Volume 30, Issue 143 (November & December 2022)                   J Adv Med Biomed Res 2022, 30(143): 477-485 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Mirzaei S, Hushmandi K, Entezari M, Bahonar A, Raei M, Akbari M E. Mesenchymal Stem Cells Trigger Epithelial to Mesenchymal Transition in the HT-29 Colorectal Cancer Cell Line. J Adv Med Biomed Res 2022; 30 (143) :477-485
URL: http://journal.zums.ac.ir/article-1-6459-en.html
Mesenchymal Stem Cells Trigger Epithelial to Mesenchymal Transition in the HT-29 Colorectal Cancer Cell Line
Sepideh Mirzaei1 , Kiavash Hushmandi2 , Maliheh Entezari3 , Alireza Bahonar2 , Mehdi Raei4 , Mohammad Esmaeil Akbari *5
1- Dept. of Biology, Faculty of Sciences, Islamic Azad University, Sciences and Research Branch, Tehran, Iran
2- Dept. of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
3- Dept. of Genetics, Islamic Azad University, Tehran Medical Sciences, Branch, Tehran, Iran
4- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
5- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran , profmeakbari@gmail.com
Abstract:   (30904 Views)

Background and Objective: Mesenchymal stem cells (MSCs) promote metastasis in colorectal cancer; however, the mechanism underlying this process is not fully understood. Epithelial to mesenchymal transition (EMT) is a key step in tumor acquisition of metastatic phenotype. We aimed to investigate the effect of MSCs on the expression of EMT markers, as well as cancer stem cell markers in HT-29 colorectal cancer cells.
Materials and Methods: MSCs were isolated from bone marrow tissue, and their multi potency was confirmed. The HT-29 cell line was prepared and co-cultured with MSCs for 3 days using 6-well transwell co-culture plates (membrane pore size: 0.4 µm). Cell morphology was observed by inverted microscopy. The expression levels of EMT-related genes, namely E-cadherin, Vimentin, and β-catenin, were investigated by the RT-qPCR method. Also, the surface expression levels of CD44 and CD133 cancer stem cell markers were analyzed by flow cytometry.
Results: The co-culture of HT-29 cells with bone marrow-derived MSCs resulted in changes in cell morphology from epithelial to mesenchymal forms. The expression of mesenchymal stem cell markers, namely Vimentin and β-catenin, were significantly increased (2.25 and 1.83 folds, respectively), while the expression of the epithelial marker, E-cadherin, was reduced (0.3 folds). The expression of CD133 was also increased (51.5%).
Conclusion: Tumor-resident mesenchymal stem cells can promote colorectal cancer metastasis inducing EMT as well as increasing cancer stem cell frequency in the tumor microenvironment. It seems that direct contact between MSCs and colorectal cancer cells is not required for the interaction. Our findings may help scientists to find effective strategies against cancer metastasis by targeting tumor-resident MSCs.

Keywords: Stem cells, Metastasis, Colorectal cancer, Epithelial Mesenchymal Transition, Biomarker
Full-Text [PDF 589 kb]   (17723 Downloads) |   |   Full-Text (HTML)  (1070 Views)  

✅ Tumor-resident mesenchymal stem cells can promote colorectal cancer metastasis inducing EMT as well as increasing cancer stem cell frequency in the tumor microenvironment. It seems that direct contact between MSCs and colorectal cancer cells is not required for the interaction. Our findings may help scientists to find effective strategies against cancer metastasis by targeting tumor-resident MSCs.


Type of Study: Original Research Article | Subject: Medical Biology
Received: 2021/03/2 | Accepted: 2021/10/20 | Published: 2022/10/10
References
1. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduc Target Ther. 2020;5(1):1-30. [DOI:10.1038/s41392-020-0116-z] [PMID] [PMCID]
2. Ouladan S, Gregorieff A. Taking a step back: Insights into the mechanisms regulating gut epithelial dedifferentiation. Int J Molec Sci. 2021;22(13):7043. [DOI:10.3390/ijms22137043] [PMID] [PMCID]
3. Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019; 14 (2): 89-103. [DOI:10.5114/pg.2018.81072] [PMID] [PMCID]
4. Barker N, Ridgway R, Van Es J, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457(7229):608-11. [DOI:10.1038/nature07602] [PMID]
5. Pang R, Law WL, Chu AC, et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6(6):603-15. [DOI:10.1016/j.stem.2010.04.001] [PMID]
6. Sahlberg SH, Spiegelberg D, Glimelius B, Stenerlöw B, Nestor M. Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PloS one. 2014;9(4):e94621. [DOI:10.1371/journal.pone.0094621] [PMID] [PMCID]
7. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111-5. [DOI:10.1038/nature05384] [PMID]
8. Shi Y, Du L, Lin L, Wang Y. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat Rev Drug Discov. 2017;16(1):35-52. [DOI:10.1038/nrd.2016.193] [PMID]
9. Galland S, Stamenkovic I. Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression. J Pathol. 2020;250(5):555-72. [DOI:10.1002/path.5357] [PMID] [PMCID]
10. Hill BS, Pelagalli A, Passaro N, Zannetti A. Tumor-educated mesenchymal stem cells promote pro-metastatic phenotype. Oncotarget. 2017;8(42):73296. [DOI:10.18632/oncotarget.20265] [PMID] [PMCID]
11. Yu X, Odenthal M, Fries JW. Exosomes as miRNA carriers: formation-function-future. Int J Molec Sci. 2016;17(12):2028. [DOI:10.3390/ijms17122028] [PMID] [PMCID]
12. Cao H, Xu E, Liu H, Wan L, Lai M. Epithelial-mesenchymal transition in colorectal cancer metastasis: a system review. Pathol Res Pract. 2015;211(8):557-69. [DOI:10.1016/j.prp.2015.05.010] [PMID]
13. Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15(2):117-34. [DOI:10.1007/s10911-010-9178-9] [PMID] [PMCID]
14. Caterson EJ, Nesti LJ, Danielson KG, Tuan RS. Human marrow-derived mesenchymal progenitor cells. Molec Biotechnol. 2002;20(3):245-56. [DOI:10.1385/MB:20:3:245]
15. Li P, Gong Z, Shultz LD, Ren G. Mesenchymal stem cells: from regeneration to cancer. Pharmacol & Therapeut. 2019;200:42-54. [DOI:10.1016/j.pharmthera.2019.04.005] [PMID] [PMCID]
16. Wang S, Miao Z, Yang Q, Wang Y, Zhang J. The dynamic roles of mesenchymal stem cells in colon cancer. Canadian J Gastroenterol Hepatol. 2018;2018. [DOI:10.1155/2018/7628763] [PMID] [PMCID]
17. Pelagalli A, Nardelli A, Fontanella R, Zannetti A. Inhibition of AQP1 hampers osteosarcoma and hepatocellular carcinoma progression mediated by bone marrow-derived mesenchymal stem cells. Int J Molec Sci. 2016;17(7):1102. [DOI:10.3390/ijms17071102] [PMID] [PMCID]
18. Shinagawa K, Kitadai Y, Tanaka M, et al. Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer. 2010;127(10):2323-33. [DOI:10.1002/ijc.25440] [PMID]
19. Takigawa H, Kitadai Y, Shinagawa K, et al. Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma. Cancer Sci. 2016;107(5):601-8. [DOI:10.1111/cas.12907] [PMID] [PMCID]
20. Zhu W, Xu W, Jiang R, et al. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Experiment Molec Pathol. 2006;80(3):267-74. [DOI:10.1016/j.yexmp.2005.07.004] [PMID]
21. Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini III F. Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2011;29(1):11-9. [DOI:10.1002/stem.559] [PMID] [PMCID]
22. Beckermann B, Kallifatidis G, Groth A, et al. VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer. 2008;99(4):622-31. [DOI:10.1038/sj.bjc.6604508] [PMID] [PMCID]
23. Shin S, Lee J, Kwon Y, et al. Comparative proteomic analysis of the mesenchymal stem cells secretome from adipose, bone marrow, placenta and wharton's jelly. Int J Molec Sci. 2021;22(2):845. [DOI:10.3390/ijms22020845] [PMID] [PMCID]
24. Murphy SV, Atala A. Amniotic fluid stem cells. In:Cetrulo KJ,Cetrulo CL,TaghizadehRR,editors.Perinatal Stem Cells 2nd ed Hoboken, NJ: Wiley‐Blackwell. 2013.p:301 [DOI:10.1002/9781118497883.ch1]
25. Cortini M, Avnet S, Baldini N. Mesenchymal stroma: role in osteosarcoma progression. Cancer Lett. 2017;405:90-9. [DOI:10.1016/j.canlet.2017.07.024] [PMID]
26. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomic. 2010;73(10):1907-20. [DOI:10.1016/j.jprot.2010.06.006] [PMID]
27. Takigawa H, Kitadai Y, Shinagawa K, et al. Mesenchymal stem cells induce epithelial to mesenchymal transition in colon cancer cells through direct cell-to-cell contact. Neoplasia. 2017;19(5):429-38. [DOI:10.1016/j.neo.2017.02.010] [PMID] [PMCID]
28. Avnet S, Lemma S, Cortini M, Di Pompo G, Perut F, Baldini N. Pre-clinical models for studying the interaction between mesenchymal stromal cells and cancer cells and the induction of stemness. Front Oncol. 2019;9:305. [DOI:10.3389/fonc.2019.00305] [PMID] [PMCID]
29. Lin SP, Lee YT, Yang SH, et al. Colon cancer stem cells resist antiangiogenesis therapy-induced apoptosis. Cancer lett. 2013;328(2):226-34. [DOI:10.1016/j.canlet.2012.08.036] [PMID]
30. Huang EH, Hynes MJ, Zhang T, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009;69(8):3382-9. [DOI:10.1158/0008-5472.CAN-08-4418] [PMID] [PMCID]
31. Chen S, Song X, Chen Z, et al. CD133 expression and the prognosis of colorectal cancer: a systematic review and meta-analysis. PloS one. 2013;8(2):e56380. [DOI:10.1371/journal.pone.0056380] [PMID] [PMCID]
32. Pino MS, Kikuchi H, Zeng M, et al. Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterol. 2010;138(4):1406-17. [DOI:10.1053/j.gastro.2009.12.010] [PMID] [PMCID]
33. Camerlingo R, Miceli R, Marra L, et al. Conditioned medium of primary lung cancer cells induces EMT in A549 lung cancer cell line by TGF-ß1 and miRNA21 cooperation. PloS one. 2019;14(7):e0219597. [DOI:10.1371/journal.pone.0219597] [PMID] [PMCID]
34. Zhang X, Hu F, Li G, et al. Human colorectal cancer-derived mesenchymal stem cells promote colorectal cancer progression through IL-6/JAK2/STAT3 signaling. Cell Death Dis. 2018;9(2):1-13. [DOI:10.1038/s41419-017-0176-3] [PMID] [PMCID]
35. Martin F, Dwyer RM, Kelly J, 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(2):317-26. [DOI:10.1007/s10549-010-0734-1] [PMID]
36. Azizi P, Mazhari S, Tokhanbigli S, et al. Paracrine signals of mesenchymal stem cells induce epithelial to mesenchymal transition in gastric cancer cells. Gastroenterol Hepatol Bed Bench. 2019;12(Suppl1):S51.
37. Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27(20):2192-206. [DOI:10.1101/gad.225334.113] [PMID] [PMCID]
38. Vu T, Datta PK. Regulation of EMT in colorectal cancer: a culprit in metastasis. Cancers. 2017;9(12):171. [DOI:10.3390/cancers9120171] [PMID] [PMCID]
Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2025 CC BY-NC 4.0 | Journal of Advances in Medical and Biomedical Research

Designed & Developed by : Yektaweb