Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells

Lan,Ling; Luo,Yong; Cui,Dai; Shi,Bing-Yin; Deng,Wei; Huo,Li-Li; Chen,Hai-Ling; Zhang,Guo-Ying; Deng,Li-Li

doi:10.3892/ijo.2013.1913

Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells

Authors:
- Ling Lan
- Yong Luo
- Dai Cui
- Bing-Yin Shi
- Wei Deng
- Li-Li Huo
- Hai-Ling Chen
- Guo-Ying Zhang
- Li-Li Deng
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Affiliations: Department of Endocrinology, Beijing Ji Shui Tan Hospital, The 4th Medical College of Peking University, Beijing, P.R. China, Department of Urology, Affiliated Beijing Anzhen Hospital of Capital Medical University, Beijing, P.R. China, Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China, Department of Endocrinology, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, P.R. China
Published online on: April 22, 2013 https://doi.org/10.3892/ijo.2013.1913
Pages: 113-120

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Abstract

Increasing evidence has shown that cancer stem cells or tumor initiating cells are the ‘root cause’ of malignant cancers. However, the exact origin of cancer stem cells still remains obscure in thyroid research. EMT has been implicated in the initiation and conversion of early-stage tumors into invasive malignancies and is associated with the stemness of cancer cells. Based on these facts, a new hypothesis was suggested that EMT induces cancer stem cell generation and tumor progression in human thyroid cancer cells in vitro. In the present study, FTC133 cells identified as EMT-negative cells were used for EMT induction by HIF‑1α transfection. Overexpression of HIF-1α induced FTC133 cells to undergo EMT, downregulated the epithelial markers E-cadherin, upregulated the mesenchymal marker vimentin, and associated with highly invasive and metastatic properties. Most importantly, the induction of EMT promoted the stem-like side population cell proportion in the FTC133 cells. These results indicate that EMT induction promotes CSC traits and cell proportions in the thyroid cancer cells, which implies that EMT could induce cancer stem cell generation and tumor progression in thyroid cancers. Further understanding of the role of EMT and cancer stem cells in cancer progression may reveal new targets for the prevention or therapy of thyroid cancers.

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1.	Are C and Shaha AR: Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors and treatment approaches. Ann Surg Oncol. 13:453–464. 2006. View Article : Google Scholar : PubMed/NCBI
2.	Jordan CT, Guzman ML and Noble M: Cancer stem cells. N Engl J Med. 355:1253–1261. 2006. View Article : Google Scholar : PubMed/NCBI
3.	Ward RJ and Dirks PB: Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol. 2:175–189. 2007. View Article : Google Scholar : PubMed/NCBI
4.	Kondo T, Setoguchi T and Taga T: Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA. 101:781–786. 2004. View Article : Google Scholar : PubMed/NCBI
5.	Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA and Brenner MK: A distinct ‘side population’ of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 101:14228–14233. 2004.
6.	Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Re. 63:5821–5828. 2003.PubMed/NCBI
7.	Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M and Kornblum HI: Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA. 100:15178–15183. 2003. View Article : Google Scholar : PubMed/NCBI
8.	Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD and Steindler DA: Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia. 39:193–206. 2002. View Article : Google Scholar : PubMed/NCBI
9.	Bonnet D and Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 3:730–737. 1997. View Article : Google Scholar : PubMed/NCBI
10.	Friedman S, Lu M, Schultz A, Thomas D and Lin RY: CD133⁺ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin. PLoS One. 4:e53952009.
11.	Zito G, Richiusa P, Bommarito A, Carissimi E, Russo L, Coppola A, Zerilli M, Rodolico V, Criscimanna A, Amato M, Pizzolanti G, Galluzzo A and Giordano C: In vitro identification and characterization of CD133(pos) cancer stem-like cells in anaplastic thyroid carcinoma cell lines. PLoS One. 3:e35442008. View Article : Google Scholar : PubMed/NCBI
12.	Thomas D, Friedman S and Lin RY: Thyroid stem cells: lessons from normal development and thyroid cancer. Endocr Relat Cancer. 15:51–58. 2008. View Article : Google Scholar : PubMed/NCBI
13.	Thomas T, Nowka K, Lan L and Derwahl M: Expression of endoderm stem cell markers: evidence for the presence of adult stem cells in human thyroid glands. Thyroid. 16:537–544. 2006. View Article : Google Scholar : PubMed/NCBI
14.	Lan L, Cui D, Nowka K and Derwahl M: Stem cells derived from goiters in adults form spheres in response to intense growth stimulation and require thyrotropin for differentiation into thyrocytes. J Clin Endocrinol Metab. 92:3681–3688. 2007. View Article : Google Scholar : PubMed/NCBI
15.	Fierabracci A, Puglisi MA, Giuliani L, Mattarocci S and Gallinella-Muzi M: Identification of an adult stem/progenitor cell-like population in the human thyroid. J Endocrinol. 198:471–487. 2008. View Article : Google Scholar : PubMed/NCBI
16.	Zheng XQ, Cui D, Xu SH, Brabant G and Dereahl M: Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: characterization of resistant cells. Int J Oncol. 37:307–315. 2010.PubMed/NCBI
17.	Mitsutake N, Iwao A, Nagai K, Namba H, Ohtsuru A, Saenko V and Yamashita S: Characterization of side population in thyroid cancer cell lines: cancer stem-like cells are enriched partly but not exclusively. Endocrinology. 148:1797–1803. 2007. View Article : Google Scholar : PubMed/NCBI
18.	Takano T and Amino N: Fetal cell carcinogenesis: a new hypothesis for better understanding of thyroid carcinoma. Thyroid. 15:432–438. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
20.	Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J and Weinberg RA: The epithelial mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
21.	Raimondi C, Gianni W, Cortesi E and Gazzaniga P: Cancer stem cells and epithelial-mesenchymal transition: revisiting minimal residual disease. Current Cancer Drug Targets. 10:496–508. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Hollier BG, Evans K and Mani SA: The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia. 14:29–43. 2009. View Article : Google Scholar : PubMed/NCBI
23.	Hayashida T, Jinno H, Kitagawa Y and Kitajima M: Cooperation of cancer stem cell properties and epithelial-mesenchymal transition in the establishment of breast cancer metastasis. J Oncol. 2011:5914272011. View Article : Google Scholar : PubMed/NCBI
24.	Goretzki PE, Frilling A, Simon D and Roeher HD: Growth regulation of normal thyroids and thyroid tumors in man. Recent Results Cancer Res. 118:48–63. 1990. View Article : Google Scholar : PubMed/NCBI
25.	Luo Y, He DL, Ning L, Shen SL, Li L, Li X, Zhau HE and Chung LW: Over-expression of hypoxia-inducible factor-1alpha increases the invasive potency of LNCaP cells in vitro. BJU Int. 98:1315–1319. 2006. View Article : Google Scholar
26.	Hundahl SA, Fleming ID, Fremgen AM and Menck HR: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer. 83:2638–2648. 1998.PubMed/NCBI
27.	Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S and Sarkar FH: Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One. 5:e124452010. View Article : Google Scholar : PubMed/NCBI
28.	Klarmann GJ, Hurt EM, Mathews LA, Zhang X, Duhagon MA, Mistree T, Thomas SB and Farrar WL: Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clin Exp Metastasis. 26:433–446. 2009. View Article : Google Scholar : PubMed/NCBI
29.	Huber MA, Kraut N and Beug H: Molecular requirements for epithelial mesenchymal transition during tumor progression. Curr Opin Cell Biol. 17:548–558. 2005. View Article : Google Scholar : PubMed/NCBI
30.	Salnikov AV, Liu L, Platen M, Gladkich J, Salnikova O, Ryschich E, Mattern J, Moldenhauer G, Werner J, Schemmer P, Buechler MW and Herr I: Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS One. 7:e463912012. View Article : Google Scholar
31.	Lu X and Kang YB: Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 16:5928–5935. 2010. View Article : Google Scholar : PubMed/NCBI
32.	Mimeault M and Batra SK: Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med. 17:30–54. 2013. View Article : Google Scholar : PubMed/NCBI
33.	Nelson WJ and Nusse R: Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 303:1483–1487. 2004. View Article : Google Scholar : PubMed/NCBI
34.	Kim K, Lu Z and Hay ED: Direct evidence for a role of beta-catenin/ LEF-1 signaling pathway in induction of EMT. Cell Biol Int. 26:463–476. 2002. View Article : Google Scholar : PubMed/NCBI
35.	Medici D, Hay ED and Olsen BR: Snail and Slug promote epithelialmesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol Biol Cell. 19:4875–4887. 2008. View Article : Google Scholar : PubMed/NCBI
36.	Yang L, Lin C and Liu ZR: P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell. 127:139–155. 2006. View Article : Google Scholar : PubMed/NCBI
37.	Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM: Cancer stem cells - perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar
38.	Hurt EM, Chan K, Serrat MA, Thomas SB, Veenstra TD and Farrar WL: Identification of vitronectin as an extrinsic inducer of cancer stem celldifferentiation and tumor formation. Stem Cell. 28:390–398. 2010.PubMed/NCBI
39.	Morel AP, Lièvre M, Thomas C, Hinkal G, Ansieau S and Puisieux A: Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 3:e28882008. View Article : Google Scholar : PubMed/NCBI