Human Wharton’s jelly mesenchymal stem cells-derived secretome could inhibit breast cancer growth in vitro and in vivo

Document Type : Original Article

Authors

1 Applied Physiology Research Center, Cardiovascular Research Institute, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Medicinal Chemistry Department, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Objective(s): Controversial results have been reported regarding the anti-tumor properties of extracellular vesicles derived from mesenchymal stem cells (MSCs). The present study was conducted to evaluate whether secretome derived from Human Wharton’s jelly mesenchymal stem cells (hWJMSCs) may stimulate or inhibit breast cancer growth in vitro and in vivo.
Materials and Methods: MTT assays was performed to determine anti-tumor effects of hWJMSCs-secretome on both MCF-7 and 4T1 tumor cells in vitro. Afterward, 4T1 breast tumors were established in different groups of Balb/C mice (12 mice/group). The tumor sizes were monitored in different treatment groups and at day 30 post-tumor inoculation (PTI), blood samples were obtained and 6 mice of each group were sacrificed for hematological and histopathological assays. The rest of the mice in each group (n=6) were left alive up to day 120 PTI to determine survival rate.
Results: We found that hWJMSCs-secretome can inhibit growth of MCF-7 and 4T1 tumor cell lines in vitro. Moreover, intratumoral administration of hWJMSCs-secretome resulted in significant tumor growth inhibition and improvement of hematological indices in vivo and prolonged survival rate of tumor bearing mice.
Conclusion: According to our findings, hWJMSCs-secretome could be considered a potent anti-tumor agent, however, further investigation should be done on other cancer models.

Keywords

References

1. Usha L, Rao G, Christopherson II K, Xu X. Mesenchymal stem cells develop tumor tropism but do not accelerate breast cancer tumorigenesis in a somatic mouse breast cancer model. PloS one 2013; 8:e67895.
2. 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.
3. Tabatabaei M, Mosaffa N, Ghods R, Nikoo S, Kazemnejad S, Khanmohammadi M, et al. Vaccination with human amniotic epithelial cells confer effective protection in a murine model of Colon adenocarcinoma. Int J cancer 2018; 142:1453-1466.
4. Yang J, Lv K, Sun J, Guan J. Anti-tumor effects of engineered mesenchymal stem cells in colon cancer model. Cancer Manag Res 2019; 11:8443-8450.
5. Ahn J-O, Coh Y-R, Lee H-W, Shin I-S, Kang S-K, Youn H-Y. Human adipose tissue-derived mesenchymal stem cells inhibit melanoma growth in vitro and in vivo. Anticancer Res 2015; 35:159-168.
6. 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.
7. Secchiero P, Zorzet S, Tripodo C, Corallini F, Melloni E, Caruso L, et al. Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin’s lymphoma xenografts. PloS one 2010; 5:e11140.
8. Ayuzawa R, Doi C, Rachakatla RS, Pyle MM, Maurya DK, Troyer D, et al. Naive human umbilical cord matrix derived stem cells significantly attenuate growth of human breast cancer cells in vitro and in vivo. Cancer Lett 2009; 280:31-37.
9. Fatima F, Nawaz M. Stem cell-derived exosomes: roles in stromal remodeling, tumor progression, and cancer immunotherapy. Chin J Cancer 2015; 34:541-553.
10. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther 2015; 23:812-823.
11. Webber J, Yeung V, Clayton A, editors. Extracellular vesicles as modulators of the cancer microenvironment. Semin Cell  Dev Biol; 201;40:27-34.
12. Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C, et al. Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics 2018; 8:1399-1410.
13. Wang X, Omar O, Vazirisani F, Thomsen P, Ekström K. Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation. PloS one 2018; 13:e0193059.
14. 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.
15. Moore C, Kosgodage U, Lange S, Inal JM. The emerging role of exosome and microvesicle‐(EMV‐) based cancer therapeutics and immunotherapy. Int J Cancer 2017; 141:428-436.
16. Wang J, Zheng Y, Zhao M. Exosome-Based Cancer Therapy: Implication for Targeting Cancer Stem Cells. Front Pharmacol 2017; 7:533-544.
17. Bruno S, Collino F, Deregibus MC, Grange C, Tetta C, Camussi G. Microvesicles Derived from Human bone marrow Mesenchymal Stem Cells Inhibit Tumor Growth. Stem Cells Dev 2013; 22:758-771.
18. Ji Y, Ma Y, Chen X, Ji X, Gao J, Zhang L, Hu J. Microvesicles released from human embryonic stem cell derived-mesenchymal stem cells inhibit proliferation of leukemia cells. Oncol Rep 2017; 38:1013-1020.
19. Wu S, Ju GQ, Du T, Zhu YJ, Liu GH. Microvesicles derived from human umbilical cord Wharton’s jelly mesenchymal stem cells attenuate bladder tumor cell growth in vitro and in vivo. PloS one 2013; 8:e61366-e61366.
20. Lindoso RS, Collino F, Vieyra A. Extracellular vesicles as regulators of tumor fate: crosstalk among cancer stem cells, tumor cells and mesenchymal stem cells. Stem Cell Investig 2017; 4:75-89.
21. Bruno S, Collino F, Iavello A, Camussi G. Effects of mesenchymal stromal cell-derived extracellular vesicles on tumor growth. Front Immunol 2014; 5:382-387.
22. Wu J, Qu Z, Fei ZW, Wu JH, Jiang CP. Role of stem cell-derived exosomes in cancer. Oncol Lett 2017; 13:2855-2866.
23. Lu L, Liu Y, Yang S, Zhao Q, Wang X, Gong W, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006; 91:1017-1026.
24. Kadir EA, Sulaiman SA, Yahya NK, Othman NH. Inhibitory effects of tualang honey on experimental breast cancer in rats: a preliminary study. Asian Pac J Cancer Prev 2013; 14:2249-2254.
25. Roberti NE. The role of histologic grading in the prognosis of patients with carcinoma of the breast. Cancer 1997; 80:1708-1716.
26. 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; 10:134-142.
27. Hendijani F, Javanmard SH, Sadeghi-aliabadi H. Human Wharton’s jelly mesenchymal stem cell secretome display antiproliferative effect on leukemia cell line and produce additive cytotoxic effect in combination with doxorubicin. Tissue Cell 2015; 47:229-234.
28. Mirabdollahi M, Haghjooyjavanmard S, Sadeghi-aliabadi H. An anticancer effect of umbilical cord-derived mesenchymal stem cell secretome on the breast cancer cell line. Cell Tissue Bank 2019; 20:423-434.
29. Lee H-Y, Hong I-S. Double-edged sword of mesenchymal stem cells: Cancer-promoting versus therapeutic potential. Cancer Sci 2017; 108:1939-1946.
30. Xu S, De Veirman K, De Becker A, Vanderkerken K, Van Riet I. Mesenchymal stem cells in multiple myeloma: a therapeutical tool or target? Leukemia 2018; 32:1500-1514.
31. Munson P, Shukla A. Exosomes: Potential in cancer diagnosis and therapy. Medicines (Basel) 2015; 2:310-327.
32. Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubet R, Sigman CC. Chemopreventive drug development: perspectives and progress. Cancer Epidemiol Biomarkers  Prev 1994; 3:85-98.
33. Bhome R, Del Vecchio F, Lee G-H, Bullock MD, Primrose JN, Sayan AE, et al. Exosomal microRNAs (exomiRs): Small molecules with a big role in cancer. Cancer Lett 2018; 420:228-235.
34. Muralidharan-Chari V, Clancy JW, Sedgwick A, D’Souza-Schorey C. Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci 2010; 123:1603-1611.
35. Barrett JC. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ Health Perspect 1993; 100:9-20.
36. Sánchez AM, Berra HH, Graciela Scharovsky O, Matar P, Gervasoni SI, Rozados VR. Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity. Ann Oncol 2004; 15:1543-1550.
37. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: Toward Cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci 2017; 18:1852-1876.
38. da Silva Meirelles L, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine  Growth Factor Rev 2009; 20:419-427.
39. Akinbami A, Popoola A, Adediran A, Dosunmu A, Oshinaike O, Adebola P, et al. Full blood count pattern of pre-chemotherapy breast cancer patients in Lagos, Nigeria. Caspian J Inter Med  2013; 4:574-579.
40. Shrivastava S, Singh N, Nigam AK, Chandel SS, Shrivastava R, Kumar S. Comparative study of hematological parameters along with effect of chemotherapy and radiotherapy in different stages of breast cancer. Inter J Res Med Sci 2017;5:311-315.
41. Dalton LW, Pinder SE, Elston CE, Ellis IO, Page DL, Dupont WD, et al. Histologic grading of breast cancer: Linkage of patient outcome with level of pathologist agreement. Mod Pathol 2000; 13:730-735.
Iranian Journal of Basic Medical Sciences
Volume 23, Issue 7
July 2020
Pages 945-953

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