The transforming growth factor (TGF-β) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-β signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-β pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however in tumor cells, TGF-β looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-β signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.

Babak Myeloma Group Department of Pathological Physiology Faculty of Medicine Masaryk University Brno 625 00 Czech Republic

Zobrazit více v PubMed

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013. PubMed DOI

Tian M, Neil JR, Schiemann WP. Transforming growth factor-β and the hallmarks of cancer. Cell Signal. 2011;23:951–962. doi: 10.1016/j.cellsig.2010.10.015. PubMed DOI PMC

Derynck R. The TGF-β Family.: Cold Spring Harbor Laboratory. 2008. Press.

Sporn MB, Todaro GJ. Autocrine secretion and malignant transformation of cells. N Engl J Med. 1980;303:878–880. doi: 10.1056/NEJM198010093031511. PubMed DOI

de Larco JE, Todaro GJ. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci USA. 1978;75:4001–4005. doi: 10.1073/pnas.75.8.4001. PubMed DOI PMC

Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastictissues. Proc Natl Acad Sci USA. 1981;78:5339–5343. doi: 10.1073/pnas.78.9.5339. PubMed DOI PMC

Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesisin vivoand stimulation of collagen formationin vitro. Proc. Natl. Acad. Sci. USA. 1986;83:4167–4171. doi: 10.1073/pnas.83.12.4167. PubMed DOI PMC

Tucker RF, Shipley GD, Moses HL, Holley RW. Growth inhibitor from BSC-1 cells closely related to platelet type β transforming growth factor. Science. 1984;226:705–707. doi: 10.1126/science.6093254. PubMed DOI

Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF, Sporn MB. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci. 1985;82:119–123. doi: 10.1073/pnas.82.1.119. PubMed DOI PMC

Massagué J, Blain SW, Lo RS. TGF[beta] signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309. doi: 10.1016/S0092-8674(00)00121-5. PubMed DOI

Patterson GI, Padgett RW. TGF beta-related pathways. Roles in Caenorhabditis elegans development. Trends Genet. 2000;16:27–33. doi: 10.1016/S0168-9525(99)01916-2. PubMed DOI

Ohta M, Greenberger JS, Anklesaria P, Bassols A, Massagué J. Two forms of transforming growth factor-beta distinguished by multipotential haematopoieticprogenitor cells. Nature. 1987;329:539–541. doi: 10.1038/329539a0. PubMed DOI

Cheifetz S, Weatherbee JA, Tsang ML, Anderson JK, Mole JE, Lucas R, Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987;48:409–415. doi: 10.1016/0092-8674(87)90192-9. PubMed DOI

Mittl PR, Priestle JP, Cox DA, McMaster G, Cerletti N, Grütter MG. The crystal structure of TGF-beta 3 and comparison to TGF-beta 2: implications for receptorbinding. Protein Sci. 1996;5:1261–1271. doi: 10.1002/pro.5560050705. PubMed DOI PMC

Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985;316:701–705. doi: 10.1038/316701a0. PubMed DOI

Dickinson ME, Kobrin MS, Silan CM, Kingsley DM, Justice MJ, Miller DA, Ceci JD, Lock LF, Lee A, Buchberg AM. Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutantloci. Genomics. 1990;6:505–520. doi: 10.1016/0888-7543(90)90480-I. PubMed DOI

Flanders KC, Lüdecke G, Engels S, Cissel DS, Roberts AB, Kondaiah P, Lafyatis R, Sporn MB, Unsicker K. Localization and actions of transforming growth factor-beta s in the embryonic nervous system. Development. 1991;113:183–191. PubMed

de Martin R, Haendler B, Hofer-Warbinek R, Gaugitsch H, Wrann M, Schlüsener H, Seifert JM, Bodmer S, Fontana A, Hofer E. Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforminggrowth factor-beta gene family. EMBO J. 1987;6:3673–3677. PubMed PMC

ten Dijke P, Hansen P, Iwata KK, Pieler C, Foulkes JG. Identification of another member of the transforming growth factor type beta gene family. Proc Natl Acad Sci USA. 1988;85:4715–4719. doi: 10.1073/pnas.85.13.4715. PubMed DOI PMC

Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, Ding J, Ferguson MW, Doetschman T. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet. 1995;11:409–414. doi: 10.1038/ng1295-409. PubMed DOI PMC

Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet. 1995;11:415–421. doi: 10.1038/ng1295-415. PubMed DOI

Dubois CM, Laprise M-H, Blanchette F, Gentry LE, Leduc R. Processing of transforming growth factor 1 Precursor by human furin convertase. J Biol Chem. 1995;270:10618–10624. doi: 10.1074/jbc.270.18.10618. PubMed DOI

Gray AM, Mason AJ. Requirement for activin A and transforming growth factor– beta 1 pro-regions in homodimer assembly. Science. 1990;247:1328–1330. doi: 10.1126/science.2315700. PubMed DOI

Miyazono K, Hellman U, Wernstedt C. Heldin CH: Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization. J Biol Chem. 1988;263:6407–6415. PubMed

Gleizes PE, Beavis RC, Mazzieri R, Shen B, Rifkin DB. Identification and characterization of an eight-cysteine repeat of the latent transforming growth factorbetabinding protein-1 that mediates bonding to the latent transforming growth factorbeta1. J Biol Chem. 1996;271:29891–29896. doi: 10.1074/jbc.271.47.29891. PubMed DOI

Taipale J, Miyazono K, Heldin CH, Keski-Oja J. Latent transforming growth factorbeta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol. 1994;124:171–181. doi: 10.1083/jcb.124.1.171. PubMed DOI PMC

Kojima S, Nara K, Rifkin DB. Requirement for transglutaminase in the activation of latent transforming growth factor-beta in bovine endothelial cells. J Cell Biol. 1993;121:439–448. doi: 10.1083/jcb.121.2.439. PubMed DOI PMC

Flaumenhaft R, Abe M, Mignatti P, Rifkin DB. Basic fibroblast growth factor-induced activation of latent transforming growth factor beta in endothelial cells: regulation ofplasminogen activator activity. J Cell Biol. 1992;118:901–909. doi: 10.1083/jcb.118.4.901. PubMed DOI PMC

Nunes I, Shapiro RL, Rifkin DB. Characterization of latent TGF-beta activation by murine peritoneal macrophages. J Immunol. 1995;155:1450–1459. PubMed

Sato Y, Rifkin DB. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule byplasmin during co-culture. J Cell Biol. 1989;109:309–315. doi: 10.1083/jcb.109.1.309. PubMed DOI PMC

Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14:163–176. PubMed PMC

Schultz-Cherry S, Murphy-Ullrich JE. Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol. 1993;122:923–932. doi: 10.1083/jcb.122.4.923. PubMed DOI PMC

Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA. et al.The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96:319–328. doi: 10.1016/S0092-8674(00)80545-0. PubMed DOI

Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol. 2002;157:493–507. doi: 10.1083/jcb.200109100. PubMed DOI PMC

Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-beta 1. Mol Endocrinol. 1996;10:1077–1083. doi: 10.1210/me.10.9.1077. PubMed DOI

Lyons RM, Keski-Oja J, Moses HL. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol. 1988;106:1659–1665. doi: 10.1083/jcb.106.5.1659. PubMed DOI PMC

Cheifetz S, Like B, Massagué J. Cellular distribution of type I and type II receptors for transforming growth factor-beta. J Biol Chem. 1986;261:9972–9978. PubMed

Cheifetz S, Andres JL, Massagué J. The transforming growth factor-beta receptor type III is a membrane proteoglycan. Domain structure of the receptor. J Biol Chem. 1988;263:16984–16991. PubMed

Cheifetz S, Bellón T, Calés C, Vera S, Bernabeu C, Massagué J, Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in humanendothelial cells. J Biol Chem. 1992;267:19027–19030. PubMed

Segarini PR, Rosen DM, Seyedin SM. Binding of transforming growth factor-beta to cell surface proteins varies with cell type. Mol Endocrinol. 1989;3:261–272. doi: 10.1210/mend-3-2-261. PubMed DOI

Gougos A, Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem. 1990;265:8361–8364. PubMed

Robledo MM, Ursa MA, Sánchez-Madrid F, Teixidó J. Associations between TGFbeta1 receptors in human bone marrow stromal cells. Br J Haematol. 1998;102:804–811. doi: 10.1046/j.1365-2141.1998.00820.x. PubMed DOI

Matsubara S, Bourdeau A, terBrugge KG, Wallace C, Letarte M. Analysis of endoglin expression in normal brain tissue and in cerebral arteriovenous malformations. Stroke. 2000;31:2653–2660. doi: 10.1161/01.STR.31.11.2653. PubMed DOI

Henry LA, Johnson DA, Sarrió D, Lee S, Quinlan PR, Crook T, Thompson AM, Reis- Filho JS, Isacke CM. Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome. Oncogene. 2011;30:1046–1058. doi: 10.1038/onc.2010.488. PubMed DOI

Sandlund J, Hedberg Y, Bergh A, Grankvist K, Ljungberg B, Rasmuson T. Endoglin (CD105) expression in human renal cell carcinoma. BJU Int. 2006;97:706–710. doi: 10.1111/j.1464-410X.2006.06006.x. PubMed DOI

Esparza-Lopez J, Montiel JL, Vilchis-Landeros MM, Okadome T, Miyazono K, López- Casillas F. Ligand binding and functional properties of betaglycan, a co-receptor of the transforming growth factor-beta superfamily. Specialized binding regions fortransforming growth factor-beta and inhibin A. J Biol Chem. 2001;276:14588–14596. doi: 10.1074/jbc.M008866200. PubMed DOI

López-Casillas F, Wrana JL, Massagué J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell. 1993;73:1435–1444. doi: 10.1016/0092-8674(93)90368-Z. PubMed DOI

Yamashita H, Ichijo H, Grimsby S, Morén A, ten Dijke P, Miyazono K. Endoglin forms a heteromeric complex with the signaling receptors for transforming growth factorbeta. J Biol Chem. 1994;269:1995–2001. PubMed

Massagué J. Receptors for the TGF-beta family. Cell. 1992. pp. 1067–1070. PubMed

Lu S-L, Zhang W-C, Akiyama Y, Nomizu T, Yuasa Y. Genomic structure of the transforming growth factor β Type II receptor gene and its mutations in hereditarynonpolyposis colorectal cancers. Cancer Res. 1996;56:4595–4598. PubMed

Sun PD, Davies DR. The cystine-knot growth-factor superfamily. Annu Rev Biophys Biomol Struct. 1995;24:269–291. doi: 10.1146/annurev.bb.24.060195.001413. PubMed DOI

Shi Y, Massagué J. Mechanisms of TGF-[beta] Signaling from Cell Membrane to the Nucleus. Cell. 2003;113:685–700. doi: 10.1016/S0092-8674(03)00432-X. PubMed DOI

Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994;370:341–347. doi: 10.1038/370341a0. PubMed DOI

Derynck R, Feng X-H. TGF-[beta] receptor signaling.Biochimica et Biophysica Acta (BBA) Reviews on Cancer. 1997;1333:F105–F150. PubMed

Finnson KW, Parker WL, Chi Y, Hoemann CD, Goldring MB, Antoniou J, Philip A. Endoglin differentially regulates TGF-β-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellulardifferentiation state in human chondrocytes. Osteoarthr Cartil. 2010;18:1518–1527. doi: 10.1016/j.joca.2010.09.002. PubMed DOI

Kerscher O, Felberbaum R, Hochstrasser M. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol. 2006;22:159–180. doi: 10.1146/annurev.cellbio.22.010605.093503. PubMed DOI

Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell. 2000;6:1365–1375. doi: 10.1016/S1097-2765(00)00134-9. PubMed DOI

Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276:12477–12480. doi: 10.1074/jbc.C100008200. PubMed DOI

Kang JS, Saunier EF, Akhurst RJ, Derynck R. The type I TGF-beta receptor is covalently modified and regulated by sumoylation. Nat Cell Biol. 2008;10:654–664. doi: 10.1038/ncb1728. PubMed DOI PMC

Chen YG. Endocytic regulation of TGF-beta signaling. Cell Res. 2009;19:58–70. doi: 10.1038/cr.2008.315. PubMed DOI

Attisano L, Wrana JL. Smads as transcriptional co-modulators. Curr Opin Cell Biol. 2000;12:235–243. doi: 10.1016/S0955-0674(99)00081-2. PubMed DOI

Liu F, Hata A, Baker JC, Doody J, Cárcamo J, Harland RM, Massagué J. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature. 1996;381:620–623. doi: 10.1038/381620a0. PubMed DOI

Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes & Development. 2005. pp. 2783–2810. PubMed

Hayashi H, Abdollah S, Qiu Y, Cai J, Xu Y-Y, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL, Falb D. The MAD-related protein smad7 associates with the TGF[beta] receptor and Functions as an antagonist of TGF[beta] signaling. Cell. 1997;89:1165–1173. doi: 10.1016/S0092-8674(00)80303-7. PubMed DOI

Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998;12:186–197. doi: 10.1101/gad.12.2.186. PubMed DOI PMC

Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE Domain Protein that Recruits Smad2 to the TGF[beta] Receptor. Cell. 1998;95:779–791. doi: 10.1016/S0092-8674(00)81701-8. PubMed DOI

Watanabe Y, Itoh S, Goto T, Ohnishi E, Inamitsu M, Itoh F, Satoh K, Wiercinska E, Yang W, Shi L. et al.TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling. Mol Cell. 2010;37:123–134. doi: 10.1016/j.molcel.2009.10.028. PubMed DOI

Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R. et al.Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Mol Cell. 2001;8:1277–1289. doi: 10.1016/S1097-2765(01)00421-X. PubMed DOI

Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature. 1999;400:687–693. doi: 10.1038/23293. PubMed DOI

Xiao Z, Liu X, Henis YI, Lodish HF. A distinct nuclear localization signal in the N terminus of Smad 3 determines its ligand-induced nuclear translocation. Proc Natl Acad Sci USA. 2000;97:7853–7858. doi: 10.1073/pnas.97.14.7853. PubMed DOI PMC

Xu L, Chen YG, Massagué J. The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation. Nat Cell Biol. 2000;2:559–562. doi: 10.1038/35019649. PubMed DOI

Xu L, Kang Y, Cöl S, Massagué J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in thecytoplasm and nucleus. Mol Cell. 2002;10:271–282. doi: 10.1016/S1097-2765(02)00586-5. PubMed DOI

Inman GJ, Nicolás FJ, Hill CS. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell. 2002;10:283–294. doi: 10.1016/S1097-2765(02)00585-3. PubMed DOI

Chen CR, Kang Y, Massagué J. Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program. Proc Natl Acad Sci USA. 2001;98:992–999. doi: 10.1073/pnas.98.3.992. PubMed DOI PMC

Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, Piek E, Bottinger EP. Genetic programs of epithelial cell plasticity directed by transforming growth factorbeta. Proc Natl Acad Sci USA. 2001;98:6686–6691. doi: 10.1073/pnas.111614398. PubMed DOI PMC

Feng X-H, Zhang Y, Wu R-Y, Derynck R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGF-β-inducedtranscriptional activation. Genes Dev. 1998;12:2153–2163. doi: 10.1101/gad.12.14.2153. PubMed DOI PMC

Pouponnot C, Jayaraman L, Massagué J. Physical and Functional Interaction of SMADs and p300/CBP. J Biol Chem. 1998;273:22865–22868. doi: 10.1074/jbc.273.36.22865. PubMed DOI

Pearson KL, Hunter T, Janknecht R. Activation of Smad1-mediated transcription by p300/CBP.Biochimica et Biophysica Acta (BBA) Gene Structure and Expression. 1999;1489:354–364. doi: 10.1016/S0167-4781(99)00166-9. PubMed DOI

Topper JN, DiChiara MR, Brown JD, Williams AJ, Falb D, Collins T, Gimbrone MA. CREB binding protein is a required coactivator for Smad-dependent, transforming growth factor β transcriptional responses in endothelial cells. Proc Natl Acad Sci. 1998;95:9506–9511. doi: 10.1073/pnas.95.16.9506. PubMed DOI PMC

Ross S, Hill CS. How the Smads regulate transcription. Int J Biochem Cell Biol. 2008;40:383–408. doi: 10.1016/j.biocel.2007.09.006. PubMed DOI

Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A. Smad proteins bind a conserved RNA sequence to promote MicroRNA maturation by Drosha. Mol Cell. 2010;39:373–384. doi: 10.1016/j.molcel.2010.07.011. PubMed DOI PMC

Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008;454:56–61. doi: 10.1038/nature07086. PubMed DOI PMC

Moustakas A, Heldin C-H. Non-Smad TGF-β signals. J Cell Sci. 2005;118:3573–3584. doi: 10.1242/jcs.02554. PubMed DOI

Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cellmigration. J Cell Sci. 2002;115:3193–3206. PubMed

Engel ME, McDonnell MA, Law BK, Moses HL. Interdependent SMAD and JNK signaling in transforming growth factor-β-mediated transcription. J Biol Chem. 1999;274:37413–37420. doi: 10.1074/jbc.274.52.37413. PubMed DOI

Yu L, Hébert MC, Zhang YE. TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J. 2002;21:3749–3759. doi: 10.1093/emboj/cdf366. PubMed DOI PMC

Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor β- mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275:36803–36810. doi: 10.1074/jbc.M005912200. PubMed DOI

Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL. Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001;12:27–36. PubMed PMC

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;178:437–451. doi: 10.1083/jcb.200611146. PubMed DOI PMC

Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, Thannickal VJ. Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal. 2007;19:761–771. doi: 10.1016/j.cellsig.2006.10.001. PubMed DOI PMC

Galliher AJ, Schiemann WP. β3 Integrin and Src facilitate transforming growth factor-β mediated induction of epithelial-mesenchymal transition in mammaryepithelial cells. Breast Cancer Res. 2006;8(4):R42. doi: 10.1186/bcr1524. PubMed DOI PMC

Park SS, Eom Y-W, Kim EH, Lee JH, Min DS, Kim S, Kim S-J, Choi KS. Involvement of c-Src kinase in the regulation of TGF-[beta]1-induced apoptosis. Oncogene. 2004;23:6272–6281. doi: 10.1038/sj.onc.1207856. PubMed DOI

Gingery A, Bradley EW, Pederson L, Ruan M, Horwood NJ, Oursler MJ. TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promoteosteoclast survival. Exp Cell Res. 2008;314:2725–2738. doi: 10.1016/j.yexcr.2008.06.006. PubMed DOI PMC

Derynck R, Akhurst RJ, Balmain A. TGF-β signaling in tumor suppression and cancer progression. Nat Genet. 2001;29:117–129. doi: 10.1038/ng1001-117. PubMed DOI

Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6:506–520. doi: 10.1038/nrc1926. PubMed DOI

Pangas SA, Matzuk MM. Genetic models for transforming growth factor beta superfamily signaling in ovarian follicle development. Mol Cell Endocrinol. 2004;225:83–91. doi: 10.1016/j.mce.2004.02.017. PubMed DOI

Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, Akhurst RJ. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasivespindle carcinomas in transgenic mice. Cell. 1996;86:531–542. doi: 10.1016/S0092-8674(00)80127-0. PubMed DOI

Amendt C, Schirmacher P, Weber H, Blessing M. Expression of a dominant negative type II TGF-beta receptor in mouse skin results in an increase in carcinoma incidenceand an acceleration of carcinoma development. Oncogene. 1998;17:25–34. doi: 10.1038/sj.onc.1202161. PubMed DOI

Wang XJ, Liefer KM, Tsai S, O'Malley BW, Roop DR. Development of gene-switch transgenic mice that inducibly express transforming growth factor beta1 in theepidermis. Proc Natl Acad Sci USA. 1999;96:8483–8488. doi: 10.1073/pnas.96.15.8483. PubMed DOI PMC

Weeks BH, He W, Olson KL, Wang XJ. Inducible expression of transforming growth factor beta1 in papillomas causes rapid metastasis. Cancer Res. 2001;61:7435–7443. PubMed

Hannon GJ. Beach D: pl5INK4B is a potentia| effector of TGF-[beta]-induced cell cycle arrest. Nature. 1994;371:257–261. doi: 10.1038/371257a0. PubMed DOI

Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA. 1995;92:5545–5549. doi: 10.1073/pnas.92.12.5545. PubMed DOI PMC

Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition tocell cycle arrest. Genes Dev. 1994;8:9–22. doi: 10.1101/gad.8.1.9. PubMed DOI

Kang Y, Chen C-R, Massagué J. A self-enabling TGF[beta] response coupled to stress signaling: smad engages stress response factor ATF3 for Id1 repression inepithelial cells. Mol Cell. 2003;11:915–926. doi: 10.1016/S1097-2765(03)00109-6. PubMed DOI

Isoe S, Naganuma H, Nakano S, Sasaki A, Satoh E, Nagasaka M, Maeda S, Nukui H. Resistance to growth inhibition by transforming growth factor—β in malignant glioma cells with functional receptors. J Neurosurg. 1998;88:529–534. doi: 10.3171/jns.1998.88.3.0529. PubMed DOI

Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–1512. doi: 10.1101/gad.13.12.1501. PubMed DOI

Reynisdóttir I, Massagué J. The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. 1997;11:492–503. doi: 10.1101/gad.11.4.492. PubMed DOI

Sandhu C, Garbe J, Bhattacharya N, Daksis J, Pan CH, Yaswen P, Koh J, Slingerland JM, Stampfer MR. Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in humanmammary epithelial cells. Mol Cell Biol. 1997;17:2458–2467. PubMed PMC

Iavarone A, Massague J. E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrest. Mol Cell Biol. 1999;19:916–922. PubMed PMC

Chen C-R, Kang Y, Siegel PM, Massagué J. E2F4/5 and p107 as smad cofactors linking the TGF[beta] Receptor to c-myc Repression. Cell. 2002;110:19–32. doi: 10.1016/S0092-8674(02)00801-2. PubMed DOI

Levy L, Hill CS. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 2006;17:41–58. doi: 10.1016/j.cytogfr.2005.09.009. PubMed DOI

Teicher BA. Malignant cells, directors of the malignant process: role of transforming growth factor-beta. Cancer Metastasis Rev. 2001;20:133–143. doi: 10.1023/A:1013177011767. PubMed DOI

Biswas S, Chytil A, Washington K, Romero-Gallo J, Gorska AE, Wirth PS, Gautam S, Moses HL, Grady WM. Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. Cancer Res. 2004;64:4687–4692. doi: 10.1158/0008-5472.CAN-03-3255. PubMed DOI

Gobbi H, Arteaga CL, Jensen RA, Simpson JF, Dupont WD, Olson SJ, Schuyler PA, Plummer WD Jr, Page DL. Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasivecarcinomas. Histopathology. 2000;36:168–177. doi: 10.1046/j.1365-2559.2000.00841.x. PubMed DOI

Bardeesy N, Cheng K-H, 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;20:3130–3146. doi: 10.1101/gad.1478706. PubMed DOI PMC

Muñoz-Antonia T, Torrellas-Ruiz M, Clavell J, Mathews LA, Muro-Cacho CA, Báez A. Aberrant methylation inactivates transforming growth factor Beta receptor I in head and neck squamous cell carcinoma. Int. J. Otolaryngol. 2009;2009:848695–848695. PubMed PMC

Lu SL, Herrington H, Reh D, Weber S, Bornstein S, Wang D, Li AG, Tang CF, Siddiqui Y, Nord J. et al.Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev. 2006;20:1331–1342. doi: 10.1101/gad.1413306. PubMed DOI PMC

Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K, Imamura T. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4–2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducingubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J. 2005;386:461–470. doi: 10.1042/BJ20040738. PubMed DOI PMC

Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, Miyazawa K. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1) Oncogene. 2004;23:6914–6923. doi: 10.1038/sj.onc.1207885. PubMed DOI

Fukuchi M, Fukai Y, Masuda N, Miyazaki T, Nakajima M, Sohda M, Manda R, Tsukada K, Kato H, Kuwano H. High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cellcarcinoma. Cancer Res. 2002;62:7162–7165. PubMed

Kim SJ, Im YH, Markowitz SD, Bang YJ. Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis. Cytokine Growth Factor Rev. 2000;11:159–168. doi: 10.1016/S1359-6101(99)00039-8. PubMed DOI

Kang SH, Bang YJ, Im YH, Yang HK, Lee DA, Lee HY, Lee HS, Kim NK, Kim SJ. Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in humangastric cancer. Oncogene. 1999;18:7280–7286. doi: 10.1038/sj.onc.1203146. PubMed DOI

Hinshelwood RA, Huschtscha LI, Melki J, Stirzaker C, Abdipranoto A, Vissel B, Ravasi T, Wells CA, Hume DA, Reddel RR, Clark SJ. Concordant epigenetic silencing of transforming growth factor-beta signaling pathway genes occurs early in breastcarcinogenesis. Cancer Res. 2007;67:11517–11527. doi: 10.1158/0008-5472.CAN-07-1284. PubMed DOI

Bristow RG, Hill RP. Hypoxia and metabolism: Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008;8:180–192. doi: 10.1038/nrc2344. PubMed DOI

Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev. 2003;83:337–376. PubMed

Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303:848–851. doi: 10.1126/science.1090922. PubMed DOI

Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, Arteaga CL, Neilson EG, Hayward SW, Moses HL. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGFalpha-,MSP- and HGF-mediated signaling networks. Oncogene. 2005;24:5053–5068. doi: 10.1038/sj.onc.1208685. PubMed DOI PMC

Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008;133:66–77. doi: 10.1016/j.cell.2008.01.046. PubMed DOI PMC

Bierie B, Stover DG, Abel TW, Chytil A, Gorska AE, Aakre M, Forrester E, Yang L, Wagner KU, Moses HL. Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res. 2008;68:1809–1819. doi: 10.1158/0008-5472.CAN-07-5597. PubMed DOI

Lee MS, Kim TY, Kim YB, Lee SY, Ko SG, Jong HS, Bang YJ, Lee JW. The signaling network of transforming growth factor beta1, protein kinase Cdelta, and integrinunderlies the spreading and invasiveness of gastric carcinoma cells. Mol Cell Biol. 2005;25:6921–6936. doi: 10.1128/MCB.25.16.6921-6936.2005. PubMed DOI PMC

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454. doi: 10.1038/nrc822. PubMed DOI

Thiery JP, Chopin D. Epithelial cell plasticity in development and tumor progression. Cancer Metastasis Rev. 1999;18:31–42. doi: 10.1023/A:1006256219004. PubMed DOI

Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010;31:220–227. doi: 10.1016/j.it.2010.04.002. PubMed DOI PMC

Lebman DA, Edmiston JS. The role of TGF-beta in growth, differentiation, and maturation of B lymphocytes. Microbes Infect. 1999;1:1297–1304. doi: 10.1016/S1286-4579(99)00254-3. PubMed DOI

Gilbert KM, Thoman M, Bauche K, Pham T, Weigle WO. Transforming growth factor-beta 1 induces antigen-specific unresponsiveness in naive T cells. Immunol Invest. 1997;26:459–472. doi: 10.3109/08820139709022702. PubMed DOI

Bommireddy R, Ormsby I, Yin M, Boivin GP, Babcock GF, Doetschman T. TGF beta 1 inhibits Ca2 + −calcineurin-mediated activation in thymocytes. J Immunol. 2003;170:3645–3652. PubMed PMC

Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA. 1987;84:5788–5792. doi: 10.1073/pnas.84.16.5788. PubMed DOI PMC

Monteleone G, Mann J, Monteleone I, Vavassori P, Bremner R, Fantini M, Del Vecchio Blanco G, Tersigni R, Alessandroni L, Mann D. et al.A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gutinflammation. J Biol Chem. 2004;279:3925–3932. PubMed

Korpal M, Kang Y. Targeting the transforming growth factor-beta signalling pathway in metastatic cancer. Eur J Cancer. 2010;46:1232–1240. doi: 10.1016/j.ejca.2010.02.040. PubMed DOI

Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. TGF-beta signalling in colon carcinogenesis. Cancer Lett. 2012;314:1–7. doi: 10.1016/j.canlet.2011.09.041. PubMed DOI

Fakhrai H, Mantil JC, Liu L, Nicholson GL, Murphy-Satter CS, Ruppert J, Shawler DL. Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther. 2006;13:1052–1060. doi: 10.1038/sj.cgt.7700975. PubMed DOI

Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, Tong A, Kumar P, Pappen B, Hamilton C. et al.Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cellvaccine in non-small-cell lung cancer. J Clin Oncol. 2006;24:4721–4730. doi: 10.1200/JCO.2005.05.5335. PubMed DOI

Gadir N, Jackson DN, Lee E, Foster DA. Defective TGF-beta signaling sensitizes human cancer cells to rapamycin. Oncogene. 2008;27:1055–1062. doi: 10.1038/sj.onc.1210721. PubMed DOI

Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–774. doi: 10.1073/pnas.90.2.770. PubMed DOI PMC

Böttner M, Krieglstein K, Unsicker K. The transforming growth factor-betas: structure, signaling, and roles in nervous system development and functions. J Neurochem. 2000;75:2227–2240. PubMed

CBTRUS. Central Brain Tumor Registry of the United States (CBTRUS): 2011 CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosedin the United States in 2004–2007. 2007. http://www.cbtrus.org/2011-NPCR-SEER/WEB-0407- Report-3-3-2011.pdf.

Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK. The WHO classification of tumors of the nervous system. J Neuropath Exp Neur. 2002;61:215–225. discussion 226-229-215-225; discussion 226–229. PubMed

Izumoto S, Arita N, Ohnishi T, Hiraga S, Taki T, Tomita N, Ohue M, Hayakawa T. Microsatellite instability and mutated type II transforming growth factor-[beta] receptor gene in gliomas. Cancer Lett. 1997;112:251–256. doi: 10.1016/S0304-3835(96)04583-1. PubMed DOI

Fujiwara K, Ikeda H, Yoshimoto T. Abnormalities in expression of genes, mRNA, and proteins of transforming growth factor-beta receptor type I and type II in humanpituitary adenomas. Clin Neuropathol. 1998;17:19–26. PubMed

Kjellman C, Olofsson SP, Hansson O, Von Schantz T, Lindvall M, Nilsson I, Salford LG, Sjögren HO, Widegren B. Expression of TGF-β isoforms, TGF-β receptors, and Smad molecules at different stages of human glioma. Int J Cancer. 2000;89:251–258. doi: 10.1002/1097-0215(20000520)89:3<251::AID-IJC7>3.0.CO;2-5. PubMed DOI

Yamada N, Kato M, Yamashita H, Nister M, Miyazono K, Heldin CH, Funa K. Enhanced expression of transforming growth factor-β and its type-I and type-II receptors in human glioblastoma. Int J Cancer. 1995;62:386–392. doi: 10.1002/ijc.2910620405. PubMed DOI

Jachimczak P, Hessdörfer B, Fabel-Schulte K, Wismeth C, Brysch W, Schlingensiepen KH, Bauer A, Blesch A, Bogdahn U. Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisenseoligonucleotides. Int. J. CancerJournal Int Du Cancer. 1996;65:332–337. PubMed

Zhang L, Sato E, Amagasaki K, Nakao A, Naganuma H. Participation of an abnormality in the transforming growth factor-β signaling pathway in resistance ofmalignant glioma cells to growth inhibition induced by that factor. J Neurosurg. 2006;105:119–128. doi: 10.3171/jns.2006.105.1.119. PubMed DOI

Bruna A, Darken RS, Rojo F, Ocaña A, Peñuelas S, Arias A, Paris R, Tortosa A, Mora J, Baselga J, Seoane J. High TGFβ-smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B Gene. Cancer Cell. 2007;11:147–160. doi: 10.1016/j.ccr.2006.11.023. PubMed DOI

Copland JA, Luxon BA, Ajani L, Maity T, Campagnaro E, Guo H, LeGrand SN, Tamboli P, Wood CG. Genomic profiling identifies alterations in TGFbeta signaling through loss of TGFbeta receptor expression in human renal cell carcinogenesis andprogression. Oncogene. 2003;22:8053–8062. doi: 10.1038/sj.onc.1206835. PubMed DOI

Hung T-T, Wang H, Kingsley EA, Risbridger GP, Russell PJ. Molecular profiling of bladder cancer: Involvement of the TGF-[beta] pathway in bladder cancer progression. Cancer Lett. 2008;265:27–38. doi: 10.1016/j.canlet.2008.02.034. PubMed DOI

Li Y, Yang K, Mao Q, Zheng X, Kong D, Xie L. Inhibition of TGF-β receptor I by siRNA suppresses the motility and invasiveness of T24 bladder cancer cells viamodulation of integrins and matrix metalloproteinase. Int Urol Nephrol. 2009;42:315–323. PubMed

Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34:193–205. doi: 10.1016/j.ctrv.2007.12.001. PubMed DOI

Sjölund J, Boström AK, Lindgren D, Manna S, Moustakas A, Ljungberg B, Johansson M, Fredlund E, Axelson H. The Notch and TGF-β Signaling Pathways Contribute to the Aggressiveness of Clear Cell Renal Cell Carcinoma. PLoS One. 2011;6:e23057. doi: 10.1371/journal.pone.0023057. PubMed DOI PMC

Komiyama S, Kurahashi T, Ishikawa M, Tanaka K, Komiyama M, Mikami M, Udagawa Y. Expression of TGFß1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin. Oncol Rep. 2011;25:1131–1138. PubMed

Antony ML, Nair R, Sebastian P, Karunagaran D. Changes in expression, and/or mutations in TGF-β receptors (TGF-β RI and TGF-β RII) and Smad 4 in humanovarian tumors. J Cancer Res Clin Oncol. 2009;136:351–361. PubMed

Chen T, Triplett J, Dehner B, Hurst B, Colligan B, Pemberton J, Graff JR, Carter JH. Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res. 2001;61:4679–4682. PubMed

Kaklamani VG, Hou N, Bian Y, Reich J, Offit K, Michel LS, Rubinstein WS, Rademaker A, Pasche B. TGFBR1*6A and cancer risk: a meta-analysis of seven case–control studies. J Clin Oncol: Official Journal of the Am J Clin Oncol. 2003;21:3236–3243. doi: 10.1200/JCO.2003.11.524. PubMed DOI

Biswas S, Trobridge P, Romero-Gallo J, Billheimer D, Myeroff LL, Willson JKV, Markowitz SD, Grady WM. Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonaloutgrowth of transforming growth factor beta resistant cells. Genes Chromosomes Cancer. 2008;47:95–106. doi: 10.1002/gcc.20511. PubMed DOI

Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H. et al.DPC4 Gene in Various Tumor Types. Cancer Res. 1996;56:2527–2530. PubMed

Do T-V, Kubba LA, Du H, Sturgis CD, Woodruff TK. Transforming growth Factor-β1, transforming growth factor-β2, and transforming growth factor-β3 enhance ovarian cancer metastatic potential by inducing a Smad3-dependent epithelial-to-mesenchymaltransition. Mol Cancer Res. 2008;6:695–705. doi: 10.1158/1541-7786.MCR-07-0294. PubMed DOI PMC

Chan MWY, Huang Y-W, Hartman-Frey C, Kuo C-T, Deatherage D, Qin H, Cheng ASL, Yan PS, Davuluri RV, Huang THM. et al.Aberrant Transforming Growth Factor β1 Signaling and SMAD4 Nuclear Translocation Confer Epigenetic Repression ofADAM19 in Ovarian Cancer. Neoplasia (New York, NY) 2008;10:908–919. PubMed PMC

Rodriguez GC, Haisley C, Hurteau J, Moser TL, Whitaker R, Bast RC Jr, Stack MS. Regulation of invasion of epithelial ovarian cancer by transforming growth factor-β. Gynecol Oncol. 2001;80:245–253. doi: 10.1006/gyno.2000.6042. PubMed DOI

Yeh KT, Chen TH, Yang HW, Chou JL, Chen LY, Yeh CM, Chen YH, Lin RI, Su HY, Chen GCW. et al.Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, RunX1T1 in ovarian cancer. Epigenetics: Official Journal of the DNA Methylation Society. 2011;6:727–739. doi: 10.4161/epi.6.6.15856. PubMed DOI PMC

Kennedy BA, Deatherage DE, Gu F, Tang B, Chan MW, Nephew KP, Huang TH, Jin VX. ChIP-seq Defined Genome-Wide Map of TGFβ/SMAD4 Targets: Implications with Clinical Outcome of Ovarian Cancer. PLoS One. 2011;6:e22606. doi: 10.1371/journal.pone.0022606. PubMed DOI PMC

Wikström P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome inprostate cancer. Prostate. 1998;37:19–29. doi: 10.1002/(SICI)1097-0045(19980915)37:1<19::AID-PROS4>3.0.CO;2-3. PubMed DOI

Yu N, Kozlowski JM, Park II, Chen L, Zhang Q, Xu D, Doll JA, Crawford SE, Brendler CB, Lee C. Overexpression of transforming growth factor [beta]1 in malignant prostate cells is partly caused by a runaway of TGF-[beta]1 auto-induction mediated through adefective recruitment of protein phosphatase 2A by TGF-[beta] type I receptor. Urology. 2010;76:1519. e1518-1519.e1513-1519.e1518-1519.e1513. PubMed PMC

Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Lang S, Kato M, Oefelein MG, Miyazono K, Nemeth JA, Kozlowski JM, Lee C. Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancertissues. Clin Cancer Res. 1996;2:1255–1261. PubMed

Guo Y, Jacobs SC, Kyprianou N. Down‐regulation of protein and mRNA expression for transforming growth factor‐β (TGF‐β1) type I and type II receptors in humanprostate cancer. Int J Cancer. 1997;71:573–579. doi: 10.1002/(SICI)1097-0215(19970516)71:4<573::AID-IJC11>3.0.CO;2-D. PubMed DOI

Turley RS, Finger EC, Hempel N, How T, Fields TA, Blobe GC. The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostatecancer. Cancer Res. 2007;67:1090–1098. doi: 10.1158/0008-5472.CAN-06-3117. PubMed DOI

Zhang Q, Rubenstein JN, Jang TL, Pins M, Javonovic B, Yang X, Kim S-J, Park I, Lee C. Insensitivity to transforming growth factor-β results from promoter methylation of cognate receptors in human prostate cancer cells (LNCaP) Mol Endocrinol. 2005;19:2390–2399. doi: 10.1210/me.2005-0096. PubMed DOI

Latil A, Pesche S, Valéri A, Fournier G, Cussenot O, Lidereau R. Expression and mutational analysis of the MADR2/smad2 gene in human prostate cancer. Prostate. 1999;40:225–231. doi: 10.1002/(SICI)1097-0045(19990901)40:4<225::AID-PROS3>3.0.CO;2-3. PubMed DOI

Yin Z, Babaian RJ, Troncoso P, Strom SS, Spitz MR, Caudell JJ, Stein JD, Kagan J. Limiting the location of putative human prostate cancer tumor suppressor genes on chromosome 18q. Oncogene. 2001;20:2273–2280. doi: 10.1038/sj.onc.1204310. PubMed DOI

Yang J, Wahdan-Alaswad R, Danielpour D. Critical role of smad2 in tumor suppression and transforming growth factor-β–induced apoptosis of prostate epithelialcells. Cancer Res. 2009;69:2185–2190. doi: 10.1158/0008-5472.CAN-08-3961. PubMed DOI PMC

Robinson SD, Silberstein GB, Roberts AB, Flanders KC, Daniel CW. Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms inmouse mammary gland development. Development. 1991;113:867–878. PubMed

Serra R, Crowley MR. Mouse models of transforming growth factor beta impact in breast development and cancer. Endocr Relat Cancer. 2005;12:749–760. doi: 10.1677/erc.1.00936. PubMed DOI

Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Kasid A, Derynck R, Dickson RB. Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell. 1987;48:417–428. doi: 10.1016/0092-8674(87)90193-0. PubMed DOI

Marrogi AJ, Munshi A, Merogi AJ, Ohadike Y, El Habashi A, Marrogi OL, Freeman SM. Study of tumor infiltrating lymphocytes and transforming growth factor β as prognostic factors in breast carcinoma. Int J Cancer. 1997;74:492–501. doi: 10.1002/(SICI)1097-0215(19971021)74:5<492::AID-IJC3>3.0.CO;2-Z. PubMed DOI

Gorsch SM, Memoli VA, Stukel TA, Gold LI, Arrick BA. Immunohistochemical Staining for Transforming Growth Factor β1 Associates with Disease Progression inHuman Breast Cancer. Cancer Res. 1992;52:6949–6952. PubMed

Desruisseau S, Palmari J, Giusti C, Romain S, Martin PM, Berthois Y. Determination of TGF[beta]1 protein level in human primary breast cancers and its relationship withsurvival. Br J Cancer. 2006;94:239–246. doi: 10.1038/sj.bjc.6602920. PubMed DOI PMC

Dalal BI, Keown PA, Greenberg AH. Immunocytochemical localization of secreted transforming growth factor-beta 1 to the advancing edges of primary tumors and tolymph node metastases of human mammary carcinoma. Am J Pathol. 1993;143:381–389. PubMed PMC

Barlow J, Yandell D, Weaver D, Casey T, Plaut K. Higher stromal expression of transforming growth factor-beta Type II Receptors is associated with poorer prognosisbreast tumors. Breast Cancer Res Treat. 2003;79:149–159. doi: 10.1023/A:1023918026437. PubMed DOI

Takenoshita S, Mogi A, Tani M, Osawa H, Sunaga H, Kakegawa H, Yanagita Y, Koida T, Kimura M, Fujita KI. et al.Absence of mutations in the analysis of coding sequences of the entire transforming growth factor-beta type II receptor gene in sporadic humanbreast cancers. Oncol Rep. 1998;5:367–371. PubMed

Kalkhoven E, Roelen BA, De Winter JP, Mummery CL, Van Den E-V, Raaij AJ, Van Der Saag PT, Van Der Burg B. Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor cell lines. Cell Growth Differ. 1995;6:1151–1161. PubMed

Chen T, Carter D, Garrigue-Antar L, Reiss M. Transforming Growth Factor β Type I Receptor Kinase Mutant Associated with Metastatic Breast Cancer. Cancer Res. 1998;58:4805–4810. PubMed

Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, Kelly P, Moeller BJ, Marks JR, Blobe GC. The type III TGF-β receptor suppresses breast cancer progression. J Clin Invest. 2007;117:206–217. doi: 10.1172/JCI29293. PubMed DOI PMC

Xie W, Mertens JC, Reiss DJ, Rimm DL, Camp RL, Haffty BG, Reiss M. Alterations of smad signaling in human breast carcinoma are associated with poor outcome. Cancer Res. 2002;62:497–505. PubMed

Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu C-G, Negrini M. et al.E2F1-Regulated MicroRNAs Impair TGFβ-Dependent Cell-Cycle Arrest and Apoptosis in Gastric Cancer. Cancer Cell. 2008;13:272–286. doi: 10.1016/j.ccr.2008.02.013. PubMed DOI

Park K, Kim SJ, Bang YJ, Park JG, Kim NK, Roberts AB, Sporn MB. Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in humangastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci USA. 1994;91:8772–8776. doi: 10.1073/pnas.91.19.8772. PubMed DOI PMC

Hahm KB, Lee KM, Kim YB, Hong WS, Lee WH, Han SU, Kim MW, Ahn BO, Oh TY, Lee MH. et al.Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice. Aliment Pharmacol Ther. 2002;16(Suppl 2):115–127. PubMed

Fu H, Hu Z, Wen J, Wang K, Liu Y. TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. Acta Biochim Biophys Sin (Shanghai) 2009;41:648–656. doi: 10.1093/abbs/gmp053. PubMed DOI

Shinto O, Yashiro M, Toyokawa T, Nishii T, Kaizaki R, Matsuzaki T, Noda S, Kubo N, Tanaka H, Doi Y. et al.Phosphorylated smad2 in advanced stage gastric carcinoma. BMC Cancer. 2010;10:652. doi: 10.1186/1471-2407-10-652. PubMed DOI PMC

Han SU, Kim HT, Seong DH, Kim YS, Park YS, Bang YJ, Yang HK, Kim SJ. Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastriccancer. Oncogene. 2004;23:1333–1341. doi: 10.1038/sj.onc.1207259. PubMed DOI

Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis. 2008;29:480–490. PubMed

Mamiya T, Yamazaki K, Masugi Y, Mori T, Effendi K, Du W, Hibi T, Tanabe M, Ueda M, Takayama T, Sakamoto M. Reduced transforming growth factor-beta receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis. Lab Invest. 2010;90:1339–1345. doi: 10.1038/labinvest.2010.105. PubMed DOI

Longerich T, Breuhahn K, Odenthal M, Petmecky K, Schirmacher P. Factors of transforming growth factor beta signalling are co-regulated in human hepatocellular carcinoma. Virchows Arch. 2004;445:589–596. doi: 10.1007/s00428-004-1118-x. PubMed DOI

Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene. 1999;18:4879–4883. doi: 10.1038/sj.onc.1202866. PubMed DOI

Yang YA, Zhang GM, Feigenbaum L, Zhang YE. Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation ofBcl-2. Cancer Cell. 2006;9:445–457. doi: 10.1016/j.ccr.2006.04.025. PubMed DOI PMC

Yamamura Y, Hua X, Bergelson S, Lodish HF. Critical Role of Smads and AP-1 complex in transforming growth factor-β-dependent Apoptosis. J Biol Chem. 2000;275:36295–36302. doi: 10.1074/jbc.M006023200. PubMed DOI

Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinomagrowth through neo-angiogenesis regulation. Hepatology. 2009;50:1140–1151. doi: 10.1002/hep.23118. PubMed DOI

Mazzocca A, Fransvea E, Dituri F, Lupo L, Antonaci S, Giannelli G. Down-regulation of connective tissue growth factor by inhibition of transforming growth factor betablocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma. Hepatology. 2010;51:523–534. doi: 10.1002/hep.23285. PubMed DOI

Flechsig P, Dadrich M, Bickelhaupt S, Jenne J, Hauser K, Timke C, Peschke P, Hahn EW, Gröne HJ, Yingling J. et al.LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-β and BMP-associated proinflammatory andproangiogenic signals. Clin Cancer Res. 2012;18:3616–3627. doi: 10.1158/1078-0432.CCR-11-2855. PubMed DOI

Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S, Cohen A. High levels of transforming growth factor beta 1 correlate with disease progression in human coloncancer. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 1995;4:549–554. PubMed

Yan Z, Winawer S, Friedman E. Two different signal transduction pathways can be activated by transforming growth factor beta 1 in epithelial cells. J Biol Chem. 1994;269:13231–13237. PubMed

Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui L-C, Bapat B, Gallinger S, Andrulis IL. et al.MADR2 Maps to 18q21 and Encodes a TGF[beta]-Regulated MAD-Related Protein That Is Functionally Mutated in Colorectal Carcinoma. Cell. 1996;86:543–552. doi: 10.1016/S0092-8674(00)80128-2. PubMed DOI

Ku JL, Park SH, Yoon KA, Shin YK, Kim KH, Choi JS, Kang HC, Kim IJ, Han IO, Park JG. Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: a novel mutation in Smad3 associated with the inactivation of TGF-beta-inducedtranscriptional activation. Cancer Lett. 2007;247:283–292. doi: 10.1016/j.canlet.2006.05.008. PubMed DOI

Ando T, Sugai T, Habano W, Jiao Y-F, Suzuki K. Analysis of SMAD4/DPC4 gene alterations in multiploid colorectal carcinomas. J Gastroenterol. 2005;40:708–715. doi: 10.1007/s00535-005-1614-z. PubMed DOI

Takagi Y, Kohmura H, Futamura M, Kida H, Tanemura H, Shimokawa K, Saji S. Somatic alterations of the DPC4 gene in human colorectal cancersin vivo. Gastroenterology. 1996;111:1369–1372. doi: 10.1053/gast.1996.v111.pm8898652. PubMed DOI

Wang H, Rajan S, Liu G, Chakrabarty S. Transforming growth factor [beta] suppresses [beta]-catenin/Wnt signaling and stimulates an adhesion response in humancolon carcinoma cells in a Smad4/DPC4 independent manner. Cancer Lett. 2008;264:281–287. doi: 10.1016/j.canlet.2008.01.039. PubMed DOI PMC

Ali NA, McKay MJ, Molloy MP. Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells. Mol Biosyst. 2010;6:2332–2332. doi: 10.1039/c0mb00016g. PubMed DOI

Nikolic A, Kojic S, Knezevic S, Krivokapic Z, Ristanovic M, Radojkovic D. Structural and functional analysis of SMAD4 gene promoter in malignant pancreatic andcolorectal tissues: Detection of two novel polymorphic nucleotide repeats. Cancer Epidemiol. 2011;35:265–271. doi: 10.1016/j.canep.2010.10.002. PubMed DOI

Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science (New York, NY) 1995;268:1336–1338. doi: 10.1126/science.7761852. PubMed DOI

Parsons R, Myeroff LL, Liu B, Willson JKV, Markowitz SD, Kinzler KW, Vogelstein B. Microsatellite Instability and Mutations of the Transforming Growth Factor β Type II Receptor Gene in Colorectal Cancer. Cancer Res. 1995;55:5548–5550. PubMed

Grady WM, Myeroff LL, Swinler SE, Rajput A, Thiagalingam S, Lutterbaugh JD, Neumann A, Brattain MG, Chang J, Kim SJ. et al.Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res. 1999;59:320–324. PubMed

Liu XQ, Rajput A, Geng L, Ongchin M, Chaudhuri A, Wang J. Restoration of transforming growth factor-beta receptor II expression in colon cancer cells withmicrosatellite instability increases metastatic potentialin vivo. J Biol Chem. 2011;286:16082–16090. doi: 10.1074/jbc.M111.221697. PubMed DOI PMC

Pasche B, Wisinski KB, Sadim M, Kaklamani V, Pennison MJ, Zeng Q, Bellam N, Zimmerman J, Yi N, Zhang K. et al.Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs. J Exp Clin Cancer Res. 2010;29:57–57. doi: 10.1186/1756-9966-29-57. PubMed DOI PMC

Gatza CE, Holtzhausen A, Kirkbride KC, Morton A, Gatza ML, Datto MB, Blobe GC. Type III TGF-β Receptor Enhances Colon Cancer Cell Migration and Anchorage- Independent Growth. Neoplasia. 2011;13:758–770. PubMed PMC

Tian X, Du H, Fu X, Li K, Li A, Zhang Y. Smad4 restoration leads to a suppression of Wnt/[beta]-catenin signaling activity and migration capacity in human coloncarcinoma cells. Biochem Biophys Res Commun. 2009;380:478–483. doi: 10.1016/j.bbrc.2009.01.124. PubMed DOI

Cottonham CL, Kaneko S, Xu L. miR-21 and miR-31 Converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem. 2010;285:35293–35302. doi: 10.1074/jbc.M110.160069. PubMed DOI PMC

Furukawa T. Molecular pathology of pancreatic cancer: implications for molecular targeting therapy. Clin Gastroenterol H: Clin Prac J Am Gastroen Assoc. 2009;7:S35–S39. PubMed

Fujisawa H, Reis RM, Nakamura M, Colella S, Yonekawa Y, Kleihues P, Ohgaki H. Loss of heterozygosity on chromosome 10 is more extensive in primary (De Novo) than in secondary glioblastomas. Lab Invest. 2000;80:65–72. doi: 10.1038/labinvest.3780009. PubMed DOI

Hahn SA, Shamsul Hoque ATM, Moskaluk CA, da Costa LT, Schutte M, Rozenblum E, Seymour AB, Weinstein CL, Yeo CJ, Hruban RH, Kern SE. Homozygous Deletion Map at 18q21.1 in Pancreatic Cancer. Cancer Res. 1996;56:490–494. PubMed

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 biliaryadenocarcinomas. Cancer Res. 1998;58:5329–5332. PubMed

Pasche B, Kolachana P, Nafa K, Satagopan J, Chen YG, Lo RS, Brener D, Yang D, Kirstein L, Oddoux C. et al.TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res. 1999;59:5678–5682. PubMed

Smirne C, Camandona M, Alabiso O, Bellone G, Emanuelli G. [High serum levels of transforming growth factor-beta1, Interleukin-10 and Vascular endothelial growthfactor in pancreatic adenocarcinoma patients] Minerva Gastroenterol Dietol. 1999;45:21–27. PubMed

Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancermetastasis. Mol Cancer Ther. 2008;7:829–840. doi: 10.1158/1535-7163.MCT-07-0337. PubMed DOI PMC

Sterlacci W, Wolf D, Savic S, Hilbe W, Schmid T, Jamnig H, Fiegl M, Tzankov A. High transforming growth factor β expression represents an important prognostic parameter for surgically resected non-small cell lung cancer. Hum Pathol. 2011;43(3):339–349. PubMed

González-Santiago AE, Mendoza-Topete LA, Sánchez-Llamas F, Troyo-Sanromán R, Gurrola-Díaz CM. TGF-β1 serum concentration as a complementary diagnostic biomarker of lung cancer: establishment of a cut-point value. J Clin Lab Anal. 2011;25:238–243. doi: 10.1002/jcla.20465. PubMed DOI PMC

Zhang H-T, Chen X-F, Wang M-H, Wang J-C, Qi Q-Y, Zhang R-M, Xu W-Q, Fei Q-Y, Wang F, Cheng Q-Q. et al.Defective expression of transforming growth factor β Receptor Type II is associated with CpG methylated promoter in primary non-smallcell lung cancer. Clin Cancer Res. 2004;10:2359–2367. doi: 10.1158/1078-0432.CCR-0959-3. PubMed DOI

Jiang X, Liu R, Lei Z, You J, Zhou Q, Zhang H. [Defective expression of TGFBR3 gene and its molecular mechanisms in non-small cell lung cancer cell lines] Zhongguo Fei Ai Za Zhi = Chinese Journal of Lung Cancer. 2010;13:451–457. PubMed PMC

Jeon H-S, Dracheva T, Yang S-H, Meerzaman D, Fukuoka J, Shakoori A, Shilo K, Travis WD, Jen J. SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-beta homeostasis in lung cancer cells. Cancer Res. 2008;68:9686–9692. doi: 10.1158/0008-5472.CAN-08-1083. PubMed DOI PMC

Xu C-C, Wu L-M, Sun W, Zhang N, Chen W-S, Fu X-N. Effects of TGF-β signaling blockade on human A549 lung adenocarcinoma cell lines. Molecular Medicine Reports. 2011;4:1007–1015. PubMed

Hu X, Cui D, Moscinski LC, Zhang X, Maccachero V, Zuckerman KS. TGFbeta regulates the expression and activities of G2 checkpoint kinases in human myeloidleukemia cells. Cytokine. 2007;37:155–162. doi: 10.1016/j.cyto.2007.03.009. PubMed DOI

Jakubowiak A, Pouponnot C, Berguido F, Frank R, Mao S, Massague J, Nimer SD. Inhibition of the transforming growth factor beta 1 signaling pathway by the AML1/ETO leukemia-associated fusion protein. J Biol Chem. 2000;275:40282–40287. doi: 10.1074/jbc.C000485200. PubMed DOI

Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Maki K, Ogawa S, Chiba S, Mitani K, Hirai H. Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis. Oncogene. 2001;20:88–96. doi: 10.1038/sj.onc.1204057. PubMed DOI

Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki Y, Hirai H. The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factorbeta-mediated growth inhibition of myeloid cells. Blood. 1998;92:4003–4012. PubMed

Jones L, Wei G, Sevcikova S, Phan V, Jain S, Shieh A, Wong JC, Li M, Dubansky J, Maunakea ML. et al.Gain of MYC underlies recurrent trisomy of the MYC chromosome in acute promyelocytic leukemia. J Exp Med. 2010;207:2581–2594. doi: 10.1084/jem.20091071. PubMed DOI PMC

Lin HK, Bergmann S, Pandolfi PP. Cytoplasmic PML function in TGF-beta signalling. Nature. 2004;431:205–211. doi: 10.1038/nature02783. PubMed DOI

Ernst T, La Rosée P, Müller MC, Hochhaus A. BCR-ABL mutations in chronic myeloid leukemia. Hematol Oncol Clin North Am. 2011;25:997–1008. doi: 10.1016/j.hoc.2011.09.005. v-vi. PubMed DOI

Atfi A, Abécassis L, Bourgeade MF. Bcr-Abl activates the AKT/Fox O3 signalling pathway to restrict transforming growth factor-beta-mediated cytostatic signals. EMBO Rep. 2005;6:985–991. doi: 10.1038/sj.embor.7400501. PubMed DOI PMC

Jonuleit T, van der Kuip H, Miething C, Michels H, Hallek M, Duyster J, Aulitzky WE. Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines. Blood. 2000;96:1933–1939. PubMed

Ogawa S, Kurokawa M, Tanaka T, Tanaka K, Hangaishi A, Mitani K, Kamada N, Yazaki Y, Hirai H. Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia. Leukemia. 1996;10:788–794. PubMed

Kurokawa M, Mitani K, Irie K, Matsuyama T, Takahashi T, Chiba S, Yazaki Y, Matsumoto K, Hirai H. The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3. Nature. 1998;394:92–96. doi: 10.1038/27945. PubMed DOI

Møller GM, Frost V, Melo JV, Chantry A. Upregulation of the TGFbeta signalling pathway by Bcr-Abl: implications for haemopoietic cell growth and chronic myeloidleukaemia. FEBS Lett. 2007;581:1329–1334. doi: 10.1016/j.febslet.2007.02.048. PubMed DOI

Wolfraim LA, Fernandez TM, Mamura M, Fuller WL, Kumar R, Cole DE, Byfield S, Felici A, Flanders KC, Walz TM. et al.Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med. 2004;351:552–559. doi: 10.1056/NEJMoa031197. PubMed DOI

Ford AM, Palmi C, Bueno C, Hong D, Cardus P, Knight D, Cazzaniga G, Enver T, Greaves M. The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells. J Clin Invest. 2009;119:826–836. PubMed PMC

Scott SA, Kimura T, Dong WF, Ichinohasama R, Bergen S, Kerviche A, Sheridan D, DeCoteau JF. Methylation status of cyclin-dependent kinase inhibitor genes within the transforming growth factor beta pathway in human T-cell lymphoblasticlymphoma/leukemia. Leuk Res. 2004;28:1293–1301. doi: 10.1016/j.leukres.2004.03.019. PubMed DOI

Mori N, Morishita M, Tsukazaki T, Giam CZ, Kumatori A, Tanaka Y, Yamamoto N. Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-bindingprotein/p300. Blood. 2001;97:2137–2144. doi: 10.1182/blood.V97.7.2137. PubMed DOI

Lee DK, Kim BC, Brady JN, Jeang KT, Kim SJ. Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-beta signaling by blocking theassociation of Smad proteins with Smad-binding element. J Biol Chem. 2002;277:33766–33775. doi: 10.1074/jbc.M200150200. PubMed DOI

Arnulf B, Villemain A, Nicot C, Mordelet E, Charneau P, Kersual J, Zermati Y, Mauviel A, Bazarbachi A, Hermine O. Human T-cell lymphotropic virus oncoprotein Tax represses TGF-beta 1 signaling in human T cells via c-Jun activation: a potentialmechanism of HTLV-I leukemogenesis. Blood. 2002;100:4129–4138. doi: 10.1182/blood-2001-12-0372. PubMed DOI

Shehata M, Schwarzmeier JD, Hilgarth M, Hubmann R, Duechler M, Gisslinger H. TGF-beta1 induces bone marrow reticulin fibrosis in hairy cell leukemia. J Clin Invest. 2004;113:676–685. PubMed PMC

Kadin ME, Cavaille-Coll MW, Gertz R, Massagué J, Cheifetz S, George D. Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci USA. 1994;91:6002–6006. doi: 10.1073/pnas.91.13.6002. PubMed DOI PMC

Knaus PI, Lindemann D, DeCoteau JF, Perlman R, Yankelev H, Hille M, Kadin ME, Lodish HF. A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol. 1996;16:3480–3489. PubMed PMC

Schiemann WP, Pfeifer WM, Levi E, Kadin ME, Lodish HF. A deletion in the gene for transforming growth factor beta type I receptor abolishes growth regulation bytransforming growth factor beta in a cutaneous T-cell lymphoma. Blood. 1999;94:2854–2861. PubMed

Nakahata S, Yamazaki S, Nakauchi H, Morishita K. Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-beta1-mediated growthsuppression in adult T-cell leukemia/lymphoma. Oncogene. 2010;29:4157–4169. doi: 10.1038/onc.2010.172. PubMed DOI

Munoz O, Fend F, de Beaumont R, Husson H, Astier A, Freedman AS. TGFbetamediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cellproliferation. Leukemia. 2004;18:2015–2025. doi: 10.1038/sj.leu.2403485. PubMed DOI

Bakkebø M, Huse K, Hilden VI, Smeland EB, Oksvold MP. TGF-β-induced growth inhibition in B-cell lymphoma correlates with Smad1/5 signalling and constitutivelyactive p38 MAPK. BMC Immunol. 2010;11:57. doi: 10.1186/1471-2172-11-57. PubMed DOI PMC

Chen G, Ghosh P, Osawa H, Sasaki CY, Rezanka L, Yang J, O'Farrell TJ, Longo DL. Resistance to TGF-beta 1 correlates with aberrant expression of TGF-beta receptor II in human B-cell lymphoma cell lines. Blood. 2007;109:5301–5307. doi: 10.1182/blood-2006-06-032128. PubMed DOI PMC

Rai D, Kim SW, McKeller MR, Dahia PL, Aguiar RC. Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis. Proc Natl Acad Sci USA. 2010;107:3111–3116. doi: 10.1073/pnas.0910667107. PubMed DOI PMC

Douglas RS, Capocasale RJ, Lamb RJ, Nowell PC, Moore JS. Chronic lymphocytic leukemia B cells are resistant to the apoptotic effects of transforming growth factorbeta. Blood. 1997;89:941–947. PubMed

Lagneaux L, Delforge A, Bron D, Massy M, Bernier M, Stryckmans P. Heterogenous response of B lymphocytes to transforming growth factor-beta in B-cell chroniclymphocytic leukaemia: correlation with the expression of TGF-beta receptors. Br J Haematol. 1997;97:612–620. doi: 10.1046/j.1365-2141.1997.792715.x. PubMed DOI

DeCoteau JF, Knaus PI, Yankelev H, Reis MD, Lowsky R, Lodish HF, Kadin ME. Loss of functional cell surface transforming growth factor beta (TGF-beta) type 1 receptorcorrelates with insensitivity to TGF-beta in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 1997;94:5877–5881. doi: 10.1073/pnas.94.11.5877. PubMed DOI PMC

Schiemann WP, Rotzer D, Pfeifer WM, Levi E, Rai KR, Knaus P, Kadin ME. Transforming growth factor-beta (TGF-beta)-resistant B cells from chronic lymphocytic leukemia patients contain recurrent mutations in the signal sequence of thetype I TGF-beta receptor. Cancer Detect Prev. 2004;28:57–64. doi: 10.1016/j.cdp.2003.11.001. PubMed DOI

Jelinek DF, Tschumper RC, Stolovitzky GA, Iturria SJ, Tu Y, Lepre J, Shah N, Kay NE. Identification of a global gene expression signature of B-chronic lymphocytic leukemia. Mol Cancer Res. 2003;1:346–361. PubMed

Lotz M, Ranheim E, Kipps TJ. Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells. J Exp Med. 1994;179:999–1004. doi: 10.1084/jem.179.3.999. PubMed DOI PMC

Spender LC, Inman GJ. TGF-beta induces growth arrest in Burkitt lymphoma cells via transcriptional repression of E2F-1. J Biol Chem. 2009;284:1435–1442. PubMed

Inman GJ, Allday MJ. Resistance to TGF-beta1 correlates with a reduction of TGFbeta type II receptor expression in Burkitt's lymphoma and Epstein-Barr virustransformedB lymphoblastoid cell lines. J Gen Virol. 2000;81:1567–1578. PubMed

Urashima M, Ogata A, Chauhan D, Hatziyanni M, Vidriales MB, Dedera DA, Schlossman RL, Anderson KC. Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells. Blood. 1996;87:1928–1938. PubMed

Hayashi T, Hideshima T, Nguyen AN, Munoz O, Podar K, Hamasaki M, Ishitsuka K, Yasui H, Richardson P, Chakravarty S. et al.Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth inthe bone marrow microenvironment. Clin Cancer Res. 2004;10:7540–7546. doi: 10.1158/1078-0432.CCR-04-0632. PubMed DOI

Amoroso SR, Huang N, Roberts AB, Potter M, Letterio JJ. Consistent loss of functional transforming growth factor beta receptor expression in murineplasmacytomas. Proc Natl Acad Sci USA. 1998;95:189–194. doi: 10.1073/pnas.95.1.189. PubMed DOI PMC

Fernandez T, Amoroso S, Sharpe S, Jones GM, Bliskovski V, Kovalchuk A, Wakefield LM, Kim SJ, Potter M, Letterio JJ. Disruption of transforming growth factor beta signaling by a novel ligand-dependent mechanism. J Exp Med. 2002;195:1247–1255. doi: 10.1084/jem.20011521. PubMed DOI PMC

de Carvalho F, Colleoni GW, Almeida MS, Carvalho AL, Vettore AL. TGFbetaR2 aberrant methylation is a potential prognostic marker and therapeutic target inmultiple myeloma. Int J Cancer. 2009;125:1985–1991. doi: 10.1002/ijc.24431. PubMed DOI

Lambert KE, Huang H, Mythreye K, Blobe GC. The type III transforming growth factor-β receptor inhibits proliferation, migration, and adhesion in human myelomacells. Mol Biol Cell. 2011;22:1463–1472. doi: 10.1091/mbc.E10-11-0877. PubMed DOI PMC

Kyrtsonis MC, Repa C, Dedoussis GV, Mouzaki A, Simeonidis A, Stamatelou M, Maniatis A. Serum transforming growth factor-beta 1 is related to the degree of immunoparesis in patients with multiple myeloma. Med Oncol. 1998;15:124–128. doi: 10.1007/BF02989591. PubMed DOI

Cook G, Campbell JD, Carr CE, Boyd KS, Franklin IM. Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in Tlymphocytes. J Leukoc Biol. 1999;66:981–988. PubMed

Matsumoto T, Abe M. TGF-β-related mechanisms of bone destruction in multiple myeloma. Bone. 2011;48:129–134. doi: 10.1016/j.bone.2010.05.036. PubMed DOI

The effect of healing phenotype-inducing cytokine formulations within soft hydrogels on encapsulated monocytes and incoming immune cells

Hierarchical patterning modes orchestrate hair follicle morphogenesis

Active transforming growth factor-β2 in the aqueous humor of posterior polymorphous corneal dystrophy patients

Stroma as an Active Player in the Development of the Tumor Microenvironment