P, Lin C-H, Huang S-H, Kostoro J, et al. Decreased expression of autophagy protein LC3 and stemness (CD44+/CD24−/low) indicate poor prognosis in triple-negative breast cancer. Hum Pathol 2016;48:48-55.
34.    Luhr M, Torgersen ML, Szalai P, Hashim A, Brech A, Staerk J, et al. The kinase PERK and the transcription factor ATF4 play distinct and essential roles in autophagy resulting from tunicamycin-induced ER stress. J Biol Chem 2019;294:8197-8217.
35.    Chen J, Wang Q, Feng X, Zhang Z, Geng L, Xu T, et al. Umbilical cord-derived mesenchymal stem cells suppress autophagy of T cells in patients with systemic lupus erythematosus via transfer of mitochondria. Stem Cells Int 2016;2016:1-16.
36.    Song G, Liu D, Geng X, Ma Z, Wang Y, Xie W, et al. Bone marrow-derived mesenchymal stem cells alleviate severe acute pancreatitis-induced multiple-organ injury in rats via suppression of autophagy. Exp Cell Res 2019;385:111674.
37.    He H, Zeng Q, Huang G, Lin Y, Lin H, Liu W, et al. Bone marrow mesenchymal stem cell transplantation exerts neuroprotective effects following cerebral ischemia/reperfusion injury by inhibiting autophagy via the PI3K/Akt pathway. Brain Res 2019;1707:124-132.
38.    Xiang J, Jiang T, Zhang W, Xie W, Tang X, Zhang J. Human umbilical cord-derived mesenchymal stem cells enhanced HK-2 cell autophagy through MicroRNA-145 by inhibiting the PI3K/AKT/mTOR signaling pathway. Exp Cell Res 2019;378:198-205.
39.    Li Y, Yang R, Guo B, Zhang H, Zhang H, Liu S, et al. Exosomal miR-301 derived from mesenchymal stem cells protects myocardial infarction by inhibiting myocardial autophagy. Biochem Biophys Res Commun 2019;514:323-328.