Cell and Tissue Research

, Volume 347, Issue 1, pp 85–101 | Cite as

Deconstructing the mechanisms and consequences of TGF-β-induced EMT during cancer progression

  • Michael K. Wendt
  • Maozhen Tian
  • William P. Schiemann
Review

Abstract

Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that regulates mammalian development, differentiation, and homeostasis in essentially all cell types and tissues. TGF-β normally exerts anticancer activities by prohibiting cell proliferation and by creating cell microenvironments that inhibit cell motility, invasion, and metastasis. However, accumulating evidence indicates that the process of tumorigenesis, particularly that associated with metastatic progression, confers TGF-β with oncogenic activities, a functional switch known as the “TGF-β paradox.” The molecular determinants governing the TGF-β paradox are complex and represent an intense area of investigation by researchers in academic and industrial settings. Recent findings link genetic and epigenetic events in mediating the acquisition of oncogenic activity by TGF-β, as do aberrant alterations within tumor microenvironments. These events coalesce to enable TGF-β to direct metastatic progression via the stimulation of epithelial-mesenchymal transition (EMT), which permits carcinoma cells to abandon polarized epithelial phenotypes in favor of apolar mesenchymal-like phenotypes. Attempts to deconstruct the EMT process induced by TGF-β have identified numerous signaling molecules, transcription factors, and microRNAs operant in mediating the initiation and resolution of this complex transdifferentiation event. In addition to its ability to enhance carcinoma cell invasion and metastasis, EMT also endows transitioned cells with stem-like properties, including the acquisition of self-renewal and tumor-initiating capabilities coupled to chemoresistance. Here, we review recent findings that delineate the pathophysiological mechanisms whereby EMT stimulated by TGF-β promotes metastatic progression and disease recurrence in human carcinomas.

Keywords

Cancer stem cells Chemoresistance Epithelial-mesenchymal transition Integrins Metastasis Transforming growth factor-β Tumor microenvironment 

References

  1. Adhikari AS, Agarwal N, Wood BM, Porretta C, Ruiz B, Pochampally RR, Iwakuma T (2010) CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res 70:4602–4612PubMedCrossRefGoogle Scholar
  2. Alexandrow MG, Kawabata M, Aakre M, Moses HL (1995) Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor β1. Proc Natl Acad Sci USA 92:3239–3243PubMedCrossRefGoogle Scholar
  3. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988PubMedCrossRefGoogle Scholar
  4. Allington TM, Galliher-Beckley AJ, Schiemann WP (2009) Activated Abl kinase inhibits oncogenic transforming growth factor-β signaling and tumorigenesis in mammary tumors. FASEB J 23:4231–4243PubMedCrossRefGoogle Scholar
  5. Anzano MA, Roberts AB, De Larco JE, Wakefield LM, Assoian RK, Roche NS, Smith JM, Lazarus JE, Sporn MB (1985) Increased secretion of type β transforming growth factor accompanies viral transformation of cells. Mol Cell Biol 5:242–247PubMedGoogle Scholar
  6. Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT (1993) Anti-transforming growth factor (TGF)-β antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-β interactions in human breast cancer progression. J Clin Invest 92:2569–2576PubMedCrossRefGoogle Scholar
  7. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ, Choi W (2009) Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69:5820–5828PubMedCrossRefGoogle Scholar
  8. Baguley BC (2010) Multiple drug resistance mechanisms in cancer. Mol Biotechnol 46:308–316PubMedCrossRefGoogle Scholar
  9. Bandyopadhyay A, Wang L, Agyin J, Tang Y, Lin S, Yeh IT, De K, Sun LZ (2010) Doxorubicin in combination with a small TGFβ inhibitor: a potential novel therapy for metastatic breast cancer in mouse models. PLoS One 5:e10365PubMedCrossRefGoogle Scholar
  10. Barr S, Thomson S, Buck E, Russo S, Petti F, Sujka-Kwok I, Eyzaguirre A, Rosenfeld-Franklin M, Gibson NW, Miglarese M, Epstein D, Iwata KK, Haley JD (2008) Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clin Exp Metastasis 25:685–693PubMedCrossRefGoogle Scholar
  11. Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, Wang RY, Brisken C, Guerra R, Andreeff M, Mani SA (2010) Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells 28:1435–1445PubMedCrossRefGoogle Scholar
  12. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507PubMedCrossRefGoogle Scholar
  13. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL (2001a) Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 12:27–36PubMedGoogle Scholar
  14. Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HL (2001b) Integrin β1 signaling is necessary for transforming growth factor-β activation of p38MAPK and epithelial plasticity. J Biol Chem 276:46707–46713PubMedCrossRefGoogle Scholar
  15. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL (2004) TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–851PubMedCrossRefGoogle Scholar
  16. Bian Y, Terse A, Du J, Hall B, Molinolo A, Zhang P, Chen W, Flanders KC, Gutkind JS, Wakefield LM, Kulkarni AB (2009) Progressive tumor formation in mice with conditional deletion of TGF-β signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway. Cancer Res 69:5918–5926PubMedCrossRefGoogle Scholar
  17. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor-β in human disease. N Engl J Med 342:1350–1358PubMedCrossRefGoogle Scholar
  18. Bose R, Wrana JL (2006) Regulation of Par6 by extracellular signals. Curr Opin Cell Biol 18:206–212PubMedCrossRefGoogle Scholar
  19. Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, Jong RA, Hislop G, Chiarelli A, Minkin S, Yaffe MJ (2007) Mammographic density and the risk and detection of breast cancer. N Engl J Med 356:227–236PubMedCrossRefGoogle Scholar
  20. Brown CB, Boyer AS, Runyan RB, Barnett JV (1999) Requirement of type III TGF-β receptor for endocardial cell transformation in the heart. Science 283:2080–2082PubMedCrossRefGoogle Scholar
  21. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9:582–589PubMedCrossRefGoogle Scholar
  22. Cabodi S, Tinnirello A, Di Stefano P, Bisaro B, Ambrosino E, Castellano I, Sapino A, Arisio R, Cavallo F, Forni G, Glukhova M, Silengo L, Altruda F, Turco E, Tarone G, Defilippi P (2006) p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-Neu oncogene-dependent breast tumorigenesis. Cancer Res 66:4672–4680PubMedCrossRefGoogle Scholar
  23. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83PubMedCrossRefGoogle Scholar
  24. Carr BI, Hayashi I, Branum EL, Moses HL (1986) Inhibition of DNA synthesis in rat hepatocytes by platelet-derived type β transforming growth factor. Cancer Res 46:2330–2334PubMedGoogle Scholar
  25. Casas E, Kim J, Bendesky A, Ohno-Machado L, Wolfe CJ, Yang J (2011) Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res 71:245–254PubMedCrossRefGoogle Scholar
  26. Cavallaro U, Christofori G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4:118–132PubMedCrossRefGoogle Scholar
  27. Challen GA, Little MH (2006) A side order of stem cells: the SP phenotype. Stem Cells 24:3–12PubMedCrossRefGoogle Scholar
  28. Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH, Liu M, Chen CT, Yu D, Hung MC (2011) p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 13:317–323PubMedCrossRefGoogle Scholar
  29. Chang H, Brown CW, Matzuk MM (2002) Genetic analysis of the mammalian transforming growth factor-β superfamily. Endocr Rev 23:787–823PubMedCrossRefGoogle Scholar
  30. Chao YL, Shepard CR, Wells A (2010) Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 9:179PubMedCrossRefGoogle Scholar
  31. Chea HK, Wright CV, Swalla BJ (2005) Nodal signaling and the evolution of deuterostome gastrulation. Dev Dyn 234:269–278PubMedCrossRefGoogle Scholar
  32. Chen CR, Kang Y, Massague J (2001) Defective repression of c-Myc in breast cancer cells: a loss at the core of the transforming growth factor β growth arrest program. Proc Natl Acad Sci USA 98:992–999PubMedCrossRefGoogle Scholar
  33. Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, Arteaga CL, Neilson EG, Hayward SW, Moses HL (2005) Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks. Oncogene 24:5053–5068PubMedCrossRefGoogle Scholar
  34. Chin TM, Quinlan MP, Singh A, Sequist LV, Lynch TJ, Haber DA, Sharma SV, Settleman J (2008) Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non-small cell lung cancer following Cisplatin exposure: a cell culture model of second-line Erlotinib treatment. Clin Cancer Res 14:6867–6876PubMedCrossRefGoogle Scholar
  35. Christofori G (2003) Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. EMBO J 22:2318–2323PubMedCrossRefGoogle Scholar
  36. Comijn J, Berx G, Vermassen P, Verschueren K, Grunsven L van, Bruyneel E, Mareel M, Huylebroeck D, Roy F van (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7:1267–1278PubMedCrossRefGoogle Scholar
  37. Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, Robertson EJ (1994) A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120:1919–1928PubMedGoogle Scholar
  38. Cottonham CL, Kaneko S, Xu L (2010) miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem 285:35293–35302PubMedCrossRefGoogle Scholar
  39. Creighton CJ, Chang JC, Rosen JM (2010) Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J Mammary Gland Biol Neoplasia 15:253–260PubMedCrossRefGoogle Scholar
  40. Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, Akhurst RJ (1996) TGFβ1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86:531–542PubMedCrossRefGoogle Scholar
  41. Davis BN, Hilyard AC, Lagna G, Hata A (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454:56–61PubMedCrossRefGoogle Scholar
  42. Deonarain MP, Kousparou CA, Epenetos AA (2009) Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs 1:12–25PubMedCrossRefGoogle Scholar
  43. Dhasarathy A, Kajita M, Wade PA (2007) The transcription factor Snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor α. Mol Endocrinol 21:2907–2918PubMedCrossRefGoogle Scholar
  44. Drake JM, Strohbehn G, Bair TB, Moreland JG, Henry MD (2009) ZEB1 enhances transendothelial migration and represses the epithelial phenotype of prostate cancer cells. Mol Biol Cell 20:2207–2217PubMedCrossRefGoogle Scholar
  45. Duivenvoorden WC, Hirte HW, Singh G (1999) Transforming growth factor β1 acts as an inducer of matrix metalloproteinase expression and activity in human bone-metastasizing cancer cells. Clin Exp Metastasis 17:27–34PubMedCrossRefGoogle Scholar
  46. Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, Tlsty TD (2008) Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci 105:14867–14872PubMedCrossRefGoogle Scholar
  47. Dykxhoorn DM, Wu Y, Xie H, Yu F, Lal A, Petrocca F, Martinvalet D, Song E, Lim B, Lieberman J (2009) miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS One 4:e7181PubMedCrossRefGoogle Scholar
  48. Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL (2008) Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One 3:e2428PubMedCrossRefGoogle Scholar
  49. Ebnet K, Suzuki A, Ohno S, Vestweber D (2004) Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 117:19–29PubMedCrossRefGoogle Scholar
  50. Fang DD, Kim YJ, Lee CN, Aggarwal S, McKinnon K, Mesmer D, Norton J, Birse CE, He T, Ruben SM, Moore PA (2010) Expansion of CD133(+) colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery. Br J Cancer 102:1265–1275PubMedCrossRefGoogle Scholar
  51. Feng XH, Derynck R (2005) Specificity and versatility in TGF-β signaling through Smads. Annu Rev Cell Dev Biol 21:659–693PubMedCrossRefGoogle Scholar
  52. Fowlis DJ, Cui W, Johnson SA, Balmain A, Akhurst RJ (1996) Altered epidermal cell growth control in vivo by inducible expression of transforming growth factor β1 in the skin of transgenic mice. Cell Growth Differ 7:679–687PubMedGoogle Scholar
  53. Frank NY, Schatton T, Frank MH (2010) The therapeutic promise of the cancer stem cell concept. J Clin Invest 120:41–50PubMedCrossRefGoogle Scholar
  54. Frederick BA, Helfrich BA, Coldren CD, Zheng D, Chan D, Bunn PA Jr, Raben D (2007) Epithelial to mesenchymal transition predicts Gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther 6:1683–1691PubMedCrossRefGoogle Scholar
  55. Galliher AJ, Schiemann WP (2006) Beta3 integrin and Src facilitate transforming growth factor-β mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res 8:R42PubMedCrossRefGoogle Scholar
  56. Galliher AJ, Schiemann WP (2007) Src phosphorylates Tyr284 in TGF-β type II receptor and regulates TGF-β stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res 67:3752–3758PubMedCrossRefGoogle Scholar
  57. Galliher-Beckley AJ, Schiemann WP (2008) Grb2 binding to Tyr284 in TβR-II is essential for mammary tumor growth and metastasis stimulated by TGF-β. Carcinogenesis 29:244–251PubMedCrossRefGoogle Scholar
  58. Gatza CE, Oh SY, Blobe GC (2010) Roles for the type III TGF-β receptor in human cancer. Cell Signal 22:1163–1174PubMedCrossRefGoogle Scholar
  59. 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 (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567PubMedCrossRefGoogle Scholar
  60. Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627PubMedCrossRefGoogle Scholar
  61. Graham TR, Zhau HE, Odero-Marah VA, Osunkoya AO, Kimbro KS, Tighiouart M, Liu T, Simons JW, O'Regan RM (2008) Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res 68:2479–2488PubMedCrossRefGoogle Scholar
  62. Greenburg G, Hay ED (1982) Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol 95:333–339PubMedCrossRefGoogle Scholar
  63. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601PubMedCrossRefGoogle Scholar
  64. Grunert S, Jechlinger M, Beug H (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4:657–665PubMedCrossRefGoogle Scholar
  65. Gutova M, Najbauer J, Gevorgyan A, Metz MZ, Weng Y, Shih CC, Aboody KS (2007) Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS One 2:e243PubMedCrossRefGoogle Scholar
  66. Hajra KM, Chen DY, Fearon ER (2002) The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 62:1613–1618PubMedGoogle Scholar
  67. Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA (2000) Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 148:779–790PubMedCrossRefGoogle Scholar
  68. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323PubMedCrossRefGoogle Scholar
  69. Hong SP, Wen J, Bang S, Park S, Song SY (2009) CD44-positive cells are responsible for Gemcitabine resistance in pancreatic cancer cells. Int J Cancer 125:2323–2331PubMedCrossRefGoogle Scholar
  70. Hu Z, Zhang Z, Guise T, Seth P (2010) Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-β receptor II-Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum Gene Ther 21:1623–1629PubMedCrossRefGoogle Scholar
  71. Ignotz RA, Massague J (1986) Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261:4337–4345PubMedGoogle Scholar
  72. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, Natesan S, Brugge JS (2005) Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 171:1023–1034PubMedCrossRefGoogle Scholar
  73. Iseri OD, Kars MD, Arpaci F, Atalay C, Pak I, Gunduz U (2011) Drug resistant MCF-7 cells exhibit epithelial-mesenchymal transition gene expression pattern. Biomed Pharmacother 65:40–45PubMedCrossRefGoogle Scholar
  74. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD (2007) Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25:1315–1321PubMedCrossRefGoogle Scholar
  75. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J (1995) Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11:415–421PubMedCrossRefGoogle Scholar
  76. Kajiyama H, Shibata K, Terauchi M, Yamashita M, Ino K, Nawa A, Kikkawa F (2007) Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol 31:277–283PubMedGoogle Scholar
  77. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedCrossRefGoogle Scholar
  78. Kang JS, Liu C, Derynck R (2009) New regulatory mechanisms of TGF-β receptor function. Trends Cell Biol 19:385–394PubMedCrossRefGoogle Scholar
  79. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537–549PubMedCrossRefGoogle Scholar
  80. Kim BG, Li C, Qiao W, Mamura M, Kasprzak B, Anver M, Wolfraim L, Hong S, Mushinski E, Potter M, Kim SJ, Fu XY, Deng C, Letterio JJ (2006) Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015–1019PubMedCrossRefGoogle Scholar
  81. Kim ES, Sohn YW, Moon A (2007) TGF-β-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett 252:147–156PubMedCrossRefGoogle Scholar
  82. Kim HJ, Litzenburger BC, Cui X, Delgado DA, Grabiner BC, Lin X, Lewis MT, Gottardis MM, Wong TW, Attar RM, Carboni JM, Lee AV (2007) Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-κB and snail. Mol Cell Biol 27:3165–3175PubMedCrossRefGoogle Scholar
  83. Kim W, Seok Kang Y, Soo Kim J, Shin NY, Hanks SK, Song WK (2008) The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in transforming growth factor-β signaling. Mol Biol Cell 19:2135–2146PubMedCrossRefGoogle Scholar
  84. Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, Cheng JQ (2008) MicroRNA-155 is regulated by the transforming growth factor β/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 28:6773–6784PubMedCrossRefGoogle Scholar
  85. Korpal M, Lee ES, Hu G, Kang Y (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283:14910–14914PubMedCrossRefGoogle Scholar
  86. Lee YH, Albig AR, Regner M, Schiemann BJ, Schiemann WP (2008) Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-β in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis 29:2243–2251PubMedCrossRefGoogle Scholar
  87. Lemoli RM, Salvestrini V, Bianchi E, Bertolini F, Fogli M, Amabile M, Tafuri A, Salati S, Zini R, Testoni N, Rabascio C, Rossi L, Martin-Padura I, Castagnetti F, Marighetti P, Martinelli G, Baccarani M, Ferrari S, Manfredini R (2009) Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34- cell population with intrinsic resistance to Imatinib. Blood 114:5191–5200PubMedCrossRefGoogle Scholar
  88. Leptin M (1991) Twist and Snail as positive and negative regulators during Drosophila mesoderm development. Genes Dev 5:1568–1576PubMedCrossRefGoogle Scholar
  89. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906PubMedCrossRefGoogle Scholar
  90. Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67PubMedCrossRefGoogle Scholar
  91. Liu T, Xu F, Du X, Lai D, Zhao Y, Huang Q, Jiang L, Huang W, Cheng W, Liu Z (2010) Establishment and characterization of multi-drug resistant, prostate carcinoma-initiating stem-like cells from human prostate cancer cell lines 22RV1. Mol Cell Biochem 340:265–273PubMedCrossRefGoogle Scholar
  92. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, Abbruzzese JL, Hortobagyi GN, Hung MC (2007) Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 67:9066–9076PubMedCrossRefGoogle Scholar
  93. Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, Teruya-Feldstein J, Reinhardt F, Onder TT, Valastyan S, Westermann F, Speleman F, Vandesompele J, Weinberg RA (2010) miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12:247–256PubMedGoogle Scholar
  94. Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA (2007) Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA 104:10069–10074PubMedCrossRefGoogle Scholar
  95. 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 (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715PubMedCrossRefGoogle Scholar
  96. Massague J (1998) TGF-β signal transduction. Annu Rev Biochem 67:753–791PubMedCrossRefGoogle Scholar
  97. Massague J (2008) TGF β in cancer. Cell 134:215–230PubMedCrossRefGoogle Scholar
  98. Massague J, Gomis RR (2006) The logic of TGFβ signaling. FEBS Lett 580:2811–2820PubMedCrossRefGoogle Scholar
  99. Masszi A, Di Ciano C, Sirokmany G, Arthur WT, Rotstein OD, Wang J, McCulloch CA, Rosivall L, Mucsi I, Kapus A (2003) Central role for Rho in TGF-β1-induced α-smooth muscle actin expression during epithelial-mesenchymal transition. Am J Physiol Renal Physiol 284:F911–F924PubMedGoogle Scholar
  100. Mendez MG, Kojima S, Goldman RD (2010) Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 24:1838–1851PubMedCrossRefGoogle Scholar
  101. Micalizzi DS, Ford HL (2009) Epithelial-mesenchymal transition in development and cancer. Future Oncol 5:1129–1143PubMedCrossRefGoogle Scholar
  102. Micalizzi DS, Farabaugh SM, Ford HL (2010a) Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 15:117–134PubMedCrossRefGoogle Scholar
  103. Micalizzi DS, Wang CA, Farabaugh SM, Schiemann WP, Ford H (2010b) Homeoprotein Six1 increases TGF-β type I receptor and converts TGF-β signaling from suppressive to supportive for tumor growth. Cancer Res 70:10371–10380PubMedCrossRefGoogle Scholar
  104. Miettinen PJ, Ebner R, Lopez AR, Derynck R (1994) TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127:2021–2036PubMedCrossRefGoogle Scholar
  105. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524PubMedCrossRefGoogle Scholar
  106. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3:e2888PubMedCrossRefGoogle Scholar
  107. Moses HL, Branum EL, Proper JA, Robinson RA (1981) Transforming growth factor production by chemically transformed cells. Cancer Res 41:2842–2848PubMedGoogle Scholar
  108. Moustakas A, Heldin CH (2005) Non-Smad TGF-β signals. J Cell Sci 118:3573–3584PubMedCrossRefGoogle Scholar
  109. Munz M, Baeuerle PA, Gires O (2009) The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 69:5627–5629PubMedCrossRefGoogle Scholar
  110. Muraoka-Cook RS, Kurokawa H, Koh Y, Forbes JT, Roebuck LR, Barcellos-Hoff MH, Moody SE, Chodosh LA, Arteaga CL (2004) Conditional overexpression of active transforming growth factor β1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res 64:9002–9011PubMedCrossRefGoogle Scholar
  111. Murillo MM, Castillo G del, Sanchez A, Fernandez M, Fabregat I (2005) Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes. Oncogene 24:4580–4587PubMedCrossRefGoogle Scholar
  112. Nakajima A, Ito Y, Asano M, Maeno M, Iwata K, Mitsui N, Shimizu N, Cui XM, Shuler CF (2007) Functional role of transforming growth factor-β type III receptor during palatal fusion. Dev Dyn 236:791–801PubMedCrossRefGoogle Scholar
  113. Neil JR, Johnson KM, Nemenoff RA, Schiemann WP (2008) Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis 29:2227–2235PubMedCrossRefGoogle Scholar
  114. Niessen CM (2007) Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 127:2525–2532PubMedCrossRefGoogle Scholar
  115. O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110PubMedCrossRefGoogle Scholar
  116. Ohashi S, Natsuizaka M, Wong GS, Michaylira CZ, Grugan KD, Stairs DB, Kalabis J, Vega ME, Kalman RA, Nakagawa M, Klein-Szanto AJ, Herlyn M, Diehl JA, Rustgi AK, Nakagawa H (2010) Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors. Cancer Res 70:4174–4184PubMedCrossRefGoogle Scholar
  117. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68:3645–3654PubMedCrossRefGoogle Scholar
  118. Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, Salto-Tellez M (2010) CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol 23:450–457PubMedCrossRefGoogle Scholar
  119. Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL (2005) Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307:1603–1609PubMedCrossRefGoogle Scholar
  120. Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, Alekseyev YO, Thiagalingam A, Abdolmaleky HM, Lenburg M, Thiagalingam S (2010) Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res 70:968–978PubMedCrossRefGoogle Scholar
  121. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902PubMedCrossRefGoogle Scholar
  122. Parvani JG, Taylor MA, Schiemann WP (2011) Noncanonical TGF-β signaling during mammary tumorigenesis. J Mammary Gland Biol Neoplasia 16:127–146PubMedCrossRefGoogle Scholar
  123. 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 (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254PubMedCrossRefGoogle Scholar
  124. Patsialou A, Wyckoff JB, Wang Y, Goswami S, Stanley ER, Condeelis JS (2009) Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res 69:9498–9506PubMedCrossRefGoogle Scholar
  125. Rahimi RA, Leof EB (2007) TGF-β signaling: a tale of two responses. J Cell Biochem 102:593–608PubMedCrossRefGoogle Scholar
  126. Raible DW (2006) Development of the neural crest: achieving specificity in regulatory pathways. Curr Opin Cell Biol 18:698–703PubMedCrossRefGoogle Scholar
  127. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115PubMedCrossRefGoogle Scholar
  128. Ridley AJ, Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70:389–399PubMedCrossRefGoogle Scholar
  129. Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB (1981) New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci USA 78:5339–5343PubMedCrossRefGoogle Scholar
  130. Saha D, Datta PK, Sheng H, Morrow JD, Wada M, Moses HL, Beauchamp RD (1999) Synergistic induction of cyclooxygenase-2 by transforming growth factor-β1 and epidermal growth factor inhibits apoptosis in epithelial cells. Neoplasia 1:508–517PubMedCrossRefGoogle Scholar
  131. Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, Najima Y, Takagi S, Aoki Y, Wake A, Taniguchi S, Shultz LD, Ishikawa F (2010) Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28:275–280PubMedGoogle Scholar
  132. Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T (1997) TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFβ knockout phenotypes. Development 124:2659–2670PubMedGoogle Scholar
  133. Sauka-Spengler T, Bronner-Fraser M (2008) A gene regulatory network orchestrates neural crest formation. Nat Rev Mol Cell Biol 9:557–568PubMedCrossRefGoogle Scholar
  134. Sayan AE, Griffiths TR, Pal R, Browne GJ, Ruddick A, Yagci T, Edwards R, Mayer NJ, Qazi H, Goyal S, Fernandez S, Straatman K, Jones GD, Bowman KJ, Colquhoun A, Mellon JK, Kriajevska M, Tulchinsky E (2009) SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proc Natl Acad Sci USA 106:14884–14889PubMedCrossRefGoogle Scholar
  135. Schiemann WP (2007) Targeted TGF-β chemotherapies: friend or foe in treating human malignancies? Expert Rev Anticancer Ther 7:609–611PubMedCrossRefGoogle Scholar
  136. Schneeberger EE, Lynch RD (2004) The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 286:C1213–C1228PubMedCrossRefGoogle Scholar
  137. Shafee N, Smith CR, Wei S, Kim Y, Mills GB, Hortobagyi GN, Stanbridge EJ, Lee EY (2008) Cancer stem cells contribute to Cisplatin resistance in BRCA1/p53-mediated mouse mammary tumors. Cancer Res 68:3243–3250PubMedCrossRefGoogle Scholar
  138. Shi MF, Jiao J, Lu WG, Ye F, Ma D, Dong QG, Xie X (2010) Identification of cancer stem cell-like cells from human epithelial ovarian carcinoma cell line. Cell Mol Life Sci 67:3915–3925PubMedCrossRefGoogle Scholar
  139. Shi Y, Massague J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685–700PubMedCrossRefGoogle Scholar
  140. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11:259–273PubMedCrossRefGoogle Scholar
  141. Silberstein GB, Daniel CW (1987) Reversible inhibition of mammary gland growth by transforming growth factor-β. Science 237:291–293PubMedCrossRefGoogle Scholar
  142. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751PubMedCrossRefGoogle Scholar
  143. Singh M, Spoelstra NS, Jean A, Howe E, Torkko KC, Clark HR, Darling DS, Shroyer KR, Horwitz KB, Broaddus RR, Richer JK (2008) ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol 21:912–923PubMedCrossRefGoogle Scholar
  144. Sivakumar R, Koga H, Selvendiran K, Maeyama M, Ueno T, Sata M (2009) Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition. Int J Oncol 34:329–338PubMedGoogle Scholar
  145. Skromne I, Stern CD (2001) Interactions between Wnt and Vg1 signalling pathways initiate primitive streak formation in the chick embryo. Development 128:2915–2927PubMedGoogle Scholar
  146. Takaishi K, Sasaki T, Kotani H, Nishioka H, Takai Y (1997) Regulation of cell-cell adhesion by Rac and Rho small G proteins in MDCK cells. J Cell Biol 139:1047–1059PubMedCrossRefGoogle Scholar
  147. Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, Hollier BG, Ram PT, Lander ES, Rosen JM, Weinberg RA, Mani SA (2010) Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA 107:15449–15454PubMedCrossRefGoogle Scholar
  148. Taylor MA, Parvani JG, Schiemann WP (2010) The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-β in normal and malignant mammary epithelial cells. J Mammary Gland Biol Neoplasia 15:169–190PubMedCrossRefGoogle Scholar
  149. Taylor MA, Amin J, Kirschmann DA, Schiemann WP (2011) Lysyl oxidase contributes to mechanotransduction-mediated regulation of transforming growth factor-β signaling in breast cancer cells. Neoplasia 13:406–418PubMedGoogle Scholar
  150. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
  151. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890PubMedCrossRefGoogle Scholar
  152. Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65:9455–9462PubMedCrossRefGoogle Scholar
  153. Thomson S, Petti F, Sujka-Kwok I, Epstein D, Haley JD (2008) Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. Clin Exp Metastasis 25:843–854PubMedCrossRefGoogle Scholar
  154. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A (2006) Transforming growth factor-β employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol 174:175–183PubMedCrossRefGoogle Scholar
  155. Tian M, Schiemann WP (2009) The TGF-β paradox in human cancer: an update. Future Oncol 5:259–271PubMedCrossRefGoogle Scholar
  156. Tian M, Schiemann WP (2010) PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis. FASEB J 24:1105–1116PubMedCrossRefGoogle Scholar
  157. Tian M, Neil JR, Schiemann WP (2011) Transforming growth factor-β and the hallmarks of cancer. Cell Signal 23:951–962PubMedCrossRefGoogle Scholar
  158. Tilghman RW, Cowan CR, Mih JD, Koryakina Y, Gioeli D, Slack-Davis JK, Blackman BR, Tschumperlin DJ, Parsons JT (2010) Matrix rigidity regulates cancer cell growth and cellular phenotype. PLoS One 5:e12905PubMedCrossRefGoogle Scholar
  159. To K, Fotovati A, Reipas KM, Law JH, Hu K, Wang J, Astanehe A, Davies AH, Lee L, Stratford AL, Raouf A, Johnson P, Berquin IM, Royer HD, Eaves CJ, Dunn SE (2010) Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere growth, and drug resistance. Cancer Res 70:2840–2851PubMedCrossRefGoogle Scholar
  160. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1:389–402PubMedCrossRefGoogle Scholar
  161. Tokar EJ, Qu W, Liu J, Liu W, Webber MM, Phang JM, Waalkes MP (2010) Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst 102:638–649PubMedCrossRefGoogle Scholar
  162. Turley EA, Veiseh M, Radisky DC, Bissell MJ (2008) Mechanisms of disease: epithelial-mesenchymal transition—does cellular plasticity fuel neoplastic progression? Nat Clin Pract Oncol 5:280–290PubMedCrossRefGoogle Scholar
  163. Viloria-Petit AM, David L, Jia JY, Erdemir T, Bane AL, Pinnaduwage D, Roncari L, Narimatsu M, Bose R, Moffat J, Wong JW, Kerbel RS, O'Malley FP, Andrulis IL, Wrana JL (2009) A role for the TGFβ-Par6 polarity pathway in breast cancer progression. Proc Natl Acad Sci USA 106:14028–14033PubMedCrossRefGoogle Scholar
  164. Visvader JE (2011) Cells of origin in cancer. Nature 469:314–322PubMedCrossRefGoogle Scholar
  165. Wang B, Yang H, Huang YZ, Yan RH, Liu FJ, Zhang JN (2010) Biologic characteristics of the side population of human small cell lung cancer cell line H446. Chin J Cancer 29:254–260PubMedGoogle Scholar
  166. Wang F, Hansen RK, Radisky D, Yoneda T, Barcellos-Hoff MH, Petersen OW, Turley EA, Bissell MJ (2002) Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. J Natl Cancer Inst 94:1494–1503PubMedCrossRefGoogle Scholar
  167. Wang SE, Xiang B, Zent R, Quaranta V, Pozzi A, Arteaga CL (2009) Transforming growth factor β induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton. Cancer Res 69:475–482PubMedCrossRefGoogle Scholar
  168. Wang W, Wyckoff JB, Goswami S, Wang Y, Sidani M, Segall JE, Condeelis JS (2007) Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer Res 67:3505–3511PubMedCrossRefGoogle Scholar
  169. Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH (2009) Acquisition of epithelial-mesenchymal transition phenotype of Gemcitabine-resistant pancreatic cancer cells is linked with activation of the Notch signaling pathway. Cancer Res 69:2400–2407PubMedCrossRefGoogle Scholar
  170. Weaver VM, Peterson OW, Wang F, Larabell CA, Briand P, Damsky C, Bissell MJ (1997) Reversion of the malignant phenotype of human breast cancer cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 137:231–245PubMedCrossRefGoogle Scholar
  171. Weaver VM, Lelievre S, Lakins JN, Chrenek MA, Jones JC, Giancotti F, Werb Z, Bissell MJ (2002) Beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2:205–216PubMedCrossRefGoogle Scholar
  172. Wendt MK, Schiemann WP (2009) Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis. Breast Cancer Res 11:R68PubMedCrossRefGoogle Scholar
  173. Wendt MK, Allington TM, Schiemann WP (2009a) Mechanisms of the epithelial-mesenchymal transition by TGF-β. Future Oncol 5:1145–1168PubMedCrossRefGoogle Scholar
  174. Wendt MK, Smith JA, Schiemann WP (2009b) p130Cas is required for mammary tumor growth and transforming growth factor-β-mediated metastasis through regulation of Smad2/3 activity. J Biol Chem 284:34145–34156PubMedCrossRefGoogle Scholar
  175. Wendt MK, Smith JA, Schiemann WP (2010) Transforming growth factor-β-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene 29:6485–6498PubMedCrossRefGoogle Scholar
  176. Whittard JD, Craig SE, Mould AP, Koch A, Pertz O, Engel J, Humphries MJ (2002) E-cadherin is a ligand for integrin α2β1. Matrix Biol 21:525–532PubMedCrossRefGoogle Scholar
  177. Wipff PJ, Rifkin DB, Meister JJ, Hinz B (2007) Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J Cell Biol 179:1311–1323PubMedCrossRefGoogle Scholar
  178. Wu H, Liang YL, Li Z, Jin J, Zhang W, Duan L, Zha X (2006) Positive expression of E-cadherin suppresses cell adhesion to fibronectin via reduction of alpha5beta1 integrin in human breast carcinoma cells. J Cancer Res Clin Oncol 132:795–803PubMedCrossRefGoogle Scholar
  179. Wyckoff JB, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall JE, Condeelis JS (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64:7022–7029PubMedCrossRefGoogle Scholar
  180. Wynn TA (2007) Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117:524–529PubMedCrossRefGoogle Scholar
  181. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210PubMedCrossRefGoogle Scholar
  182. Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829PubMedCrossRefGoogle Scholar
  183. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939PubMedCrossRefGoogle Scholar
  184. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC, Moses HL (2008) Abrogation of TGF-β signaling in mammary carcinomas recruits Gr-1+ CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23–35PubMedCrossRefGoogle Scholar
  185. Yauch RL, Januario T, Eberhard DA, Cavet G, Zhu W, Fu L, Pham TQ, Soriano R, Stinson J, Seshagiri S, Modrusan Z, Lin CY, O'Neill V, Amler LC (2005) Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of Erlotinib in lung cancer patients. Clin Cancer Res 11:8686–8698PubMedCrossRefGoogle Scholar
  186. Yazhou C, Wenlv S, Weidong Z, Licun W (2004) Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breast. Tumour Biol 25:290–295PubMedCrossRefGoogle Scholar
  187. Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, Piek E, Bottinger EP (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc Natl Acad Sci USA 98:6686–6691PubMedCrossRefGoogle Scholar
  188. Zavadil J, Narasimhan M, Blumenberg M, Schneider RJ (2007) Transforming growth factor-β and microRNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 185:157–161PubMedCrossRefGoogle Scholar
  189. Zeng Q, Phukan S, Xu Y, Sadim M, Rosman DS, Pennison M, Liao J, Yang GY, Huang CC, Valle L, Di Cristofano A, Chapelle A de la, Pasche B (2009) Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer Res 69:678–686PubMedCrossRefGoogle Scholar
  190. Zha J, Lackner MR (2010) Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin Cancer Res 16:2512–2517PubMedCrossRefGoogle Scholar
  191. Zhang N, Li R, Tao KS, Cao DY, Ti ZY, Ding R, Cai L, Zhang FQ, Dou KF (2010) Characterization of a stem-like population in hepatocellular carcinoma MHCC97 cells. Oncol Rep 23:827–831PubMedCrossRefGoogle Scholar
  192. Zhang W, Alt-Holland A, Margulis A, Shamis Y, Fusenig NE, Rodeck U, Garlick JA (2006) E-cadherin loss promotes the initiation of squamous cell carcinoma invasion through modulation of integrin-mediated adhesion. J Cell Sci 119:283–291PubMedCrossRefGoogle Scholar
  193. Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR (1993) Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation. Nature 361:543–547PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Michael K. Wendt
    • 1
  • Maozhen Tian
    • 1
  • William P. Schiemann
    • 1
  1. 1.Case Comprehensive Cancer Center, Division of General Medical Sciences—OncologyCase Western Reserve UniversityClevelandUSA

Personalised recommendations