Frontiers of Medicine

, Volume 12, Issue 4, pp 387–411 | Cite as

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

  • Kohei MiyazonoEmail author
  • Yoko Katsuno
  • Daizo Koinuma
  • Shogo Ehata
  • Masato Morikawa
Open Access


Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.


TGF-β EMT lung cancer pancreatic cancer latent form immune function GARP 



We thank all the members of the Molecular Pathology Laboratory at The University of Tokyo, especially Drs. Kei Takahashi, Shimpei I. Kubota, and Akihiro Katsura, for discussion. We also thank Prof. Hiroki R. Ueda (Department of Systems Pharmacology, The University of Tokyo) for collaboration. This research is supported by KAKENHI, grants-in-aid for scientific research on Innovative Area on Integrated Analysis and Regulation of Cellular Diversity (No. 17H06326, KM), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) and Scientific Research (S) (No. 15H05774, KM) from the Japan Society for the Promotion of Science (JSPS). This work is also supported by Project for Cancer Research and Therapeutic Evolution (P-CREATE; No. 17cm0106313h0002, SE) from the Japan Agency for Medical Research and Development (AMED). KM was supported by Yasuda Medical Foundation.


  1. 1.
    Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 2016; 8(5): a021873Google Scholar
  2. 2.
    Shilling SH, Hjelmeland AB, Rich JN, Wang XF. TGF-β: multipotential cytokine. In: Derynck R, Miyazono K, eds. The TGF-β Family. New York: Cold Spring Harbor Laboratory Press, 2007: 49–77Google Scholar
  3. 3.
    Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci USA 1981; 78(9): 5339–5343Google Scholar
  4. 4.
    Moses HL, Branum EL, Proper JA, Robinson RA. Transforming growth factor production by chemically transformed cells. Cancer Res 1981; 41(7): 2842–2848Google Scholar
  5. 5.
    Moses HL, Roberts AB, Derynck R. The discovery and early days of TGF-β: a historical perspective. Cold Spring Harb Perspect Biol 2016; 8(7): a021865Google Scholar
  6. 6.
    Miettinen PJ, Ebner R, Lopez AR, Derynck R. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 1994; 127(6 Pt 2): 2021–2036Google Scholar
  7. 7.
    Bierie B, Moses HL. Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006; 6(7): 506–520Google Scholar
  8. 8.
    Massagué J. TGFβ in cancer. Cell 2008; 134(2): 215–230Google Scholar
  9. 9.
    Seoane J, Gomis RR. TGF-β family signaling in tumor suppression and cancer progression. Cold Spring Harb Perspect Biol 2017; 9 (12): a022277Google Scholar
  10. 10.
    Colak S, ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer 2017; 3(1): 56–71Google Scholar
  11. 11.
    Grady WM, Markowitz SD. TGF-β signaling pathway in tumor suppression. In: Derynck R, Miyazono K, eds. The TGF-β Family. New York: Cold Spring Harbor Laboratory Press, 2007: 889–937Google Scholar
  12. 12.
    Roberts AB, Wakefield LM. The two faces of transforming growth factor β in carcinogenesis. Proc Natl Acad Sci USA 2003; 100(15): 8621–8623Google Scholar
  13. 13.
    Davis H, Raja E, Miyazono K, Tsubakihara Y, Moustakas A. Mechanisms of action of bone morphogenetic proteins in cancer. Cytokine Growth Factor Rev 2016; 27: 81–92Google Scholar
  14. 14.
    Wakefield LM, Hill CS. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer 2013; 13(5): 328–341Google Scholar
  15. 15.
    Robertson IB, Rifkin DB. Regulation of the bioavailability of TGF-β and TGF-β-related proteins. Cold Spring Harb Perspect Biol 2016; 8(6): a021907Google Scholar
  16. 16.
    Stockis J, Colau D, Coulie PG, Lucas S. Membrane protein GARP is a receptor for latent TGF-β on the surface of activated human Treg. Eur J Immunol 2009; 39(12): 3315–3322Google Scholar
  17. 17.
    Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM. GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009; 106(32): 13445–13450Google Scholar
  18. 18.
    Heldin CH, Miyazono K, ten Dijke P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390 (6659): 465–471Google Scholar
  19. 19.
    Feng XH, Derynck R. Specificity and versatility in TGF-β signaling through Smads. Annu Rev Cell Dev Biol 2005; 21(1): 659–693Google Scholar
  20. 20.
    Yan X, Xiong X, Chen YG. Feedback regulation of TGF-β signaling. Acta Biochim Biophys Sin (Shanghai) 2018; 50(1): 37–50Google Scholar
  21. 21.
    Miyazawa K, Miyazono K. Regulation of TGF-β family signaling by inhibitory Smads. Cold Spring Harb Perspect Biol 2017; 9(3): a022095Google Scholar
  22. 22.
    Zhang YE. Non-Smad signaling pathways of the TGF-β family. Cold Spring Harb Perspect Biol 2017; 9(2): a022129Google Scholar
  23. 23.
    Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, Smith SM, Derynck R. TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 2007; 26(17): 3957–3967Google Scholar
  24. 24.
    Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, Zhang S, Heldin CH, Landström M. The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinaseindependent manner. Nat Cell Biol 2008; 10(10): 1199–1207Google Scholar
  25. 25.
    Yamashita M, Fatyol K, Jin C, Wang X, Liu Z, Zhang YE. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β. Mol Cell 2008; 31(6): 918–924Google Scholar
  26. 26.
    Zhang L, Zhou F, García de Vinuesa A, de Kruijf EM, Mesker WE, Hui L, Drabsch Y, Li Y, Bauer A, Rousseau A, Sheppard KA, Mickanin C, Kuppen PJ, Lu CX, ten Dijke P. TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. Mol Cell 2013; 51(5): 559–572Google Scholar
  27. 27.
    Mu Y, Sundar R, Thakur N, Ekman M, Gudey SK, Yakymovych M, Hermansson A, Dimitriou H, Bengoechea-Alonso MT, Ericsson J, Heldin CH, Landström M. TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer. Nat Commun 2011; 2(1): 330Google Scholar
  28. 28.
    Gudey SK, Sundar R, Mu Y, Wallenius A, Zang G, Bergh A, Heldin CH, Landström M. TRAF6 stimulates the tumor-promoting effects of TGFβ type I receptor through polyubiquitination and activation of presenilin 1. Sci Signal 2014; 7(307): ra2Google Scholar
  29. 29.
    Deheuninck J, Luo K. Ski and SnoN, potent negative regulators of TGF-β signaling. Cell Res 2009; 19(1): 47–57Google Scholar
  30. 30.
    Xu P, Lin X, Feng XH. Posttranslational regulation of Smads. Cold Spring Harb Perspect Biol 2016; 8(12): a022087Google Scholar
  31. 31.
    Morikawa M, Koinuma D, Miyazono K, Heldin CH. Genomewide mechanisms of Smad binding. Oncogene 2013; 32(13): 1609–1615Google Scholar
  32. 32.
    Hata A, Lieberman J. Dysregulation of microRNA biogenesis and gene silencing in cancer. Sci Signal 2015; 8(368): re3Google Scholar
  33. 33.
    Wang J, Shao N, Ding X, Tan B, Song Q, Wang N, Jia Y, Ling H, Cheng Y. Crosstalk between transforming growth factor-β signaling pathway and long non-coding RNAs in cancer. Cancer Lett 2016; 370(2): 296–301Google Scholar
  34. 34.
    Siegel PM, Massagué J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev Cancer 2003; 3(11): 807–821Google Scholar
  35. 35.
    Zhang Y, Alexander PB, Wang XF. TGF-β family signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol 2017; 9(4): a022145Google Scholar
  36. 36.
    Sánchez-Capelo A. Dual role for TGF-β1 in apoptosis. Cytokine Growth Factor Rev 2005; 16(1): 15–34Google Scholar
  37. 37.
    Derynck R, Muthusamy BP, Saeteurn KY. Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition. Curr Opin Cell Biol 2014; 31: 56–66Google Scholar
  38. 38.
    Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell 2016; 166(1): 21–45Google Scholar
  39. 39.
    Moustakas A, Heldin CH. Mechanisms of TGFβ-induced epithelial-mesenchymal transition. J Clin Med 2016; 5(7): 63Google Scholar
  40. 40.
    Sakaki-Yumoto M, Katsuno Y, Derynck R. TGF-β family signaling in stem cells. Biochim Biophys Acta 2013; 1830(2): 2280–2296Google Scholar
  41. 41.
    Ikushima H, Miyazono K. TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer 2010; 10(6): 415–424Google Scholar
  42. 42.
    Caja L, Kahata K, Moustakas A. Context-dependent action of transforming growth factor β family members on normal and cancer stem cells. Curr Pharm Des 2012; 18(27): 4072–4086Google Scholar
  43. 43.
    Katsuno Y, Lamouille S, Derynck R. TGF-β signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol 2013; 25(1): 76–84Google Scholar
  44. 44.
    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. Molecular definition of breast tumor heterogeneity. Cancer Cell 2007; 11(3): 259–273Google Scholar
  45. 45.
    Böttinger EP. TGF-β and fibrosis. In: Derynck R, Miyazono K, eds. The TGF-β Family. New York: Cold Spring Harbor Laboratory Press, 2007: 989–1021Google Scholar
  46. 46.
    Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 2013; 13(11): 788–799Google Scholar
  47. 47.
    Kim KK, Sheppard D, Chapman HA. TGF-β1 signaling and tissue fibrosis. Cold Spring Harb Perspect Biol 2018; 10(4): a022293Google Scholar
  48. 48.
    Goumans MJ, ten Dijke P. TGF-β signaling in control of cardiovascular function. Cold Spring Harb Perspect Biol 2018; 10(2): a022210Google Scholar
  49. 49.
    Komuro A, Yashiro M, Iwata C, Morishita Y, Johansson E, Matsumoto Y, Watanabe A, Aburatani H, Miyoshi H, Kiyono K, Shirai YT, Suzuki HI, Hirakawa K, Kano MR, Miyazono K. Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor β signaling. J Natl Cancer Inst 2009; 101(8): 592–604Google Scholar
  50. 50.
    Watabe T, Nishihara A, Mishima K, Yamashita J, Shimizu K, Miyazawa K, Nishikawa S, Miyazono K. TGF-β receptor kinase inhibitor enhances growth and integrity of embryonic stem cellderived endothelial cells. J Cell Biol 2003; 163(6): 1303–1311Google Scholar
  51. 51.
    Yoshimatsu Y, Watabe T. Roles of TGF-β signals in endothelialmesenchymal transition during cardiac fibrosis. Int J Inflam 2011; 2011: 724080Google Scholar
  52. 52.
    Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008; 133(1): 66–77Google Scholar
  53. 53.
    Yoshimura A, Wakabayashi Y, Mori T. Cellular and molecular basis for the regulation of inflammation by TGF-β. J Biochem 2010; 147(6): 781–792Google Scholar
  54. 54.
    Li MO, Flavell RA. TGF-β: a master of all T cell trades. Cell 2008; 134(3): 392–404Google Scholar
  55. 55.
    Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by TGFβ. Nat Rev Immunol 2010; 10(8): 554–567Google Scholar
  56. 56.
    Sanjabi S, Oh SA, Li MO. Regulation of the immune response by TGF-β: from conception to autoimmunity and infection. Cold Spring Harb Perspect Biol 2017; 9(6): a022236Google Scholar
  57. 57.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunziata N, Doetschman T. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 1992; 359(6397): 693–699Google Scholar
  58. 58.
    Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 1993; 90(2): 770–774Google Scholar
  59. 59.
    Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. Conversion of peripheral CD4+CD25–naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med 2003; 198(12): 1875–1886Google Scholar
  60. 60.
    Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 2008; 9(6): 632–640Google Scholar
  61. 61.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24(2): 179–189Google Scholar
  62. 62.
    Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 2007; 448(7152): 484–487Google Scholar
  63. 63.
    Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ. Nat Immunol 2005; 6 (6): 600–607Google Scholar
  64. 64.
    Miyazono K, Ehata S, Koinuma D. Tumor-promoting functions of transforming growth factor-β in progression of cancer. Ups J Med Sci 2012; 117(2): 143–152Google Scholar
  65. 65.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178–196Google Scholar
  66. 66.
    Brabletz S, Brabletz T. The ZEB/miR-200 feedback loop—a motor of cellular plasticity in development and cancer? EMBO Rep 2010; 11(9): 670–677Google Scholar
  67. 67.
    Lamouille S, Subramanyam D, Blelloch R, Derynck R. Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr Opin Cell Biol 2013; 25(2): 200–207Google Scholar
  68. 68.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008; 10(5): 593–601Google Scholar
  69. 69.
    Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Farshid G, Lim YY, Lindeman GJ, Shannon MF, Drew PA, Khew-Goodall Y, Goodall GJ. An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell 2011; 22(10): 1686–1698Google Scholar
  70. 70.
    Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 2008; 9(6): 582–589Google Scholar
  71. 71.
    Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 2008; 22(7): 894–907Google Scholar
  72. 72.
    Siemens H, Jackstadt R, Hünten S, Kaller M, Menssen A, Götz U, Hermeking H. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 2011; 10(24): 4256–4271Google Scholar
  73. 73.
    Lu M, Jolly MK, Levine H, Onuchic JN, Ben-Jacob E. MicroRNAbased regulation of epithelial-hybrid-mesenchymal fate determination. Proc Natl Acad Sci USA 2013; 110(45): 18144–18149Google Scholar
  74. 74.
    Tian XJ, Zhang H, Xing J. Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition. Biophys J 2013; 105(4): 1079–1089Google Scholar
  75. 75.
    Zhang J, Tian XJ, Zhang H, Teng Y, Li R, Bai F, Elankumaran S, Xing J. TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal 2014; 7(345): ra91Google Scholar
  76. 76.
    Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC, Wang SB, Wang YZ, Yang Y, Yang N, Zhou WP, Yang GS, Sun SH. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 2014; 25(5): 666–681Google Scholar
  77. 77.
    Richards EJ, Zhang G, Li ZP, Permuth-Wey J, Challa S, Li Y, Kong W, Dan S, Bui MM, Coppola D, Mao WM, Sellers TA, Cheng JQ. Long non-coding RNAs (lncRNA) regulated by transforming growth factor (TGF) β: lncRNA-hit-mediated TGFβ-induced epithelial to mesenchymal transition in mammary epithelia. J Biol Chem 2015; 290(11): 6857–6867Google Scholar
  78. 78.
    Terashima M, Tange S, Ishimura A, Suzuki T. MEG3 long noncoding RNA contributes to the epigenetic regulation of epithelial-mesenchymal transition in lung cancer cell lines. J Biol Chem 2017; 292(1): 82–99Google Scholar
  79. 79.
    Katsura A, Suzuki HI, Ueno T, Mihira H, Yamazaki T, Yasuda T, Watabe T, Mano H, Yamada Y, Miyazono K. MicroRNA-31 is a positive modulator of endothelial-mesenchymal transition and associated secretory phenotype induced by TGF-β. Genes Cells 2016; 21(1): 99–116Google Scholar
  80. 80.
    Lamouille S, Derynck R. Cell size and invasion in TGF-β-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 2007; 178(3): 437–451Google Scholar
  81. 81.
    Pon YL, Zhou HY, Cheung AN, Ngan HY, Wong AS. p70 S6 kinase promotes epithelial to mesenchymal transition through Snail induction in ovarian cancer cells. Cancer Res 2008; 68(16): 6524–6532Google Scholar
  82. 82.
    Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, Lee EY, Weiss HL, O’Connor KL, Gao T, Evers BM. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011; 71(9): 3246–3256Google Scholar
  83. 83.
    Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R. TGF-β-induced activation of mTOR complex 2 drives epithelialmesenchymal transition and cell invasion. J Cell Sci 2012; 125(Pt 5): 1259–1273Google Scholar
  84. 84.
    Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL. Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro. Neoplasia 2004; 6(5): 603–610Google Scholar
  85. 85.
    Buonato JM, Lazzara MJ. ERK1/2 blockade prevents epithelialmesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition. Cancer Res 2014; 74(1): 309–319Google Scholar
  86. 86.
    Amatangelo MD, Goodyear S, Varma D, Stearns ME. c-Myc expression and MEK1-induced Erk2 nuclear localization are required for TGF-β induced epithelial-mesenchymal transition and invasion in prostate cancer. Carcinogenesis 2012; 33(10): 1965–1975Google Scholar
  87. 87.
    Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 2005; 307 (5715): 1603–1609Google Scholar
  88. 88.
    Gunaratne A, Thai BL, Di Guglielmo GM. Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor β-induced epithelial-to-mesenchymal transition. Mol Cell Biol 2013; 33(5): 874–886Google Scholar
  89. 89.
    Mihira H, Suzuki HI, Akatsu Y, Yoshimatsu Y, Igarashi T, Miyazono K, Watabe T. TGF-β-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A. J Biochem 2012; 151(2): 145–156Google Scholar
  90. 90.
    Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grünert S. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002; 156(2): 299–313Google Scholar
  91. 91.
    Horiguchi K, Shirakihara T, Nakano A, Imamura T, Miyazono K, Saitoh M. Role of Ras signaling in the induction of Snail by transforming growth factor-β. J Biol Chem 2009; 284(1): 245–253Google Scholar
  92. 92.
    Vasilaki E, Morikawa M, Koinuma D, Mizutani A, Hirano Y, Ehata S, Sundqvist A, Kawasaki N, Cedervall J, Olsson AK, Aburatani H, Moustakas A, Miyazono K, Heldin CH. Ras and TGF-β signaling enhance cancer progression by promoting the DNp63 transcriptional program. Sci Signal 2016; 9(442): ra84Google Scholar
  93. 93.
    Arase M, Tamura Y, Kawasaki N, Isogaya K, Nakaki R, Mizutani A, Tsutsumi S, Aburatani H, Miyazono K, Koinuma D. Dynamics of chromatin accessibility during TGF-β-induced EMT of Rastransformed mammary gland epithelial cells. Sci Rep 2017; 7(1): 1166Google Scholar
  94. 94.
    Östman A, Augsten M. Cancer-associated fibroblasts and tumor growth—bystanders turning into key players. Curr Opin Genet Dev 2009; 19(1): 67–73Google Scholar
  95. 95.
    Pietras K, Östman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 2010; 316(8): 1324–1331Google Scholar
  96. 96.
    Otranto M, Sarrazy V, Bonté F, Hinz B, Gabbiani G, Desmoulière A. The role of the myofibroblast in tumor stroma remodeling. Cell Adhes Migr 2012; 6(3): 203–219Google Scholar
  97. 97.
    Shirakihara T, Horiguchi K, Miyazawa K, Ehata S, Shibata T, Morita I, Miyazono K, Saitoh M. TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J 2011; 30(4): 783–795Google Scholar
  98. 98.
    Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP. ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 2009; 33(5): 591–601Google Scholar
  99. 99.
    Horiguchi K, Sakamoto K, Koinuma D, Semba K, Inoue A, Inoue S, Fujii H, Yamaguchi A, Miyazawa K, Miyazono K, Saitoh M. TGF-β drives epithelial-mesenchymal transition through dEF1-mediated downregulation of ESRP. Oncogene 2012; 31(26): 3190–3201Google Scholar
  100. 100.
    Chen PY, Qin L, Barnes C, Charisse K, Yi T, Zhang X, Ali R, Medina PP, Yu J, Slack FJ, Anderson DG, Kotelianski V, Wang F, Tellides G, Simons M. FGF regulates TGF-β signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression. Cell Reports 2012; 2(6): 1684–1696Google Scholar
  101. 101.
    Chen PY, Qin L, Tellides G, Simons M. Fibroblast growth factor receptor 1 is a key inhibitor of TGFβ signaling in the endothelium. Sci Signal 2014; 7(344): ra90Google Scholar
  102. 102.
    Correia AC, Moonen JR, Brinker MG, Krenning G. FGF2 inhibits endothelial-mesenchymal transition through microRNA-20amediated repression of canonical TGF-β signaling. J Cell Sci 2016; 129(3): 569–579Google Scholar
  103. 103.
    Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 2012; 11(10): 790–811Google Scholar
  104. 104.
    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 epithelialmesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4): 704–715Google Scholar
  105. 105.
    Scheel C, Weinberg RA. Cancer stem cells and epithelialmesenchymal transition: concepts and molecular links. Semin Cancer Biol 2012; 22(5-6): 396–403Google Scholar
  106. 106.
    Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL, Weinberg RA. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011; 145(6): 926–940Google Scholar
  107. 107.
    Huang S, Hölzel M, Knijnenburg T, Schlicker A, Roepman P, McDermott U, Garnett M, Grernrum W, Sun C, Prahallad A, Groenendijk FH, Mittempergher L, Nijkamp W, Neefjes J, Salazar R, ten Dijke P, Uramoto H, Tanaka F, Beijersbergen RL, Wessels LF, Bernards R. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 2012; 151(5): 937–950Google Scholar
  108. 108.
    Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe RF, Vahdat LT, Altorki NK, Mittal V, Gao D. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015; 527(7579): 472–476Google Scholar
  109. 109.
    Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303(5659): 848–851Google Scholar
  110. 110.
    Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, Onder TT, Wang ZC, Richardson AL, Weinberg RA, Orimo A. Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA 2010; 107(46): 20009–20014Google Scholar
  111. 111.
    Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinomaassociated fibroblasts. Cancer Res 2007; 67(21): 10123–10128Google Scholar
  112. 112.
    Cuccarese MF, Dubach JM, Pfirschke C, Engblom C, Garris C, Miller MA, Pittet MJ, Weissleder R. Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging. Nat Commun 2017; 8: 14293Google Scholar
  113. 113.
    Kubota SI, Takahashi K, Nishida J, Morishita Y, Ehata S, Tainaka K, Miyazono K, Ueda HR. Whole-body profiling of cancer metastasis with single-cell resolution. Cell Reports 2017; 20(1): 236–250Google Scholar
  114. 114.
    Sullivan JP, Minna JD, Shay JW. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer Metastasis Rev 2010; 29(1): 61–72Google Scholar
  115. 115.
    Collisson EA, Campbell JD, Brooks AN, Berger AH, Lee W, Chmielecki J, Beer DG, Cope L, Creighton CJ, Danilova L, Ding L, Getz G, Hammerman PS, Neil Hayes D, Hernandez B, Herman JG, Heymach JV, Jurisica I, Kucherlapati R, Kwiatkowski D, Ladanyi M, Robertson G, Schultz N, Shen R, Sinha R, Sougnez C, Tsao MS, Travis WD, Weinstein JN, Wigle DA, Wilkerson MD, Chu A, Cherniack AD, Hadjipanayis A, Rosenberg M, Weisenberger DJ, Laird PW, Radenbaugh A, Ma S, Stuart JM, Averett Byers L, Baylin SB, Govindan R, Meyerson M, Rosenberg M, Gabriel SB, Cibulskis K, Sougnez C, Kim J, Stewart C, Lichtenstein L, Lander ES, Lawrence MS, Getz G, Kandoth C, Fulton R, Fulton LL, McLellan MD, Wilson RK, Ye K, Fronick CC, Maher CA, Miller CA, Wendl MC, Cabanski C, Ding L, Mardis E, Govindan R, Creighton CJ, Wheeler D, Balasundaram M, Butterfield YSN, Carlsen R, Chu A, Chuah E, Dhalla N, Guin R, Hirst C, Lee D, Li HI, Mayo M, Moore RA, Mungall AJ, Schein JE, Sipahimalani P, Tam A, Varhol R, Gordon Robertson A, Wye N, Thiessen N, Holt RA, Jones SJM, Marra MA, Campbell JD, Brooks AN, Chmielecki J, Imielinski M, Onofrio RC, Hodis E, Zack T, Sougnez C, Helman E, Sekhar Pedamallu C, Mesirov J, Cherniack AD, Saksena G, Schumacher SE, Carter SL, Hernandez B, Garraway L, Beroukhim R, Gabriel SB, Getz G, Meyerson M, Hadjipanayis A, Lee S, Mahadeshwar HS, Pantazi A, Protopopov A, Ren X, Seth S, Song X, Tang J, Yang L, Zhang J, Chen PC, Parfenov M, Wei Xu A, Santoso N, Chin L, Park PJ, Kucherlapati R, Hoadley KA, Todd Auman J, Meng S, Shi Y, Buda E, Waring S, Veluvolu U, Tan D, Mieczkowski PA, Jones CD, Simons JV, Soloway MG, Bodenheimer T, Jefferys SR, Roach J, Hoyle AP, Wu J, Balu S, Singh D, Prins JF, Marron JS, Parker JS, Neil Hayes D, Perou CM, Liu J, Cope L, Danilova L, Weisenberger DJ, Maglinte DT, Lai PH, Bootwalla MS, Van Den Berg DJ, Triche T Jr, Baylin SB, Laird PW, Rosenberg M, Chin L, Zhang J, Cho J, DiCara D, Heiman D, Lin P, Mallard W, Voet D, Zhang H, Zou L, Noble MS, Lawrence MS, Saksena G, Gehlenborg N, Thorvaldsdottir H, Mesirov J, Nazaire MD, Robinson J, Getz G, Lee W, Arman Aksoy B, Ciriello G, Taylor BS, Dresdner G, Gao J, Gross B, Seshan VE, Ladanyi M, Reva B, Sinha R, Onur Sumer S, Weinhold N, Schultz N, Shen R, Sander C, Ng S, Ma S, Zhu J, Radenbaugh A, Stuart JM, Benz CC, Yau C, Haussler D, Spellman PT, Wilkerson MD, Parker JS, Hoadley KA, Kimes PK, Neil Hayes D, Perou CM, Broom BM, Wang J, Lu Y, Kwok Shing Ng P, Diao L, Averett Byers L, Liu W, Heymach JV, Amos CI, Weinstein JN, Akbani R, Mills GB, Curley E, Paulauskis J, Lau K, Morris S, Shelton T, Mallery D, Gardner J, Penny R, Saller C, Tarvin K, Richards WG, Cerfolio R, Bryant A, Raymond DP, Pennell NA, Farver C, Czerwinski C, Huelsenbeck-Dill L, Iacocca M, Petrelli N, Rabeno B, Brown J, Bauer T, Dolzhanskiy O, Potapova O, Rotin D, Voronina O, Nemirovich-Danchenko E, Fedosenko KV, Gal A, Behera M, Ramalingam SS, Sica G, Flieder D, Boyd J, Weaver JE, Kohl B, Huy Quoc Thinh D, Sandusky G, Juhl H, Duhig E, Illei P, Gabrielson E, Shin J, Lee B, Rogers K, Trusty D, Brock MV, Williamson C, Burks E, Rieger-Christ K, Holway A, Sullivan T, Wigle DA, Asiedu MK, Kosari F, Travis WD, Rekhtman N, Zakowski M, Rusch VW, Zippile P, Suh J, Pass H, Goparaju C, Owusu-Sarpong Y, Bartlett JMS, Kodeeswaran S, Parfitt J, Sekhon H, Albert M, Eckman J, Myers JB, Cheney R, Morrison C, Gaudioso C, Borgia JA, Bonomi P, Pool M, Liptay MJ, Moiseenko F, Zaytseva I, Dienemann H, Meister M, Schnabel PA, Muley TR, Peifer M, Gomez-Fernandez C, Herbert L, Egea S, Huang M, Thorne LB, Boice L, Hill Salazar A, Funkhouser WK, Kimryn Rathmell W, Dhir R, Yousem SA, Dacic S, Schneider F, Siegfried JM, Hajek R, Watson MA, McDonald S, Meyers B, Clarke B, Yang IA, Fong KM, Hunter L, Windsor M, Bowman RV, Peters S, Letovanec I, Khan KZ, Jensen MA, Snyder EE, Srinivasan D, Kahn AB, Baboud J, Pot DA, Mills Shaw KR, Sheth M, Davidsen T, Demchok JA, Yang L, Wang Z, Tarnuzzer R, Claude Zenklusen J, Ozenberger BA, Sofia HJ, Travis WD, Cheney R, Clarke B, Dacic S, Duhig E, Funkhouser WK, Illei P, Farver C, Rekhtman N, Sica G, S J, Tsao MS; Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; 511(7511): 543–550Google Scholar
  116. 116.
    Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, Miyazono K. Thyroid transcription factor-1 inhibits transforming growth factor-β-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. Cancer Res 2009; 69(7): 2783–2791Google Scholar
  117. 117.
    Larsen JE, Nathan V, Osborne JK, Farrow RK, Deb D, Sullivan JP, Dospoy PD, Augustyn A, Hight SK, Sato M, Girard L, Behrens C, Wistuba II, Gazdar AF, Hayward NK, Minna JD. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest 2016; 126(9): 3219–3235Google Scholar
  118. 118.
    Kawata M, Koinuma D, Ogami T, Umezawa K, Iwata C, Watabe T, Miyazono K. TGF-β-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by proinflammatory cytokines derived from RAW 264.7 macrophage cells. J Biochem 2012; 151(2): 205–216Google Scholar
  119. 119.
    Lazzaro D, Price M, de Felice M, Di Lauro R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 1991; 113(4): 1093–1104Google Scholar
  120. 120.
    Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, Hubbard DD, DuPage MJ, Whittaker CA, Hoersch S, Yoon S, Crowley D, Bronson RT, Chiang DY, Meyerson M, Jacks T. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 2011; 473(7345): 101–104Google Scholar
  121. 121.
    Yamaguchi T, Hosono Y, Yanagisawa K, Takahashi T. NKX2-1/ TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer Cell 2013; 23(6): 718–723Google Scholar
  122. 122.
    Minoo P, Hu L, Zhu N, Borok Z, Bellusci S, Groffen J, Kardassis D, Li C. SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains. Nucleic Acids Res 2008; 36(1): 179–188Google Scholar
  123. 123.
    Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 2013; 19(11): 1438–1449Google Scholar
  124. 124.
    Mizutani A, Koinuma D, Tsutsumi S, Kamimura N, Morikawa M, Suzuki HI, Imamura T, Miyazono K, Aburatani H. Cell typespecific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte nuclear factor 4a in HepG2 cells. J Biol Chem 2011; 286(34): 29848–29860Google Scholar
  125. 125.
    Mullen AC, Orlando DA, Newman JJ, Lovén J, Kumar RM, Bilodeau S, Reddy J, Guenther MG, DeKoter RP, Young RA. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 2011; 147(3): 565–576Google Scholar
  126. 126.
    Isogaya K, Koinuma D, Tsutsumi S, Saito RA, Miyazawa K, Aburatani H, Miyazono K. A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent gene expression. Cell Res 2014; 24 (8): 994–1008Google Scholar
  127. 127.
    Sakurai T, Isogaya K, Sakai S, Morikawa M, Morishita Y, Ehata S, Miyazono K, Koinuma D. RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma. Oncogene 2016; 35(38): 5000–5009Google Scholar
  128. 128.
    Taguchi K, Yamamoto M. The KEAP1-NRF2 system in cancer. Front Oncol 2017; 7: 85Google Scholar
  129. 129.
    Kawasaki N, Isogaya K, Dan S, Yamori T, Takano H, Yao R, Morishita Y, Taguchi L, Morikawa M, Heldin CH, Noda T, Ehata S, Miyazono K, Koinuma D. TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling. Cell Discov 2018; 4(1): 1Google Scholar
  130. 130.
    Ying Z, Tian H, Li Y, Lian R, Li W, Wu S, Zhang HZ, Wu J, Liu L, Song J, Guan H, Cai J, Zhu X, Li J, Li M. CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling. J Clin Invest 2017; 127(5): 1725–1740Google Scholar
  131. 131.
    George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK. Comprehensive genomic profiles of small cell lung cancer. Nature 2015; 524(7563): 47–53Google Scholar
  132. 132.
    Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 2003; 4(3): 181–189Google Scholar
  133. 133.
    Jiang T, Collins BJ, Jin N, Watkins DN, Brock MV, Matsui W, Nelkin BD, Ball DW. Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res 2009; 69(3): 845–854Google Scholar
  134. 134.
    Borromeo MD, Savage TK, Kollipara RK, He M, Augustyn A, Osborne JK, Girard L, Minna JD, Gazdar AF, Cobb MH, Johnson JE. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Reports 2016; 16(5): 1259–1272Google Scholar
  135. 135.
    de Jonge RR, Garrigue-Antar L, Vellucci VF, Reiss M. Frequent inactivation of the transforming growth factor β type II receptor in small-cell lung carcinoma cells. Oncol Res 1997; 9(2): 89–98Google Scholar
  136. 136.
    Hougaard S, Krarup M, Nørgaard P, Damstrup L, Spang-Thomsen M, Poulsen HS. High value of the radiobiological parameter Dq correlates to expression of the transforming growth factor β type II receptor in a panel of small cell lung cancer cell lines. Lung Cancer 1998; 20(1): 65–69Google Scholar
  137. 137.
    Murai F, Koinuma D, Shinozaki-Ushiku A, Fukayama M, Miyaozono K, Ehata S. EZH2 promotes progression of small cell lung cancer by suppressing the TGF-β-Smad-ASCL1 pathway. Cell Discov 2015; 1(1): 15026Google Scholar
  138. 138.
    Kimura M, Takenobu H, Akita N, Nakazawa A, Ochiai H, Shimozato O, Fujimura Y, Koseki H, Yoshino I, Kimura H, Nakagawara A, Kamijo T. Bmi1 regulates cell fate via tumor suppressor WWOX repression in small-cell lung cancer cells. Cancer Sci 2011; 102(5): 983–990Google Scholar
  139. 139.
    Byers LA, Wang J, Nilsson MB, Fujimoto J, Saintigny P, Yordy J, Giri U, Peyton M, Fan YH, Diao L, Masrorpour F, Shen L, Liu W, Duchemann B, Tumula P, Bhardwaj V, Welsh J, Weber S, Glisson BS, Kalhor N, Wistuba II, Girard L, Lippman SM, Mills GB, Coombes KR, Weinstein JN, Minna JD, Heymach JV. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov 2012; 2(9): 798–811Google Scholar
  140. 140.
    Hubaux R, Thu KL, Coe BP, MacAulay C, Lam S, Lam WL. EZH2 promotes E2F-driven SCLC tumorigenesis through modulation of apoptosis and cell-cycle regulation. J Thorac Oncol 2013; 8(8): 1102–1106Google Scholar
  141. 141.
    Sato T, Kaneda A, Tsuji S, Isagawa T, Yamamoto S, Fujita T, Yamanaka R, Tanaka Y, Nukiwa T, Marquez VE, Ishikawa Y, Ichinose M, Aburatani H. PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer. Sci Rep 2013; 3(1): 1911Google Scholar
  142. 142.
    Poirier JT, Gardner EE, Connis N, Moreira AL, de Stanchina E, Hann CL, Rudin CM. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2. Oncogene 2015; 34(48): 5869–5878Google Scholar
  143. 143.
    Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439(7078): 871–874Google Scholar
  144. 144.
    Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG. MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to Aurora kinase Inhibition. Cancer Cell 2017; 31(2): 270–285Google Scholar
  145. 145.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66(1): 7–30Google Scholar
  146. 146.
    Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2011; 378(9791): 607–620Google Scholar
  147. 147.
    Engholm G, Ferlay J, Christensen N, Bray F, Gjerstorff ML, Klint A, Køtlum JE, Olafsdóttir E, Pukkala E, Storm HH. NORDCAN — a Nordic tool for cancer information, planning, quality control and research. Acta Oncol 2010; 49(5): 725–736Google Scholar
  148. 148.
    Hidalgo M. Pancreatic cancer. N Engl J Med 2010; 362(17): 1605–1617Google Scholar
  149. 149.
    Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000; 6(8): 2969–2972Google Scholar
  150. 150.
    Makohon-Moore A, Iacobuzio-Donahue CA. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer 2016; 16(9): 553–565Google Scholar
  151. 151.
    Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996; 271(5247): 350–353Google Scholar
  152. 152.
    Drost J, van Jaarsveld RH, Ponsioen B, Zimberlin C, van Boxtel R, Buijs A, Sachs N, Overmeer RM, Offerhaus GJ, Begthel H, Korving J, van de Wetering M, Schwank G, Logtenberg M, Cuppen E, Snippert HJ, Medema JP, Kops GJ, Clevers H. Sequential cancer mutations in cultured human intestinal stem cells. Nature 2015; 521(7550): 43–47Google Scholar
  153. 153.
    Matano M, Date S, Shimokawa M, Takano A, Fujii M, Ohta Y, Watanabe T, Kanai T, Sato T. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med 2015; 21(3): 256–262Google Scholar
  154. 154.
    Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993; 9(4): 138–141Google Scholar
  155. 155.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science 2013; 339 (6127): 1546–1558Google Scholar
  156. 156.
    Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 2017; 32(2): 185–203.e13Google Scholar
  157. 157.
    Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, Hruban RH, Maitra A, Kinzler K, Vogelstein B, Goggins M. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012; 142(4): 730–733.e9Google Scholar
  158. 158.
    Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 1998; 58(20): 4740–4744Google Scholar
  159. 159.
    Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000; 60(7): 2002–2006Google Scholar
  160. 160.
    Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grützmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016; 531(7592): 47–52Google Scholar
  161. 161.
    Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N; Australian Pancreatic Cancer Genome Initiative, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491(7424): 399–405Google Scholar
  162. 162.
    Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Wani S, Wilson PJ, Markham E, Cloonan N, Anderson MJ, Fink JL, Holmes O, Kazakoff SH, Leonard C, Newell F, Poudel B, Song S, Taylor D, Waddell N, Wood S, Xu Q, Wu J, Pinese M, Cowley MJ, Lee HC, Jones MD, Nagrial AM, Humphris J, Chantrill LA, Chin V, Steinmann AM, Mawson A, Humphrey ES, Colvin EK, Chou A, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Pettitt JA, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, Graham JS, Niclou SP, Bjerkvig R, Grützmann R, Aust D, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Falconi M, Zamboni G, Tortora G, Tempero MA; Australian Pancreatic Cancer Genome Initiative, Gill AJ, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Pearson JV, Biankin AV, Grimmond SM. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518(7540): 495–501Google Scholar
  163. 163.
    Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, Choti MA, Yeo CJ, McCue P, White MA, Knudsen ES. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun 2015; 6(1): 6744Google Scholar
  164. 164.
    Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, Denroche RE, Liang SB, Brown AM, Kim JC, Wang T, Simpson JT, Beck T, Borgida A, Buchner N, Chadwick D, Hafezi-Bakhtiari S, Dick JE, Heisler L, Hollingsworth MA, Ibrahimov E, Jang GH, Johns J, Jorgensen LG, Law C, Ludkovski O, Lungu I, Ng K, Pasternack D, Petersen GM, Shlush LI, Timms L, Tsao MS, Wilson JM, Yung CK, Zogopoulos G, Bartlett JM, Alexandrov LB, Real FX, Cleary SP, Roehrl MH, McPherson JD, Stein LD, Hudson TJ, Campbell PJ, Gallinger S. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 2016; 538(7625): 378–382Google Scholar
  165. 165.
    Sundqvist A, Morikawa M, Ren J, Vasilaki E, Kawasaki N, Kobayashi M, Koinuma D, Aburatani H, Miyazono K, Heldin CH, van Dam H, ten Dijke P. JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion. Nucleic Acids Res 2018; 46(3): 1180–1195Google Scholar
  166. 166.
    Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE. Genetic alterations of the transforming growth factor β receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 1998; 58(23): 5329–5332Google Scholar
  167. 167.
    Su GH, Bansal R, Murphy KM, Montgomery E, Yeo CJ, Hruban RH, Kern SE. ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Proc Natl Acad Sci USA 2001; 98(6): 3254–3257Google Scholar
  168. 168.
    Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K, Schulick R, Winter J, Herman JM, Laheru D, Klein AP, Vogelstein B, Kinzler KW, Velculescu VE, Hruban RH. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009; 15(14): 4674–4679Google Scholar
  169. 169.
    Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ, Adsay V, Abrams RA, Cameron JL, Kern SE, Yeo CJ, Hruban RH, Goggins M. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 2001; 7(12): 4115–4121Google Scholar
  170. 170.
    Hingorani SR, Petricoin EF III, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003; 4(6): 437–450Google Scholar
  171. 171.
    Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 2006; 20(22): 3130–3146Google Scholar
  172. 172.
    Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady WM, Deng CX, Hruban RH, Adsay NV, Tuveson DA, Hingorani SR. KrasG12D and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 2007; 11(3): 229–243Google Scholar
  173. 173.
    Kuang C, Xiao Y, Liu X, Stringfield TM, Zhang S, Wang Z, Chen Y. In vivo disruption of TGF-β signaling by Smad7 leads to premalignant ductal lesions in the pancreas. Proc Natl Acad Sci USA 2006; 103(6): 1858–1863Google Scholar
  174. 174.
    Ijichi H, Chytil A, Gorska AE, Aakre ME, Fujitani Y, Fujitani S, Wright CV, Moses HL. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev 2006; 20(22): 3147–3160Google Scholar
  175. 175.
    Xi Q, Wang Z, Zaromytidou AI, Zhang XH, Chow-Tsang LF, Liu JX, Kim H, Barlas A, Manova-Todorova K, Kaartinen V, Studer L, Mark W, Patel DJ, Massagué J. A poised chromatin platform for TGF-β access to master regulators. Cell 2011; 147(7): 1511–1524Google Scholar
  176. 176.
    Vincent DF, Gout J, Chuvin N, Arfi V, Pommier RM, Bertolino P, Jonckheere N, Ripoche D, Kaniewski B, Martel S, Langlois JB, Goddard-Léon S, Colombe A, Janier M, Van Seuningen I, Losson R, Valcourt U, Treilleux I, Dubus P, Bardeesy N, Bartholin L. Tif1g suppresses murine pancreatic tumoral transformation by a Smad4-independent pathway. Am J Pathol 2012; 180(6): 2214–2221Google Scholar
  177. 177.
    Levy L, Hill CS. Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 2006; 17(1-2): 41–58Google Scholar
  178. 178.
    Rowland-Goldsmith MA, Maruyama H, Matsuda K, Idezawa T, Ralli M, Ralli S, Korc M. Soluble type II transforming growth factor-β receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis. Mol Cancer Ther 2002; 1(3): 161–167Google Scholar
  179. 179.
    Gaspar NJ, Li L, Kapoun AM, Medicherla S, Reddy M, Li G, O’Young G, Quon D, Henson M, Damm DL, Muiru GT, Murphy A, Higgins LS, Chakravarty S, Wong DH. Inhibition of transforming growth factor β signaling reduces pancreatic adenocarcinoma growth and invasiveness. Mol Pharmacol 2007; 72(1): 152–161Google Scholar
  180. 180.
    Murakami T, Hiroshima Y, Miyake K, Hwang HK, Kiyuna T, DeLong JC, Lwin TM, Matsuyama R, Mori R, Kumamoto T, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM. Color-coded intravital imaging demonstrates a transforming growth factor-β (TGF-β) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model. Cell Cycle 2017; 16(10): 1008–1014Google Scholar
  181. 181.
    Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ. LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008; 7(4): 829–840Google Scholar
  182. 182.
    Ostapoff KT, Cenik BK, Wang M, Ye R, Xu X, Nugent D, Hagopian MM, Topalovski M, Rivera LB, Carroll KD, Brekken RA. Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. Cancer Res 2014; 74(18): 4996–5007Google Scholar
  183. 183.
    Fujiwara Y, Nokihara H, Yamada Y, Yamamoto N, Sunami K, Utsumi H, Asou H, TakahashI O, Ogasawara K, Gueorguieva I, Tamura T. Phase 1 study of galunisertib, a TGF-β receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2015; 76(6): 1143–1152Google Scholar
  184. 184.
    Ikeda M, Takahashi H, Kondo S, Lahn MMF, Ogasawara K, Benhadji KA, Fujii H, Ueno H. Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer. Cancer Chemother Pharmacol 2017; 79(6): 1169–1177Google Scholar
  185. 185.
    Moustakas A, Heldin CH. Non-Smad TGF-β signals. J Cell Sci 2005; 118(Pt 16): 3573–3584Google Scholar
  186. 186.
    Lonardo E, Hermann PC, Mueller MT, Huber S, Balic A, Miranda-Lorenzo I, Zagorac S, Alcala S, Rodriguez-Arabaolaza I, Ramirez JC, Torres-Ruíz R, Garcia E, Hidalgo M, Cebrián DÁ, Heuchel R, Löhr M, Berger F, Bartenstein P, Aicher A, Heeschen C. Nodal/ activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 2011; 9(5): 433–446Google Scholar
  187. 187.
    Hoshino Y, Nishida J, Katsuno Y, Koinuma D, Aoki T, Kokudo N, Miyazono K, Ehata S. Smad4 decreases the population of pancreatic cancer-initiating cells through transcriptional repression of ALDH1A1. Am J Pathol 2015; 185(5): 1457–1470Google Scholar
  188. 188.
    Whittle MC, Izeradjene K, Rani PG, Feng L, Carlson MA, DelGiorno KE, Wood LD, Goggins M, Hruban RH, Chang AE, Calses P, Thorsen SM, Hingorani SR. RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell 2015; 161(6): 1345–1360Google Scholar
  189. 189.
    David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, Iacobuzio-Donahue CA, Massagué J. TGF-β tumor suppression through a lethal EMT. Cell 2016; 164(5): 1015–1030Google Scholar
  190. 190.
    Gore J, Korc M. Pancreatic cancer stroma: friend or foe? Cancer Cell 2014; 25(6): 711–712Google Scholar
  191. 191.
    Zhan HX, Zhou B, Cheng YG, Xu JW, Wang L, Zhang GY, Hu SY. Crosstalk between stromal cells and cancer cells in pancreatic cancer: new insights into stromal biology. Cancer Lett 2017; 392: 83–93Google Scholar
  192. 192.
    Takahashi K, Ehata S, Koinuma D, Morishita Y, Soda M, Mano H, Miyazono K. Pancreatic tumor microenvironment confers highly malignant properties on pancreatic cancer cells. Oncogene 2018; 37(21): 2757–2772Google Scholar
  193. 193.
    Ding N, Yu RT, Subramaniam N, Sherman MH, Wilson C, Rao R, Leblanc M, Coulter S, He M, Scott C, Lau SL, Atkins AR, Barish GD, Gunton JE, Liddle C, Downes M, Evans RM. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 2013; 153(3): 601–613Google Scholar
  194. 194.
    Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, Martin P, Tseng TW, Dawson DW, Donahue TR, Masamune A, Shimosegawa T, Apte MV, Wilson JS, Ng B, Lau SL, Gunton JE, Wahl GM, Hunter T, Drebin JA, O’Dwyer PJ, Liddle C, Tuveson DA, Downes M, Evans RM. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014; 159(1): 80–93Google Scholar
  195. 195.
    Akhurst RJ. Targeting TGF-β signaling for therapeutic gain. Cold Spring Harb Perspect Biol 2017; 9(10): a022301Google Scholar
  196. 196.
    Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB. Transforming growth factor-β in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 1983; 258(11): 7155–7160Google Scholar
  197. 197.
    Kong FM, Anscher MS, Murase T, Abbott BD, Iglehart JD, Jirtle RL. Elevated plasma transforming growth factor-β1 levels in breast cancer patients decrease after surgical removal of the tumor. Ann Surg 1995; 222(2): 155–162Google Scholar
  198. 198.
    Shim KS, Kim KH, Han WS, Park EB. Elevated serum levels of transforming growth factor-β1 in patients with colorectal carcinoma: its association with tumor progression and its significant decrease after curative surgical resection. Cancer 1999; 85(3): 554–561Google Scholar
  199. 199.
    Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011; 20(5): 576–590Google Scholar
  200. 200.
    Wolfman NM, McPherron AC, Pappano WN, Davies MV, Song K, Tomkinson KN, Wright JF, Zhao L, Sebald SM, Greenspan DS, Lee SJ. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proc Natl Acad Sci USA 2003; 100(26): 15842–15846Google Scholar
  201. 201.
    Yoshinaga K, Obata H, Jurukovski V, Mazzieri R, Chen Y, Zilberberg L, Huso D, Melamed J, Prijatelj P, Todorovic V, Dabovic B, Rifkin DB. Perturbation of transforming growth factor (TGF)-β1 association with latent TGF-β binding protein yields inflammation and tumors. Proc Natl Acad Sci USA 2008; 105(48): 18758–18763Google Scholar
  202. 202.
    Isogai Z, Ono RN, Ushiro S, Keene DR, Chen Y, Mazzieri R, Charbonneau NL, Reinhardt DP, Rifkin DB, Sakai LY. Latent transforming growth factor β-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem 2003; 278(4): 2750–2757Google Scholar
  203. 203.
    Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA. Latent TGF-β structure and activation. Nature 2011; 474(7351): 343–349Google Scholar
  204. 204.
    Annes JP, Chen Y, Munger JS, Rifkin DB. Integrin aVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J Cell Biol 2004; 165(5): 723–734Google Scholar
  205. 205.
    Dong X, Zhao B, Iacob RE, Zhu J, Koksal AC, Lu C, Engen JR, Springer TA. Force interacts with macromolecular structure in activation of TGF-β. Nature 2017; 542(7639): 55–59Google Scholar
  206. 206.
    Ollendorff V, Noguchi T, de Lapeyriere O, Birnbaum D. The GARP gene encodes a new member of the family of leucine-rich repeat-containing proteins. Cell Growth Differ 1994; 5(2): 213–219Google Scholar
  207. 207.
    Stockis J, Dedobbeleer O, Lucas S. Role of GARP in the activation of latent TGF-β1. Mol Biosyst 2017; 13(10): 1925–1935Google Scholar
  208. 208.
    Probst-Kepper M, Geffers R, Kröger A, Viegas N, Erck C, Hecht HJ, Lünsdorf H, Roubin R, Moharregh-Khiabani D, Wagner K, Ocklenburg F, Jeron A, Garritsen H, Arstila TP, Kekäläinen E, Balling R, Hauser H, Buer J, Weiss S. GARP: a key receptor controlling FOXP3 in human regulatory T cells. J Cell Mol Med 2009; 13(9b 9B): 3343–3357Google Scholar
  209. 209.
    Gauthy E, Cuende J, Stockis J, Huygens C, Lethé B, Collet JF, Bommer G, Coulie PG, Lucas S. GARP is regulated by miRNAs and controls latent TGF-β1 production by human regulatory T cells. PLoS One 2013; 8(9): e76186Google Scholar
  210. 210.
    Zhou Q, Haupt S, Prots I, Thümmler K, Kremmer E, Lipsky PE, Schulze-Koops H, Skapenko A. miR-142-3p is involved in CD25+ CD4 T cell proliferation by targeting the expression of glycoprotein A repetitions predominant. J Immunol 2013; 190(12): 6579–6588Google Scholar
  211. 211.
    Wu BX, Li A, Lei L, Kaneko S, Wallace C, Li X, Li Z. Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis. J Biol Chem 2017; 292(44): 18091–18097Google Scholar
  212. 212.
    Stockis J, Liénart S, Colau D, Collignon A, Nishimura SL, Sheppard D, Coulie PG, Lucas S. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin aVβ8. Proc Natl Acad Sci USA 2017; 114(47): E10161–E10168Google Scholar
  213. 213.
    Kitagawa Y, Sakaguchi S. Molecular control of regulatory T cell development and function. Curr Opin Immunol 2017; 49: 64–70Google Scholar
  214. 214.
    Takimoto T, Wakabayashi Y, Sekiya T, Inoue N, Morita R, Ichiyama K, Takahashi R, Asakawa M, Muto G, Mori T, Hasegawa E, Saika S, Hara T, Nomura M, Yoshimura A. Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development. J Immunol 2010; 185(2): 842–855Google Scholar
  215. 215.
    Ravi R, Noonan KA, Pham V, Bedi R, Zhavoronkov A, Ozerov IV, Makarev E, V Artemov A, Wysocki PT, Mehra R, Nimmagadda S, Marchionni L, Sidransky D, Borrello IM, Izumchenko E, Bedi A. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 2018; 9(1): 741Google Scholar
  216. 216.
    Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 2007; 178 (1): 280–290Google Scholar
  217. 217.
    Wang R, Zhu J, Dong X, Shi M, Lu C, Springer TA. GARP regulates the bioavailability and activation of TGFβ. Mol Biol Cell 2012; 23(6): 1129–1139Google Scholar
  218. 218.
    Wang R, Wan Q, Kozhaya L, Fujii H, Unutmaz D. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression. PLoS One 2008; 3(7): e2705Google Scholar
  219. 219.
    Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009; 106 (32): 13439–13444Google Scholar
  220. 220.
    O’Connor MN, Salles II, Cvejic A, Watkins NA, Walker A, Garner SF, Jones CI, Macaulay IC, Steward M, Zwaginga JJ, Bray SL, Dudbridge F, de Bono B, Goodall AH, Deckmyn H, Stemple DL, Ouwehand WH; Bloodomics Consortium. Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins. Blood 2009; 113(19): 4754–4762Google Scholar
  221. 221.
    Zhu ZF, Meng K, Zhong YC, Qi L, Mao XB, Yu KW, Zhang W, Zhu PF, Ren ZP, Wu BW, Ji QW, Wang X, Zeng QT. Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study. PLoS One 2014; 9 (2): e88775Google Scholar
  222. 222.
    Liu Y, Zhao X, Zhong Y, Meng K, Yu K, Shi H, Wu B, Tony H, Zhu J, Zhu R, Peng Y, Mao Y, Cheng P, Mao X, Zeng Q. Heme oxygenase-1 restores impaired GARP+CD4+CD25+ regulatory T cells from patients with acute coronary syndrome by upregulating LAP and GARP expression on activated T lymphocytes. Cell Physiol Biochem 2015; 35(2): 553–570Google Scholar
  223. 223.
    Szepetowski P, Ollendorff V, Grosgeorge J, Courseaux A, Birnbaum D, Theillet C, Gaudray P. DNA amplification at 11q13.5-q14 in human breast cancer. Oncogene 1992; 7(12): 2513–2517Google Scholar
  224. 224.
    Metelli A, Wu BX, Fugle CW, Rachidi S, Sun S, Zhang Y, Wu J, Tomlinson S, Howe PH, Yang Y, Garrett-Mayer E, Liu B, Li Z. Surface expression of TGFβ docking receptor GARP promotes oncogenesis and immune tolerance in breast cancer. Cancer Res 2016; 76(24): 7106–7117Google Scholar
  225. 225.
    Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP+CTLA-4+Foxp3+ T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res 2013; 73(8): 2435–2444Google Scholar
  226. 226.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252–264Google Scholar
  227. 227.
    Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Senbabaoglu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554(7693): 544–548Google Scholar
  228. 228.
    Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Cañellas A, Hernando-Momblona X, Byrom D, Matarin JA, Calon A, Rivas EI, Nebreda AR, Riera A, Attolini CS, Batlle E. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018; 554(7693): 538–543Google Scholar
  229. 229.
    Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, Yu H, Qin G, Sircar A, Hernández VM, Jenkins MH, Fontana RE, Deshpande A, Locke G, Sabzevari H, Radvanyi L, Lo KM. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med 2018; 10(424): eaan5488Google Scholar
  230. 230.
    Anderton MJ, Mellor HR, Bell A, Sadler C, Pass M, Powell S, Steele SJ, Roberts RR, Heier A. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol 2011; 39(6): 916–924Google Scholar
  231. 231.
    Rachidi S, Metelli A, Riesenberg B, Wu BX, Nelson MH, Wallace C, Paulos CM, Rubinstein MP, Garrett-Mayer E, Hennig M, Bearden DW, Yang Y, Liu B, Li Z. Platelets subvert T cell immunity against cancer via GARP-TGFβ axis. Sci Immunol 2017; 2(11): eaai7911Google Scholar
  232. 232.
    Cuende J, Liénart S, Dedobbeleer O, van der Woning B, De Boeck G, Stockis J, Huygens C, Colau D, Somja J, Delvenne P, Hannon M, Baron F, Dumoutier L, Renauld JC, De Haard H, Saunders M, Coulie PG, Lucas S. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci Transl Med 2015; 7(284): 284ra56Google Scholar
  233. 233.
    Tan AR, Alexe G, Reiss M. Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat 2009; 115(3): 453–495Google Scholar
  234. 234.
    Imamura T, Hikita A, Inoue Y. The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis. Breast Cancer 2012; 19(2): 118–124Google Scholar
  235. 235.
    Sundqvist A, ten Dijke P, van Dam H. Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity. Breast Cancer Res 2012; 14(1): 204Google Scholar
  236. 236.
    Naka K, Hirao A. Regulation of hematopoiesis and hematological disease by TGF-β family signaling molecules. Cold Spring Harb Perspect Biol 2017; 9(9): a027987Google Scholar
  237. 237.
    Constam DB, Philipp J, Malipiero UV, ten Dijke P, Schachner M, Fontana A. Differential expression of transforming growth factor-β1, -β2, and -β3 by glioblastoma cells, astrocytes, and microglia. J Immunol 1992; 148(5): 1404–1410Google Scholar
  238. 238.
    Krasagakis K, Thölke D, Farthmann B, Eberle J, Mansmann U, Orfanos CE. Elevated plasma levels of transforming growth factor (TGF)-β1 and TGF-β2 in patients with disseminated malignant melanoma. Br J Cancer 1998; 77(9): 1492–1494Google Scholar
  239. 239.
    Perera RM, Bardeesy N. Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov 2015; 5(12): 1247–1261Google Scholar

Copyright information

© The Author(s) 2018

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the appropriate credit is given to the original author(s) and the source, and a link is provided to the Creative Commons license, which indicates if changes are made.

Authors and Affiliations

  • Kohei Miyazono
    • 1
    Email author
  • Yoko Katsuno
    • 1
  • Daizo Koinuma
    • 1
  • Shogo Ehata
    • 1
  • Masato Morikawa
    • 1
  1. 1.Department of Molecular Pathology, Graduate School of MedicineThe University of TokyoBunkyo-ku, TokyoJapan

Personalised recommendations