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研究生:余承佳
研究生(外文):Cheng-Chia Yu
論文名稱:口腔癌癌症幹細胞分選、特性、及調節對口腔癌腫瘤化之探討
論文名稱(外文):Isolation, functional characterization, and regulation of oral cancer stem-like cells (OC-SLCs) on oral cancer tumorigenesis
指導教授:羅正汎
指導教授(外文):Jeng-Fan Lo
學位類別:博士
校院名稱:國立陽明大學
系所名稱:口腔生物研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:150
中文關鍵詞:癌症幹細胞
外文關鍵詞:cancer stem cells
相關次數:
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摘要
口腔鱗狀細胞癌盛行率於世界排名第六。超過50%的病患在五年內死於此疾病其預後比例相當差。近年來有研究發現在高異質性癌症組織中有一子群細胞具有幹細胞特性,稱為癌幹細胞。癌幹細胞的理論指出腫瘤內只有少數之癌細胞具備有正常幹細胞分化及分裂之特徵,及「自我更新」的能力,進而促進腫瘤新生。癌幹細胞證實對腫瘤的起始、增生、轉移扮演相當重要的角色。癌幹細胞的存在可解釋為何病患經過化學治療或放射線治療後,癌症會有復發的情形。
因此,本研究將分離出口腔癌幹細胞並探討其生化及生理特性,進而協助未來口腔癌治療標的之設定。實驗主要利用無血清幹細胞篩選培養基從口腔癌細胞株及口腔癌腫瘤組織細胞分離出口腔癌幹細胞球體(spheres)。口腔癌幹細胞球體會高度表現幹細胞標記如(Oct-4, Nanog, CD117, Nestin, CD133)及抗藥性通道基因ABCG2且具備細胞分化特性。細胞體內(in vitro)及體外(in vitro)腫瘤生成力試驗則發現口腔癌癌幹細胞展現高度致癌力。臨床病理意義上,Oct-4, Nanog及CD133幹細胞標記表現與腫瘤惡性正相關性,可以用來預測口腔癌患者的預後存活率。
本實驗進一步探討調控口腔癌幹細胞生物特性的分子機制,首先利用微陣列分析出S100A4基因(為表皮細胞間質轉化(EMT)及癌轉移標記的調控者)會高度表現於口腔癌幹細胞,因此本實驗更進一步探討S100A4蛋白之表現調控口腔癌幹細胞生物特性的分子機制。抑制S100A4蛋白表現會降低口腔癌癌細胞自我更新能力,次族群( Side population)細胞,及ALDH1酵素活性;相反地,過度表現S100A4蛋白會增進口腔癌癌細胞的癌幹細胞特性。此外,抑制S100A4表現會抑制口腔癌細胞體內及體外之腫瘤生成能力。臨床上,表現較高S100A4口腔癌患者,病患的存活時間較低且復發情形亦顯著增加。
本研究結果證實口腔癌有少部分細胞具備幹細胞及癌細胞重要特性稱為口腔癌幹細胞。而S100A4會調控口腔癌癌症幹細胞自我更新及腫瘤生成能力,抑制S100A4可降低口腔癌癌症幹細胞族群來影響口腔癌腫瘤生成。
ABSTRACT
Head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC), is a lethal cancer with clinical, pathological, phenotypical, and biological heterogeneity. The prognosis of OSCC remains dismal; more than 50% of patients die of this disease or complications within 5 years. Therefore, identification of cellular–molecular events that regulates the carcinogenesis processes of OSCC should, therefore, facilitate the monitoring, therapy or prevention of OSCC.
Despite being monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. Recent evidences have suggested that the initiation, propagation and metastasis of tumors are driven by a small subpopulation of cells, termed cancer stem cells (CSCs) or termed cancer initiating cells (CICs). CSCs can self-renewal to generate additional CSCs and also differentiate to generate phenotypically diverse cancer cells with limited proliferative potential. Importantly, the existence of CSCs might explain cancer recurrences, even after clinical treatment with either radiotherapy or chemotherapy on cancer patients. Therefore, the purpose of this research is to isolate and characterize CSCs from OSCC for future translational oncology research, and eventually to improve anti-cancer therapy for OSCC patients. To isolate CSCs from OSCC cells (OSCCs), I successfully enriched oral cancer stem-like cells (OC-SLCs) by cultivating oral cancer cells under the defined serum-free medium, plus bFGF and EGF. Consequently, the differential gene expression profile between enriched OC-SLCs and parental OSCCs was elucidated transcriptionally and translationally. In addition, the in vitro and in vivo tumorigenicity assays of parental OSCCs and enriched OC-SLCs were examined. Furthermore, immunohistochemical staining of stemness genes (Oct-4, Nanog, and CD133) on OSCC patient tissues was performed. Finally, I will investigate the molecular mechanisms in maintaining the OC-SLCs biological properties.
Compared to the parental OSCCs (under 10% serum cultivation), these enriched OC-SLCs highly expressed the stem/progenitor cell markers (Oct-4, Nanog, CD117, Nestin and CD133), and also up-regulated the expression of ABCG2, a member of ABC transporter family capable of transporting anti-cancer drugs. The migration/invasion/malignancy capabilities of OC-SLCs were also significantly augmented than parental OSCCs shown by in vitro and in vivo assays. Elevated expression of CD133 was showed in the enriched OC-SLCs from OSCC patients’ tumors. Positive correlations of Oct-4, Nanog or CD133 expression on tumor stage were demonstrated on 52 OSCC patient tissues. Kaplan-Meier analyses exhibited that Nanog/Oct-4/CD133 triple positive patients predicted the worst survival prognosis of OSCC patients. Overall, my data showed that the isolated OC-SLCs possess both the characteristics of stem cells and malignant tumors, and these cancer stem-like cell properties in OSCC and other cancers should be warranted in the future translational oncology with the ultimate objective of improving anti-cancer therapy.
Subsequently, the molecular mechanisms by which to operate the physiological characteristics in OC-SLCs remain unclear. Herein I determined the critical role of S100A4, a common mediator of epithelial–mesenchymal transition (EMT) and metastasis, in the maintenance of stemness characteristics and cancerous phenotype in OSCCs. First, Affymetrix microarray analysis was performed to identify S100A4 as the putative candidate mediating the cancer stemness properties of OC-SLCs. Stable knockdown and overexpression of S100A4 expression in OSCCs was achieved by lentiviral-mediated system. Consequently, the stemness properties of OC-SLCs in OSCCs with S100A4 down-regulation or overexpression were elucidated, respectively. The in vitro tumorigenic properties of cell migration, cell invasion, and foci formation between S100A4-knockdown and control OSCCs were determined. Furthermore, stable S100A4-knockdown SAS cell or control SAS cells were transplanted into nude mice for evaluating in vivo tumorigenicity. Finally, immunohistochemical staining of S100A4 on OSCC patient tissues was examined.
Here we first found out that S100A4 transcripts were significantly up-regulated in enriched OC-SLCs by Affymetrix microarray analysis. Consequently, we demonstrated that the expression of S100A4 was enhanced transcriptionally and translationally by reverse transcript PCR and western blot analyses. Lentiviral small hairpin RNA interference mediated down-regulation of S100A4 significantly reduced the self-renewal ability, side population cells and ALDH1 enzymatic activity positive cells in OSCCs. Furthermore, down-regulation of S100A4 enhanced the differentiation capability but inversely diminished “stemness” genes of OC-SLCs. In opposite, stable over-expression of S100A4 enhanced the CSC properties in OSCCs. Of note, knockdown of S100A4 lessened tumorigenicity of OSCCs both in vitro and in vivo. In addition, S100A4 expression was positively correlated the clinical grading and predicted the worse survival prognosis of OSCC patients by immunohistochemistry analyses. Finally, knockdown of endogenous S100A4 resulted in down-regulation of Wnt5A, Notch2, p-Akt/PI3K and up-regulation of PTEN in OSCCs.
In conclusion, these studies first elucidated the crucial role of S100A4 signaling pathways in the maintenance of stemness and tumorigenicity of OC-SLCs. Targeting S100A4 signaling might be a potential therapeutic target for OSCC by eliminating CSCs.
THESIS CONTENTS
CONTENTS................................................ I
LIST OF TABLES....................................... V
LIST OF FIGURES.......................................... VI
LIST OF ABBREVIATIONS............................ X
CHINESE ABSTRCT......................................... 1
ABSTRCT................................................... 3
VITA.................................................. 147
CHAPTER I. INTRODUCTION............................ 7
CHAPTER II.MATERIAL AND METHODS.................... 19
CHAPTER III.RESULTS.................................. 33
CHAPTER IV. DISSCUSION............................... 52
CHAPTER V.CONCLUSIONS................................... 65
CHAPTER VI.REFERENCES....................................122
CHAPTER VII. APPENDIX................................ 144
REFERENCES
1. Chen YJ, Lin SC, Kao T, Chang CS, Hong PS, Shieh TM, Chang KW: Genome-wide profiling of oral squamous cell carcinoma. J Pathol 204:326-332, 2004
2. Pentenero M, Gandolfo S, Carrozzo M: Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck 27:1080-1091, 2005
3. Hardisson D: Molecular pathogenesis of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 260:502-508, 2003
4. Chen YJ, Chang JT, Liao CT, Wang HM, Yen TC, Chiu CC, Lu YC, Li HF, Cheng AJ: Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci 99:1507-1514, 2008
5. Ho PS, Ko YC, Yang YH, Shieh TY, Tsai CC: The incidence of oropharyngeal cancer in Taiwan: an endemic betel quid chewing area. J Oral Pathol Med 31:213-219, 2002
6. Maier H, Dietz A, Gewelke U, Heller WD, Weidauer H: Tobacco and alcohol and the risk of head and neck cancer. Clin Investig 70:320-327, 1992
7. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, Peters G, Lee DJ, Leaf A, Ensley J, Cooper J: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003
8. Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, Lin CH, Chen IH, Huang SF, Cheng AJ, Yen TC: Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol 15:915-922, 2008
9. Locke M, Heywood M, Fawell S, Mackenzie IC: Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res 65:8944-8950, 2005
10. Costea DE, Tsinkalovsky O, Vintermyr OK, Johannessen AC, Mackenzie IC: Cancer stem cells - new and potentially important targets for the therapy of oral squamous cell carcinoma. Oral Dis 12:443-454, 2006
11. Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature 414:105-111, 2001
12. Visvader JE, Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755-768, 2008
13. Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells. Science 197:461-463, 1977
14. Huntly BJ, Gilliland DG: Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 5:311-321, 2005
15. Jordan CT, Guzman ML, Noble M: Cancer stem cells. N Engl J Med 355:1253-1261, 2006
16. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM: Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66:9339-9344, 2006
17. Dalerba P, Cho RW, Clarke MF: Cancer stem cells: models and concepts. Annu Rev Med 58:267-284, 2007
18. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645-648, 1994
19. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983-3988, 2003
20. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821-5828, 2003
21. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB: Identification of human brain tumour initiating cells. Nature 432:396-401, 2004
22. Kondo T, Setoguchi T, Taga T: Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 101:781-786, 2004
23. Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson RJ: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8:323-335, 2005
24. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA: Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391-403, 2006
25. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG: Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65:5506-5511, 2005
26. Zucchi I, Sanzone S, Astigiano S, Pelucchi P, Scotti M, Valsecchi V, Barbieri O, Bertoli G, Albertini A, Reinbold RA, Dulbecco R: The properties of a mammary gland cancer stem cell. Proc Natl Acad Sci U S A 104:10476-10481, 2007
27. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T: Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823-835, 2005
28. Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, Van Belle PA, Xu X, Elder DE, Herlyn M: A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65:9328-9337, 2005
29. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH: Identification of cells initiating human melanomas. Nature 451:345-349, 2008
30. Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, Huber M, Hohl D, Cano A, Birchmeier W, Huelsken J: Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452:650-653, 2008
31. Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP: Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68:4311-4320, 2008
32. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM: Identification of pancreatic cancer stem cells. Cancer Res 67:1030-1037, 2007
33. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ: Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946-10951, 2005
34. Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR, Wang TC: Gastric cancer originating from bone marrow-derived cells. Science 306:1568-1571, 2004
35. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature 445:111-115, 2007
36. Du L, Wang H, He L, Zhang J, Ni B, Wang X, Jin H, Cahuzac N, Mehrpour M, Lu Y, Chen Q: CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res 14:6751-6760, 2008
37. Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ, Guan XY: Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542-2556, 2007
38. Yang ZF, Ngai P, Ho DW, Yu WC, Ng MN, Lau CK, Li ML, Tam KH, Lam CT, Poon RT, Fan ST: Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 47:919-928, 2008
39. Mackenzie IC: Stem cell properties and epithelial malignancies. Eur J Cancer 42:1204-1212, 2006
40. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE: Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 104:973-978, 2007
41. Okamoto A, Chikamatsu K, Sakakura K, Hatsushika K, Takahashi G, Masuyama K: Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck. Oral Oncol, 2008
42. Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW: A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 90:5013-5021, 1997
43. Neuzil J, Stantic M, Zobalova R, Chladova J, Wang X, Prochazka L, Dong L, Andera L, Ralph SJ: Tumour-initiating cells vs. cancer 'stem' cells and CD133: what's in the name? Biochem Biophys Res Commun 355:855-859, 2007
44. Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D'Angelica M, Kemeny N, Lyden D, Rafii S: CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 118:2111-2120, 2008
45. Dean M, Fojo T, Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer 5:275-284, 2005
46. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, Taniguchi H: Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 44:240-251, 2006
47. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK: Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci U S A 103:11154-11159, 2006
48. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG: Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res 65:6207-6219, 2005
49. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G: ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555-567, 2007
50. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756-760, 2006
51. Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K, Clarke MF: The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356:217-226, 2007
52. Baumann M, Krause M, Hill R: Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545-554, 2008
53. Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY: CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27:1749-1758, 2008
54. Ghods AJ, Irvin D, Liu G, Yuan X, Abdulkadir IR, Tunici P, Konda B, Wachsmann-Hogiu S, Black KL, Yu JS: Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells 25:1645-1653, 2007
55. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC: Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100:672-679, 2008
56. Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H: A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 60:461-472, 1990
57. Rosner MH, Vigano MA, Ozato K, Timmons PM, Poirier F, Rigby PW, Staudt LM: A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature 345:686-692, 1990
58. Burdon T, Smith A, Savatier P: Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol 12:432-438, 2002
59. Boiani M, Scholer HR: Regulatory networks in embryo-derived pluripotent stem cells. Nat Rev Mol Cell Biol 6:872-884, 2005
60. Pesce M, Wang X, Wolgemuth DJ, Scholer H: Differential expression of the Oct-4 transcription factor during mouse germ cell differentiation. Mech Dev 71:89-98, 1998
61. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A: Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379-391, 1998
62. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A: Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643-655, 2003
63. Okita K, Ichisaka T, Yamanaka S: Generation of germline-competent induced pluripotent stem cells. Nature 448:313-317, 2007
64. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin, II, Thomson JA: Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917-1920, 2007
65. Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ: Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141-146, 2008
66. Ezeh UI, Turek PJ, Reijo RA, Clark AT: Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 104:2255-2265, 2005
67. Hu T, Liu S, Breiter DR, Wang F, Tang Y, Sun S: Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res 68:6533-6540, 2008
68. Gidekel S, Pizov G, Bergman Y, Pikarsky E: Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4:361-370, 2003
69. Abelev GI, Lazarevich NL: Control of differentiation in progression of epithelial tumors. Adv Cancer Res 95:61-113, 2006
70. Seigel GM, Hackam AS, Ganguly A, Mandell LM, Gonzalez-Fernandez F: Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis 13:823-832, 2007
71. Trosko JE: From adult stem cells to cancer stem cells: Oct-4 Gene, cell-cell communication, and hormones during tumor promotion. Ann N Y Acad Sci 1089:36-58, 2006
72. Pan G, Thomson JA: Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 17:42-49, 2007
73. Ratajczak MZ, Machalinski B, Wojakowski W, Ratajczak J, Kucia M: A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues. Leukemia 21:860-867, 2007
74. Santagata S, Ligon KL, Hornick JL: Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors. Am J Surg Pathol 31:836-845, 2007
75. Gu G, Yuan J, Wills M, Kasper S: Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res 67:4807-4815, 2007
76. Freberg CT, Dahl JA, Timoskainen S, Collas P: Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol Biol Cell 18:1543-1553, 2007
77. Hoei-Hansen CE, Kraggerud SM, Abeler VM, Kaern J, Rajpert-De Meyts E, Lothe RA: Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol Cancer 6:12, 2007
78. Gupta GP, Massague J: Cancer metastasis: building a framework. Cell 127:679-695, 2006
79. Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740-746, 2003
80. Lee JM, Dedhar S, Kalluri R, Thompson EW: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172:973-981, 2006
81. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T: Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer 5:744-749, 2005
82. 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, Weinberg RA: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704-715, 2008
83. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A: Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE 3:e2888, 2008
84. Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA: Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci U S A 104:10069-10074, 2007
85. Ito M, Kizawa K: Expression of calcium-binding S100 proteins A4 and A6 in regions of the epithelial sac associated with the onset of hair follicle regeneration. J Invest Dermatol 116:956-963, 2001
86. Ito M, Kizawa K, Toyoda M, Morohashi M: Label-retaining cells in the bulge region are directed to cell death after plucking, followed by healing from the surviving hair germ. J Invest Dermatol 119:1310-1316, 2002
87. Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, Lin JS, Sawicki JA, Cotsarelis G: Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 22:411-417, 2004
88. Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E: Defining the epithelial stem cell niche in skin. Science 303:359-363, 2004
89. Helfman DM, Kim EJ, Lukanidin E, Grigorian M: The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer 92:1955-1958, 2005
90. Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N: Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res 65:3772-3780, 2005
91. Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, Chodosh LA: The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8:197-209, 2005
92. Grigorian M, Ambartsumian N, Lykkesfeldt AE, Bastholm L, Elling F, Georgiev G, Lukanidin E: Effect of mts1 (S100A4) expression on the progression of human breast cancer cells. Int J Cancer 67:831-841, 1996
93. Saleem M, Kweon MH, Johnson JJ, Adhami VM, Elcheva I, Khan N, Bin Hafeez B, Bhat KM, Sarfaraz S, Reagan-Shaw S, Spiegelman VS, Setaluri V, Mukhtar H: S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci U S A 103:14825-14830, 2006
94. Takenaga K, Nakamura Y, Sakiyama S: Expression of antisense RNA to S100A4 gene encoding an S100-related calcium-binding protein suppresses metastatic potential of high-metastatic Lewis lung carcinoma cells. Oncogene 14:331-337, 1997
95. Mahon PC, Baril P, Bhakta V, Chelala C, Caulee K, Harada T, Lemoine NR: S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer. Cancer Res 67:6786-6795, 2007
96. Schneider M, Hansen JL, Sheikh SP: S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases? J Mol Med 86:507-522, 2008
97. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R: BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964-968, 2003
98. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R: Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13:952-961, 2007
99. Stein U, Arlt F, Walther W, Smith J, Waldman T, Harris ED, Mertins SD, Heizmann CW, Allard D, Birchmeier W, Schlag PM, Shoemaker RH: The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology 131:1486-1500, 2006
100. Harris MA, Yang H, Low BE, Mukherje J, Guha A, Bronson RT, Shultz LD, Israel MA, Yun K: Cancer stem cells are enriched in the side population cells in a mouse model of glioma. Cancer Res 68:10051-10059, 2008
101. Gongoll S, Peters G, Mengel M, Piso P, Klempnauer J, Kreipe H, von Wasielewski R: Prognostic significance of calcium-binding protein S100A4 in colorectal cancer. Gastroenterology 123:1478-1484, 2002
102. Rudland PS, Platt-Higgins A, Renshaw C, West CR, Winstanley JH, Robertson L, Barraclough R: Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. Cancer Res 60:1595-1603, 2000
103. Davies BR, O'Donnell M, Durkan GC, Rudland PS, Barraclough R, Neal DE, Mellon JK: Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer. J Pathol 196:292-299, 2002
104. Lu SY, Chang KW, Liu CJ, Tseng YH, Lu HH, Lee SY, Lin SC: Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte. Carcinogenesis 27:1273-1284, 2006
105. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J: Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80, 2004
106. Yu YH, Kuo HK, Chang KW: The evolving transcriptome of head and neck squamous cell carcinoma: a systematic review. PLoS ONE 3:e3215, 2008
107. Futschik ME, Carlisle B: Noise-robust soft clustering of gene expression time-course data. J Bioinform Comput Biol 3:965-988, 2005
108. Dennis G, Jr., Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4:P3, 2003
109. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499-507, 2008
110. Muller FJ, Laurent LC, Kostka D, Ulitsky I, Williams R, Lu C, Park IH, Rao MS, Shamir R, Schwartz PH, Schmidt NO, Loring JF: Regulatory networks define phenotypic classes of human stem cell lines. Nature 455:401-405, 2008
111. Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:Article3, 2004
112. Strimmer K: A unified approach to false discovery rate estimation. BMC Bioinformatics 9:303, 2008
113. Peri S, Navarro JD, Amanchy R, Kristiansen TZ, Jonnalagadda CK, Surendranath V, Niranjan V, Muthusamy B, Gandhi TK, Gronborg M, Ibarrola N, Deshpande N, Shanker K, Shivashankar HN, Rashmi BP, Ramya MA, Zhao Z, Chandrika KN, Padma N, Harsha HC, Yatish AJ, Kavitha MP, Menezes M, Choudhury DR, Suresh S, Ghosh N, Saravana R, Chandran S, Krishna S, Joy M, Anand SK, Madavan V, Joseph A, Wong GW, Schiemann WP, Constantinescu SN, Huang L, Khosravi-Far R, Steen H, Tewari M, Ghaffari S, Blobe GC, Dang CV, Garcia JG, Pevsner J, Jensen ON, Roepstorff P, Deshpande KS, Chinnaiyan AM, Hamosh A, Chakravarti A, Pandey A: Development of human protein reference database as an initial platform for approaching systems biology in humans. Genome Res 13:2363-2371, 2003
114. Hadnagy A, Gaboury L, Beaulieu R, Balicki D: SP analysis may be used to identify cancer stem cell populations. Exp Cell Res 312:3701-3710, 2006
115. Haddad RI, Shin DM: Recent advances in head and neck cancer. N Engl J Med 359:1143-1154, 2008
116. Prince ME, Ailles LE: Cancer stem cells in head and neck squamous cell cancer. J Clin Oncol 26:2871-2875, 2008
117. Clarke MF, Fuller M: Stem cells and cancer: two faces of eve. Cell 124:1111-1115, 2006
118. Cho RW, Clarke MF: Recent advances in cancer stem cells. Curr Opin Genet Dev 18:48-53, 2008
119. Hill RP, Perris R: "Destemming" cancer stem cells. J Natl Cancer Inst 99:1435-1440, 2007
120. Phillips TM, McBride WH, Pajonk F: The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777-1785, 2006
121. Tang Y, Kitisin K, Jogunoori W, Li C, Deng CX, Mueller SC, Ressom HW, Rashid A, He AR, Mendelson JS, Jessup JM, Shetty K, Zasloff M, Mishra B, Reddy EP, Johnson L, Mishra L: Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling. Proc Natl Acad Sci U S A 105:2445-2450, 2008
122. Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, Calhoun-Davis T, Zaehres H, Daley GQ, Tang DG: Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27:993-1005, 2009
123. Machida K, Tsukamoto H, Mkrtchyan H, Duan L, Dynnyk A, Liu HM, Asahina K, Govindarajan S, Ray R, Ou JH, Seki E, Deshaies R, Miyake K, Lai MM: Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci U S A 106:1548-1553, 2009
124. Hill A, McFarlane S, Johnston PG, Waugh DJ: The emerging role of CD44 in regulating skeletal micrometastasis. Cancer Lett 237:1-9, 2006
125. Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L: Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res 10:R10, 2008
126. Mack B, Gires O: CD44s and CD44v6 expression in head and neck epithelia. PLoS ONE 3:e3360, 2008
127. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN: Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501-513, 2009
128. Polyak K, Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265-273, 2009
129. Garrett SC, Varney KM, Weber DJ, Bresnick AR: S100A4, a mediator of metastasis. J Biol Chem 281:677-680, 2006
130. Lobo NA, Shimono Y, Qian D, Clarke MF: The biology of cancer stem cells. Annu Rev Cell Dev Biol 23:675-699, 2007
131. Sathornsumetee S, Cao Y, Marcello JE, Herndon JE, 2nd, McLendon RE, Desjardins A, Friedman HS, Dewhirst MW, Vredenburgh JJ, Rich JN: Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 26:271-278, 2008
132. Das B, Tsuchida R, Malkin D, Koren G, Baruchel S, Yeger H: Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells 26:1818-1830, 2008
133. Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ: Genome-wide Association of Hypoxia-inducible Factor (HIF)-1{alpha} and HIF-2{alpha} DNA Binding with Expression Profiling of Hypoxia-inducible Transcripts. J Biol Chem 284:16767-16775, 2009
134. Helczynska K, Larsson AM, Holmquist Mengelbier L, Bridges E, Fredlund E, Borgquist S, Landberg G, Pahlman S, Jirstrom K: Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Res 68:9212-9220, 2008
135. Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, Labosky PA, Simon MC, Keith B: HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20:557-570, 2006
136. Keith B, Simon MC: Hypoxia-inducible factors, stem cells, and cancer. Cell 129:465-472, 2007
137. Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Selivanova G, Lukanidin E: Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem 276:22699-22708, 2001
138. Fernandez-Fernandez MR, Veprintsev DB, Fersht AR: Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor. Proc Natl Acad Sci U S A 102:4735-4740, 2005
139. Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y: p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7:165-171, 2005
140. Feinberg AP, Tycko B: The history of cancer epigenetics. Nat Rev Cancer 4:143-153, 2004
141. Sherbet GV: Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy. Cancer Lett 280:15-30, 2009
142. Nakamura N, Takenaga K: Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin Exp Metastasis 16:471-479, 1998
143. Sato N, Maitra A, Fukushima N, van Heek NT, Matsubayashi H, Iacobuzio-Donahue CA, Rosty C, Goggins M: Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res 63:4158-4166, 2003
144. Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, Brown M, Viens P, Xerri L, Bertucci F, Stassi G, Dontu G, Birnbaum D, Wicha MS: Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69:1302-1313, 2009
145. Farnie G, Clarke RB, Spence K, Pinnock N, Brennan K, Anderson NG, Bundred NJ: Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst 99:616-627, 2007
146. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ: Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441:475-482, 2006
147. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, Schultz PG, Reddy VA: The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A 106:268-273, 2009
148. Majeti R, Becker MW, Tian Q, Lee TL, Yan X, Liu R, Chiang JH, Hood L, Clarke MF, Weissman IL: Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc Natl Acad Sci U S A 106:3396-3401, 2009
149. Wang SJ, Bourguignon LY: Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer. Arch Otolaryngol Head Neck Surg 132:771-778, 2006
150. Cabezon T, Celis JE, Skibshoj I, Klingelhofer J, Grigorian M, Gromov P, Rank F, Myklebust JH, Maelandsmo GM, Lukanidin E, Ambartsumian N: Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer. Int J Cancer 121:1433-1444, 2007
151. Hemandas AK, Salto-Tellez M, Maricar SH, Leong AF, Leow CK: Metastasis-associated protein S100A4--a potential prognostic marker for colorectal cancer. J Surg Oncol 93:498-503, 2006
152. Gupta S, Hussain T, MacLennan GT, Fu P, Patel J, Mukhtar H: Differential expression of S100A2 and S100A4 during progression of human prostate adenocarcinoma. J Clin Oncol 21:106-112, 2003
153. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, Watkins DN, Matsui W: Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A 104:4048-4053, 2007
154. Park CY, Tseng D, Weissman IL: Cancer stem cell-directed therapies: recent data from the laboratory and clinic. Mol Ther 17:219-230, 2009
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