Epithelial-mesenchymal transition and stemness of breast cancer cells: Effect of viscoelasticity of the substrate to mimics microenvironment

Main Article Content

Masami Okamoto

Abstract

Metastasis is one of the greatest challenges in cancer treatment today. Normal mammary epithelial cells are optimally supported by interaction with a soft matrix (microenvironment) with elastic modulus of about 800 Pa. However, after transformation, breast tissue becomes progressively stiffer and tumour cells become significantly more contractile and hyper-responsive to matrix elasticity. In addition, importantly, the cancer cells penetrate into blood vessel and enter the circulation during metastasis. The modulus of fluid such as blood or mucus has very low stiffness of around 50 Pa. For this reason, the critical association between cancer cell phenotype and the change of matrix rigidity with an order of magnitude smaller should be emphasizing. This review highlights the current understanding of epithelial-mesenchymal transition and cancer stem cells in metastasis, and identified importance for investigation on artificial extracellular matrix with different viscoelastic properties, which is required to mimics in vivo microenvironment. The substrate damping coefficient (tand) as potential physical parameter emerged the important linkage to cellular motility, cancer stemness, and epithelial-mesenchymal transition induction. Although further investigation is required to clarify the efficacy of environmental stimuli (tand) for tumors exhibiting stem cell-like properties, this review indicates that the cancer cells incubated on softer substrate might lead to express cancer stem cell biomarkers exhibiting high expression.

Keywords: breast cancer, metastasis, epithelial-mesenchymal transition, cancer stem cells, viscoelastic properties, microenvironment

Article Details

How to Cite
OKAMOTO, Masami. Epithelial-mesenchymal transition and stemness of breast cancer cells: Effect of viscoelasticity of the substrate to mimics microenvironment. Medical Research Archives, [S.l.], v. 11, n. 10, oct. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4580>. Date accessed: 11 dec. 2023. doi: https://doi.org/10.18103/mra.v11i10.4580.
Section
Research Articles

References

1. Health, Labour and Welfare Ministry, Japan. Accessed August 18 2023. http://www.mhlw.go.jp/toukei/saikin/hw/jinkou/geppo/nengai21/dl/h7.pdf
2. Cancer morbidity and mortality. Accessed August 18 2023. https://ganjoho.jp/reg_stat/statistics/stat/short _pred.html
3. Schroeder A, Heller DA, Winslow MM, Dahlman JE, Pratt GW, Langer R, Lacks T, Anderson DG. Treating metastatic cancer with nanotechnology. Nat Rev Cancer. 2012;12, 39-50.
4. Hanahan D, Weinberg RA. Weinberg, Hallmarks of Cancer: The Next Generation. Cell. 2011;144-5:646-74.
5. Craene BD, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97-110.
6. Taddei ML, Giannoni E, Comito G, Chiarugi P. Microenvironment and tumor cell plasticity: An easy way out. Cancer letters. 2013;341:80-96.
7. McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 2014;16:717-27.
8. Gil J, Stembalska A, Pesz KA, Sasjadek MM. Sasjadek, Cancer stem cells: the theory and perspectives in cancer therapy. J App Genet. 2008;49:193-99.
9. Giordano A, Gao H, Anfossi S, Cohen E, Mego M, Lee B-N, Tin S, Laurentiis MD, Parker CA, Alvarez RH, Valero V, Ueno NT, Placido SD, Mani SA, Estava FJ, Cristofanilli M, Reuben JM. Epithelial-mesenchymal transition and stemcellmarkers in patients with HER2-positivemetastatic breast cancer. Mol Cancer Ther. 2012;11:2526-34.
10. Sasaki R, Ohta R, Okamoto M. Stemness of breast cancer cells incubated on viscoelastic gel substrates. Int Phys Med Rehab J. 2022;7(3):136-137.
11. Ishikawa Y, Sasaki R, Domura R, Okamoto M, Cellular morphologies, motility, and epithelial-mesenchymal transition of breast cancer cells incubated on viscoelastic gel substrates in hypoxia. Mater Today Chem. 2019;13:8-17.
12. Wang YC, Ludwigson M, Lakes RS. Deformation of extreme viscoelastic metals and composites, Mater Mater Sci Eng A. 2004;370:41-49.
13. Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009;9:108-22.
14. Gikes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev. 2014;14:430-439.
15. Xiong GF, Xu R. Function of cancer cell-derived extracellular matrix in tumor progression. J Cancer Metastasis Treat. 2016;2:357-364.
16. Insua-Rodriguez J, Oskarsson T. The extracellular matrix in breast cancer. Adv drug Deliv Rev. 2016;97:41-55.
17. Lu P, Weaver VM, Werb Z. The extracellular matrix: A dynamic niche in cancer progression. J Cell Biol. 2012;196:395-406.
18. Provenzano P P, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Medicine. 2006;4(1):38.
19. Riching, KM, Cox BL, Salick MR, Pehlke C, Riching AS, Ponik SM, Bass, BR, Crone WC, Jiang Y, Weaver AM, Eliceiri KW, Keely PJ. 3D Collagen Alignment Limits Protrusions to Enhance Breast Cancer Cell Persistence. Biophys J. 2014;107:2546-2558.
20. Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009;9(2):108-122.
21. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King, CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM. Tensional homeostasis and the malignant phenotype. Cancer cell. 2005;8:241-254.
22. Robert JP Jr, Yu-Li W. Cell locomotion and focal adhesions are regulated by substrate flexibility. PNAS. 1997;94:13661-13665.
23. Wang H-B, Dembo M, Wang Yu-L. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am J Physiol. Cell Physiol. 2000;279:C1345-C1350.
24. Ulrich TA, de Juan Pardo EM, Kumar S. The Mechanical Rigidity of the Extracellular Matrix Regulates the Structure, Motility, and Proliferation of Glioma Cells. Cancer Research. 2009;69(10):4167-4174.
25. O’brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106-10.
26. Yang D, Wang H, Zhang J, Li C, Lu Z, Liu J, Lin C, Li G, Qian H. In vitro characterization of stem cell-like properties of drug-resistant colon cancer subline. Oncol Res. 2013;21:51-7.
27. Matsuda Y, Kure S, Ishiwata T. Nestin and other putative cancer stem cell markers in pancreatic cancer. Med Mol Morphol. 2012;45:59-65.
28. Chen S, Song X, Chen Z, Li X, Li M, Liu H, Li J. CD133 expression and the prognosis of colorectal cancer: a systematic review and meta-analysis. PLoS ONE. 2013;8:e56380.
29. 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:e94621.
30. Schneider M, Huber J, Hadaschik B, Siegers GM, Heinz-Herbert F, Schuler J. Characterization of colon cancer cells: a functional approach characterizing CD133 as a potential stem cell marker. BMC Cancer. 2012;12:96-107.
31. Xie J, Xiao Y, Zhu X-Y, Ning Z-Y, Xu H-F. Hypoxia regulates stemness of breast cancer MDA-MB-231 cells. Med Oncol. 2016;33:42.
32. Ohta R, Okamoto M. Stemness and epithelial–mesenchymal transition of breast cancer cells incubated on viscoelastic gel substrates. Nihon Reoroji Gakkaishi. 2021;49(3):163-170.
33. Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28:15-33.
34. Nieman MT, Prudoff RS, Johnson KR, Wheelock MJ. N-Cadherin Promotes Motility in Human Breast Cancer Cells Regardless of their E-Cadherin Expression. J Cell Biol. 1999;147(3):631-43.
35. Hulit J, Suyama K, Chung S, Keren R, Agiostratidou G, Shan W, Dong X, Williams TM, Lisanti MP, Knudsen K, Hazan RB. N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res. 2007;67(7):3106-16.
36. Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi J, Nevo J, Gjerdrum C, Tiron C, Lorens JB, Ivaska J. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30(12):1436-48.
37. Satelli A, Li S, Vimentin as a potential molecular target in cancer therapy Or Vimentin, an overview and its potential as a molecular target for cancer therapy. Cell Mol Life Sci. 2011;68(18):3033-46.
38. Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Medicine. 2013;19:1438-39.
39. Polyak K, Weinberg RA, Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265-73.
40. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442-54.
41. Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H, Mori M. Epithelial–mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2010;101:293-99.
42. Olmeda D, Moreno-Bueno G, Flores JM, Fabra A, Portillo F, Cano A. SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells. Cancer Res. 2007;67:11721-31.
43. Nasrollahi S, Pathak A. Topographic confinement of epithelial clusters induces epithelial-to-mesenchymal transition in compliant matrices. Sci Rep. 2016;6:18831.
44. Zavadil J, Böttinger E. TGF-β and epithelial-to-mesenchymal transitions. Oncogene. 2005; 24(37):5764-74.
45. Janda E, Evolo M, Lehmann K, Downward J, Beug H, Grieco M. Raf plus TGFΒ-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin. Oncogene. 2006; 25(54):7117-30.
46. Peinado H, Olmeda D, Cano A. Snail, ZEB and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415-28.
47. Wei SC, Fattet L, Tsai JH, Guo Y, Pai VH, Majeski HE, Chen AC, Sah RL, Robert L, Taylor SS, Engler AJ, Yang J. Matrix stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015;17(5):678-88.
48. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593-601.
49. Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, Berx G, Cano A, Beug H, Foisner R. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005;24(14):2375-85.
50. Gilkes DM, Bajpai S, Chaturvedi P, Wirtz D, Semenza GL. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem. 2013; 288(15):10819-29.
51. Gilkes DM, Xiang L, Lee SJ, Chaturvedi P, Hubbi ME, Wirtz D, Semenza GL. Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells. PANAS. 2014;111(3):E284-E393.
52. Schito L, Semenza GL. Hypoxia-Inducible Factors: Master Regulators of Cancer Progression. Trends in Cancer. 2016;2(12):758-70.
53. Kreso A, Dick JE. Evolution of the cancer stem cell model. Stem Cell. 2014;14:275-91.
54. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331: 1559-64.
55. Giancotti FG. Mechanisms governing metastatic dormancy and reactivation. Cell. 2013;155:750-64.
56. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1. Oncogene. 2009;28:3949-59.
57. Gao T, Li J-z, Lu Y, Zhang C-y, Li Q, Mao J, Li L-h. The mechanism between epithelial mesenchymal transition in breast cancer and hypoxia microenvironment. Biomed Pharmacotherapy. 2016;80:393-405.
58. Hashimoto O, Shimizu K, Semba S, Chiba S, Ku Y, Yokozaki H, Hori Y. Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1-dependent manner in pancreatic cancer cells. Pathobiology. 2010;78:181-92.
59. Lin FY, Chang CY, Nguyen H, Li H, Fishel ML, Lin CC. Viscoelastic hydrogels for interrogating pancreatic cancer-stromal cell interactions. Mater Today Bio. 2023;19:100576.
60. Chang AC, Uto K, Abdellatef SA, Nakanishi J. Precise Tuning and Characterization of Viscoelastic Interfaces for the Study of Early Epithelial–Mesenchymal Transition Behaviors. Langmuir. 2022;38:5307-5341.
61. Barriga EH, Mayor R. Adjustable viscoelasticity allows for efficient collective cell migration. Semin Cell Dev Biol. 2019;93:55-68.