Transforming growth factor-β: A therapeutic target for cancer

Human Vaccines and Immunotherapeutics

Volumn 13, Issue 8, 2017, Pages 1741-1750

  Haque, Sulsal ^a   Morris, John C ^a,b  

^a UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF CINCINNATI   (United States)

Author keywords

Antisense oligonucleotide; cancer; epithelial mesenchymal transition; monoclonal antibody; transforming growth factor

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; BELAGENPUMATUCEL L; CANCER VACCINE; FRESOLIMUMAB; GALUNISERTIB; LERDELIMUMAB; METELIMUMAB; PEPTIDE APTAMER; PROGRAMMED DEATH 1 LIGAND 2; PROGRAMMED DEATH 1 RECEPTOR; TRABEDERSON; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR; TUMOR PROMOTER; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; MONOCLONAL ANTIBODY;

ANGIOGENESIS; ANTISENSE THERAPY; CARCINOGENESIS; CELL PROLIFERATION; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; IMMUNE DEFICIENCY; IMMUNE RESPONSE; IMMUNOMODULATION; MALIGNANT NEOPLASM; NONHUMAN; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; PROTEIN FUNCTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECOMBINANT DNA TECHNOLOGY; REVIEW; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; TUMOR GROWTH; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; ANIMAL; APOPTOSIS; CELL DIFFERENTIATION; DRUG EFFECTS; GENETICS; IMMUNOLOGY; METABOLISM; MOUSE; NEOPLASM; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL DIFFERENTIATION; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; MICE; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; OLIGONUCLEOTIDES, ANTISENSE; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA;

EID: 85027446528     PISSN: 21645515     EISSN: 2164554X     Source Type: Journal    
DOI: 10.1080/21645515.2017.1327107     Document Type: Review

References (144)

1. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001; 29(2):117-29; PMID:11586292; https://doi.org/10.1038/ng1001-117
2. Dumont N, Arteaga CL. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 2003; 3(6):531-6; PMID:12842082; https://doi.org/10.1016/S1535-6108(03)00135-1
3. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67:753-91; PMID:9759503; https://doi.org/10.1146/annurev.biochem.67.1.753
4. Wojtowicz-Praga S. Reversal of tumor-induced immunosuppression by TGF-beta inhibitors. Invest New Drugs 2003; 21(1):21-32; PMID:12795527; https://doi.org/10.1023/A:1022951824806
5. Lopez-Casillas F, Wrana JL, Massague J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell 1993; 73(7):1435-44; PMID:8391934; https://doi.org/10.1016/0092-8674(93)90368-Z
6. Sankar S, Mahooti-Brooks N, Centrella M, McCarthy TL, Madri JA. Expression of transforming growth factor type III receptor in vascular endothelial cells increases their responsiveness to transforming growth factor beta 2. J Biol Chem 1995; 270(22):13567-72; PMID:7768960; https://doi.org/10.1074/jbc.270.22.13567
7. Savage C, Das P, Finelli AL, et al. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components. Proc Natl Acad Sci U S A 1996; 93(2):790-4; PMID:8570636; https://doi.org/10.1073/pnas.93.2.790
8. Dou C, Lee J, Liu B, Liu F, Massague J, Xuan S, Lai E. BF-1 interferes with transforming growth factor beta signaling by associating with Smad partners. Mol Cell Biol 2000; 20(17):6201-11; PMID:10938097; https://doi.org/10.1128/MCB.20.17.6201-6211.2000
9. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 1995; 121(6):1845-54; PMID:7600998
10. Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 1997; 124(13):2659-70; PMID:9217007
11. 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(4):409-14; PMID:7493021; https://doi.org/10.1038/ng1295-409
12. Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 2002; 115(Pt 15):3193-206; PMID:12118074
13. Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 2000; 275(47):36803-10; PMID:10969078; https://doi.org/10.1074/jbc.M005912200
14. Yu L, Hebert MC, Zhang YE. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 2002; 21(14):3749-59; PMID:12110587; https://doi.org/10.1093/emboj/cdf366
15. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996; 271(5247):350-3; PMID:8553070; https://doi.org/10.1126/science.271.5247.350
16. Riggins GJ, Kinzler KW, Vogelstein B, Thiagalingam S. Frequency of Smad gene mutations in human cancers. Cancer Res 1997; 57(13):2578-80; PMID:9205057
17. Halder SK, Beauchamp RD, Datta PK. Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. Exp Cell Res 2005; 307(1):231-46; PMID:15922743; https://doi.org/10.1016/j.yexcr.2005.03.009
18. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K. Smad6 inhibits signalling by the TGF-beta superfamily. Nature 1997; 389(6651):622-6; PMID:9335505; https://doi.org/10.1038/39355
19. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997; 389(6651):631-5; PMID:9335507; https://doi.org/10.1038/39369
20. Alevizopoulos K, Vlach J, Hennecke S, Amati B. Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J 1997; 16(17):5322-33; PMID:9311992; https://doi.org/10.1093/emboj/16.17.5322
21. Lasorella A, Noseda M, Beyna M, Yokota Y, Iavarone A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 2000; 407(6804):592-8; PMID:11034201; https://doi.org/10.1038/35036504
22. Seoane J, Pouponnot C, Staller P, Schader M, Eilers M, Massague J. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol 2001; 3(4):400-8; PMID:11283614; https://doi.org/10.1038/35070086
23. Wu S, Cetinkaya C, Munoz-Alonso MJ, von der Lehr N, Bahram F, Beuger V, Eilers M, Leon J, Larsson LG. Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene 2003; 22(3):351-60; PMID:12545156; https://doi.org/10.1038/sj.onc.1206145
24. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001; 12(1):27-36; PMID:11160820; https://doi.org/10.1091/mbc.12.1.27
25. Hu PP, Shen X, Huang D, Liu Y, Counter C, Wang XF. The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta. J Biol Chem 1999; 274(50):35381-7; PMID:10585406; https://doi.org/10.1074/jbc.274.50.35381
26. Wikstrom P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate 1998; 37(1):19-29; PMID:9721065; https://doi.org/10.1002/(SICI)1097-0045(19980915)37:1%3c19::AID-PROS4%3e3.0.CO;2-3
27. 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(2):320-4; PMID:9927040
28. Grady WM, Willis JE, Trobridge P, Romero-Gallo J, Munoz N, Olechnowicz J, Ferguson K, Gautam S, Markowitz SD. Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations. Int J Cancer 2006; 118(3):600-8; PMID:16108056
29. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995; 268(5215):1336-8; PMID:7761852
30. Parsons R, Myeroff LL, Liu B, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 1995; 55(23):5548-50; PMID:7585632
31. Lucke CD, Philpott A, Metcalfe JC, Thompson AM, Hughes-Davies L, Kemp PR, Hesketh R. Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer. Cancer Res 2001; 61(2):482-5; PMID:11212236
32. de Jonge RR, Garrigue-Antar L, Vellucci VF, Reiss M. Frequent inactivation of the transforming growth factor beta type II receptor in small-cell lung carcinoma cells. Oncol Res 1997; 9(2):89-98; PMID:9167190
33. Wang D, Kanuma T, Mizunuma H, Takama F, Ibuki Y, Wake N, Mogi A, Shitara Y, Takenoshita S. Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer. Cancer Res 2000; 60(16):4507-12; PMID:10969799
34. Chen T, Carter D, Garrigue-Antar L, Reiss M. Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer. Cancer Res 1998; 58(21):4805-10; PMID:9809982
35. Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 1998; 58(23):5329-32; PMID:9850059
36. 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 by transforming growth factor beta in a cutaneous T-cell lymphoma. Blood 1999; 94(8):2854-61; PMID:10515889
37. 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(11):2527-30; PMID:8653691
38. Hahn SA, Hoque AT, Moskaluk CA, da Costa LT, Schutte M, Rozenblum E, Seymour AB, Weinstein CL, Yeo CJ, Hruban RH, et al. Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res 1996; 56(3):490-4; PMID:8564959
39. Bruna A, Darken RS, Rojo F, Ocaña A, Peñuelas S, Arias A, Paris R, Tortosa A, Mora J, Baselga J, et al. High TGFbeta-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(2):147-60; PMID:17292826
40. Chod J, Zavadova E, Halaska MJ, Strnad P, Fucikova T, Rob L. Preoperative transforming growth factor-beta 1 (TGF-beta 1) plasma levels in operable breast cancer patients. Eur J Gynaecol Oncol 2008; 29(6):613-6; PMID:19115689
41. Fischer JR, Darjes H, Lahm H, Schindel M, Drings P, Krammer PH. Constitutive secretion of bioactive transforming growth factor beta 1 by small cell lung cancer cell lines. Eur J Cancer 1994; 30A(14):2125-9; PMID:7857713
42. Labidi SI, Menetrier-Caux C, Chabaud S, Chassagne C, Sebban C, Gargi T, Biron P, Blay JY, Ghesquières H. Serum cytokines in follicular lymphoma. Correlation of TGF-beta and VEGF with survival. Ann Hematol 2010; 89(1):25-33; PMID:19582455
43. Langenskiold M, Holmdahl L, Falk P, Angenete E, Ivarsson ML. Increased TGF-beta 1 protein expression in patients with advanced colorectal cancer. J Surg Oncol 2008; 97(5):409-15; PMID:18176914
44. Shariat SF, Walz J, Roehrborn CG, Zlotta AR, Perrotte P, Suardi N, Saad F, Karakiewicz PI. External validation of a biomarker-based preoperative nomogram predicts biochemical recurrence after radical prostatectomy. J Clin Oncol 2008; 26(9):1526-31; PMID:18349404
45. Shirai Y, Kawata S, Tamura S, Ito N, Tsushima H, Takaishi K, Kiso S, Matsuzawa Y. Plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases. Cancer 1994; 73(9):2275-9; PMID:7513247
46. von Rahden BH, Stein HJ, Feith M, Pühringer F, Theisen J, Siewert JR, Sarbia M. Overexpression of TGF-beta1 in esophageal (Barrett's) adenocarcinoma is associated with advanced stage of disease and poor prognosis. Mol Carcinog 2006; 45(10):786-94; PMID:16921482
47. Miettinen PJ, Ebner R, Lopez AR, Derynck R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells:involvement of type I receptors. J Cell Biol 1994; 127(6 Pt 2):2021-36; PMID:7806579
48. Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998; 8(23):1243-52; PMID:9822576
49. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996; 10(19):2462-77; PMID:8843198
50. Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J 1987; 6(7):1899-904; PMID:2820711
51. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4):704-15; PMID:18485877
52. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008; 3(8):e2888; PMID:18682804
53. Ito N, Kawata S, Tamura S, Shirai Y, Kiso S, Tsushima H, Matsuzawa Y. Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma. Cancer Lett 1995; 89(1):45-8; PMID:7882301
54. Madri JA, Pratt BM, Tucker AM. Phenotypic modulation of endothelial cells by transforming growth factor-beta depends upon the composition and organization of the extracellular matrix. J Cell Biol 1988; 106(4):1375-84; PMID:3283153
55. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alitalo K. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 1994; 269(9):6271-4; PMID:8119973
56. Petersen M, Pardali E, van der Horst G, Cheung H, van den Hoogen C, van der Pluijm G, Ten Dijke P. Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene 2010; 29(9):1351-61; PMID:20010874
57. Shin JH, Shim JW, Kim DS, Shim JY. TGF-beta effects on airway smooth muscle cell proliferation, VEGF release and signal transduction pathways. Respirology 2009; 14(3):347-53; PMID:19192227
58. Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, Lüttges J, Klöppel G, Graeven U, Eilert-Micus C, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci U S A 2000; 97(17):9624-9; PMID:10944227
59. Lu S, Lee J, Revelo M, Wang X, Lu S, Dong Z. Smad3 is overexpressed in advanced human prostate cancer and necessary for progressive growth of prostate cancer cells in nude mice. Clin Cancer Res 2007; 13(19):5692-702; PMID:17908958
60. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 2002; 21(7):1743-53; PMID:11927558
61. Roelen BA, van Rooijen MA, Mummery CL. Expression of ALK-1, a type 1 serine/threonine kinase receptor, coincides with sites of vasculogenesis and angiogenesis in early mouse development. Dev Dyn 1997; 209(4):418-30; PMID:9264265
62. Marie JC, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 2006; 25(3):441-54; PMID:16973387
63. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359(6397):693-9; PMID:1436033
64. Chen W, Wahl SM. TGF-beta:the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 2003; 14(2):85-9; PMID:12651220
65. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 2005; 202(8):1075-85; PMID:16230475
66. Kao JY, Gong Y, Chen CM, Zheng QD, Chen JJ. Tumor-derived TGF-beta reduces the efficacy of dendritic cell/tumor fusion vaccine. J Immunol 2003; 170(7):3806-11; PMID:12646647
67. Kobie JJ, Wu RS, Kurt RA, Lou S, Adelman MK, Whitesell LJ, Ramanathapuram LV, Arteaga CL, Akporiaye ET. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 2003; 63(8):1860-4; PMID:12702574
68. Mule JJ, Schwarz SL, Roberts AB, Sporn MB, Rosenberg SA. Transforming growth factor-beta inhibits the in vitro generation of lymphokine-activated killer cells and cytotoxic T cells. Cancer Immunol Immunother 1988; 26(2):95-100; PMID:2452015
69. Ruffini PA, Rivoltini L, Silvani A, Boiardi A, Parmiani G. Factors, including transforming growth factor beta, released in the glioblastoma residual cavity, impair activity of adherent lymphokine-activated killer cells. Cancer Immunol Immunother 1993; 36(6):409-16; PMID:8500113
70. Baker BF, Monia BP. Novel mechanisms for antisense-mediated regulation of gene expression. Biochim Biophys Acta 1999; 1489(1):3-18; PMID:10806993
71. Crooke ST. Molecular mechanisms of action of antisense drugs. Biochim Biophys Acta 1999; 1489(1):31-44; PMID:10806995
72. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B, Jachimczak P. Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. Cytokine Growth Factor Rev 2006; 17(1-2):129-39
73. Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, Kielmanowicz M, Schneider A. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci 2011; 102(6):1193-200; PMID:21366804
74. Schlingensiepen R, Goldbrunner M, Szyrach MN, Stauder G, Jachimczak P, Bogdahn U, Schulmeyer F, Hau P, Schlingensiepen KH. Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates:toxicology and safety. Oligonucleotides 2005; 15(2):94-104; PMID:15989424
75. Bogdahn U, Hau P, Stockhammer G, Venkataramana NK, Mahapatra AK, Suri A, Balasubramaniam A, Nair S, Oliushine V, Parfenov V, et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen:results of a randomized and controlled phase IIb study. Neuro Oncol 2011; 13(1):132-42; PMID:20980335
76. Hau P, Jachimczak P, Schlingensiepen R, Schulmeyer F, Jauch T, Steinbrecher A, Brawanski A, Proescholdt M, Schlaier J, Buchroithner J, et al. Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas:from preclinical to phase I/II studies. Oligonucleotides 2007; 17(2):201-12; PMID:17638524
77. Nagaraj NS, Datta PK. Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opin Investig Drugs 2010; 19(1):77-91; PMID:20001556
78. Kim SG, Song JY. Therapeutic targeting of oncogenic transforming growth factor-beta1 signaling by antisense oligonucleotides in oral squamous cell carcinoma. Oncol Rep 2012; 28(2):539-44; PMID:22581233
79. 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 cell vaccine in non-small-cell lung cancer. J Clin Oncol 2006; 24(29):4721-30; PMID:16966690
80. Nemunaitis J, Nemunaitis M, Senzer N, Snitz P, Bedell C, Kumar P, Pappen B, Maples PB, Shawler D, Fakhrai H. Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther 2009; 16(8):620-4; PMID:19287371
81. Giaccone G, Bazhenova LA, Nemunaitis J, Tan M, Juhász E, Ramlau R, van den Heuvel MM, Lal R, Kloecker GH, Eaton KD, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 2015; 51(16):2321-9; PMID:26283035
82. Giaccone G, Bazhenova LA, Nemunaitis J, Tan M, Juhász E, Ramlau R, van den Heuvel MM, Lal R, Kloecker GH, Eaton KD, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 2015; 51(16):2321-9; PMID:26283035
83. Nam JS, Terabe M, Mamura M, Kang MJ, Chae H, Stuelten C, Kohn E, Tang B, Sabzevari H, Anver MR, et al. An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res 2008; 68(10):3835-43; PMID:18483268
84. Chen X, Yang Y, Zhou Q, Weiss JM, Howard OZ, McPherson JM, Wakefield LM, Oppenheim JJ. Effective chemoimmunotherapy with anti-TGFbeta antibody and cyclophosphamide in a mouse model of breast cancer. PLoS One 2014; 9(1):e85398; PMID:24416401
85. Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman ML, Arteaga CL. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 2007; 117(5):1305-13; PMID:17415413
86. Ganapathy V, Ge R, Grazioli A, Xie W, Banach-Petrosky W, Kang Y, Lonning S, McPherson J, Yingling JM, Biswas S, et al. Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer 2010; 9:122; PMID:20504320
87. Tabe Y, Shi YX, Zeng Z, Jin L, Shikami M, Hatanaka Y, Miida T, Hsu FJ, Andreeff M, Konopleva M. TGF-beta-Neutralizing Antibody 1D11 Enhances Cytarabine-Induced Apoptosis in AML Cells in the Bone Marrow Microenvironment. PLoS One 2013; 8(6):e62785; PMID:23826077
88. Ling H, Roux E, Hempel D, Tao J, Smith M, Lonning S, Zuk A, Arbeeny C, Ledbetter S. Transforming growth factor beta neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats. PLoS One 2013; 8(1):e54499; PMID:23349909
89. Hulper P, Schulz-Schaeffer W, Dullin C, Hoffmann P, Harper J, Kurtzberg L, Lonning S, Kugler W, Lakomek M, Erdlenbruch B. Tumor localization of an anti-TGF-beta antibody and its effects on gliomas. Int J Oncol 2011; 38(1):51-9; PMID:21109925
90. Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT. Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. The Journal of clinical investigation 1993; 92(6):2569-76; PMID:7504687
91. Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, Hsu FJ, Berzofsky JA, Lawrence DP. Phase I study of GC1008 (fresolimumab):a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One 2014; 9(3):e90353; PMID:24618589
92. Stevenson JP, Kindler HL, Papasavvas E, Sun J, Jacobs-Small M, Hull J, Schwed D, Ranganathan A, Newick K, Heitjan DF, et al. Immunological effects of the TGFbeta-blocking antibody GC1008 in malignant pleural mesothelioma patients. Oncoimmunology 2013; 2(8):e26218; PMID:24179709
93. Sarper M, Cortes E, Lieberthal TJ, Del Rio Hernandez A. ATRA modulates mechanical activation of TGF-beta by pancreatic stellate cells. Sci Rep 2016; 6:27639; PMID:27375161
94. Zheng H, Wang J, Koteliansky VE, Gotwals PJ, Hauer-Jensen M. Recombinant soluble transforming growth factor beta type II receptor ameliorates radiation enteropathy in mice. Gastroenterology 2000; 119(5):1286-96; PMID:11054386
95. Zhao W, Kobayashi M, Ding W, Yuan L, Seth P, Cornain S, Wang J, Okada F, Hosokawa M. Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II. Cancer Immunol Immunother 2002; 51(7):381-8; PMID:; PMID:12192538
96. Rowland-Goldsmith MA, Maruyama H, Kusama T, Ralli S, Korc M. Soluble type II transforming growth factor-beta (TGF-beta) receptor inhibits TGF-beta signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin Cancer Res 2001; 7(9):2931-40; PMID:11555612
97. Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, Easterly E, Roebuck LR, Ryan S, Gotwals PJ, et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 2002; 109(12):1551-9; PMID:12070302
98. Suzuki E, Kapoor V, Cheung HK, Ling LE, DeLong PA, Kaiser LR, Albelda SM. Soluble type II transforming growth factor-beta receptor inhibits established murine malignant mesothelioma tumor growth by augmenting host antitumor immunity. Clin Cancer Res 2004; 10(17):5907-18; PMID:15355924
99. Zhang M, Berndt BE, Chen JJ, Kao JY. Expression of a soluble TGF-beta receptor by tumor cells enhances dendritic cell/tumor fusion vaccine efficacy. J Immunol 2008; 181(5):3690-7; PMID:18714045
100. Hu Z, Gerseny H, Zhang Z, Chen YJ, Berg A, Zhang Z, Stock S, Seth P. Oncolytic adenovirus expressing soluble TGFbeta receptor II-Fc-mediated inhibition of established bone metastases:a safe and effective systemic therapeutic approach for breast cancer. Mol Ther 2011; 19(9):1609-18; PMID:21712815
101. Hu Z, Gupta J, Zhang Z, Gerseny H, Berg A, Chen YJ, Zhang Z, Du H, Brendler CB, Xiao X, et al. Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-beta inhibits established bone metastasis in a prostate cancer mouse model. Hum Gene Ther 2012; 23(8):871-82; PMID:22551458
102. Zhang Z, Hu Z, Gupta J, Krimmel JD, Gerseny HM, Berg AF, Robbins JS, Du H, Prabhakar B, Seth P. Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host. Cancer Gene Ther 2012; 19(9):630-6; PMID:22744210
103. Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, Kelly P, Moeller BJ, Marks JR, Blobe GC. The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest 2007; 117(1):206-17; PMID:17160136
104. Lee JD, Hempel N, Lee NY, Blobe GC. The type III TGF-beta receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-beta signaling. Carcinogenesis 2010; 31(2):175-83; PMID:19955393
105. Naumann U, Maass P, Gleske AK, Aulwurm S, Weller M, Eisele G. Glioma gene therapy with soluble transforming growth factor-beta receptors II and III. Int J Oncol 2008; 33(4):759-65; PMID:18813789
106. Finger EC, Turley RS, Dong M, How T, Fields TA, Blobe GC. TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis 2008; 29(3):528-35; PMID:18174241
107. Bandyopadhyay A, Lopez-Casillas F, Malik SN, Montiel JL, Mendoza V, Yang J, Sun LZ. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 2002; 62(16):4690-5; PMID:12183427
108. Bandyopadhyay A, Zhu Y, Cibull ML, Bao L, Chen C, Sun L. A soluble transforming growth factor beta type III receptor suppresses tumorigenicity and metastasis of human breast cancer MDA-MB-231 cells. Cancer Res 1999; 59(19):5041-6; PMID:10519421
109. Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, et al. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity:SB-431542. Mol Pharmacol 2002; 62(1):58-64; PMID:12065755
110. Lu Y, Jiang F, Zheng X, Katakowski M, Buller B, To SS, Chopp M. TGF-beta1 promotes motility and invasiveness of glioma cells through activation of ADAM17. Oncol Rep 2011; 25(5):1329-35; PMID:21359495
111. Takeuchi K, Abe M, Hiasa M, Oda A, Amou H, Kido S, Harada T, Tanaka O, Miki H, Nakamura S, et al. Tgf-Beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS One 2010; 5(3):e9870; PMID:20360846
112. Miles FL, Tung NS, Aguiar AA, Kurtoglu S, Sikes RA. Increased TGF-beta1-mediated suppression of growth and motility in castrate-resistant prostate cancer cells is consistent with Smad2/3 signaling. Prostate 2012; 72(12):1339-50; PMID:22228025
113. Tanaka H, Shinto O, Yashiro M, Yamazoe S, Iwauchi T, Muguruma K, Kubo N, Ohira M, Hirakawa K. Transforming growth factor beta signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol Rep 2010; 24(6):1637-43; PMID:21042762
114. Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K, Ishikawa Y, Nomura K, Yokoo H, Shimizu T, et al. Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci 2007; 98(1):127-33; PMID:17129361
115. Shinto O, Yashiro M, Kawajiri H, Shimizu K, Shimizu T, Miwa A, Hirakawa K. Inhibitory effect of a TGFbeta receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells. Br J Cancer 2010; 102(5):844-51; PMID:20145621
116. Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, Mangadu R, Liu YW, Platten M, Herrlinger U, et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 2004; 64(21):7954-61; PMID:15520202
117. 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 in the bone marrow microenvironment. Clin Cancer Res 2004; 10(22):7540-6; PMID:15569984
118. Zhou L, Nguyen AN, Sohal D, Ying Ma J, Pahanish P, Gundabolu K, Hayman J, Chubak A, Mo Y, Bhagat TD, et al. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood 2008; 112(8):3434-43; PMID:18474728
119. Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S, Protter A, Murphy A, Chakravarty J, Dugar S, et al. Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clin Cancer Res 2006; 12(14 Pt 1):4315-30; PMID:16857807
120. Medicherla S, Li L, Ma JY, Kapoun AM, Gaspar NJ, Liu YW, Mangadu R, O'Young G, Protter AA, Schreiner GF, et al. Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment. Anticancer Res 2007; 27(6B):4149-57; PMID:18229422
121. Gaspar NJ, Li L, Kapoun AM, Medicherla S, Reddy M, Li G, O'Young G, Quon D, Henson M, Damm DL, et al. Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. Molecular Pharmacol 2007; 72(1):152-61; PMID:17400764
122. Mohammad KS, Javelaud D, Fournier PG, Niewolna M, McKenna CR, Peng XH, Duong V, Dunn LK, Mauviel A, Guise TA. TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res 2011; 71(1):175-84; PMID:21084275
123. Xu Q, Zhang XM, Duan KZ, Gu XY, Han M, Liu BL, Zhao ZQ, Zhang YQ. Peripheral TGF-beta1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents. J Neurosci 2013; 33(49):19099-111; PMID:24305807
124. 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 cancer metastasis. Mol Cancer Ther 2008; 7(4):829-40; PMID:18413796
125. Zhang B, Halder SK, Kashikar ND, Cho YJ, Datta A, Gorden DL, Datta PK. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology 2010; 138(3):969-80 e1-3
126. Zhang B, Halder SK, Zhang S, Datta PK. Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Lett 2009; 277(1):114-20; PMID:19147275
127. Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology 2009; 50(4):1140-51; PMID:19711426
128. Fransvea E, Mazzocca A, Santamato A, Azzariti A, Antonaci S, Giannelli G. Kinase activation profile associated with TGF-beta-dependent migration of HCC cells:a preclinical study. Cancer Chemother Pharmacol 2011; 68(1):79-86; PMID:20844878
129. Dituri F, Mazzocca A, Fernando J, Papappicco P, Fabregat I, De Santis F, Paradiso A, Sabbà C, Giannelli G. Differential inhibition of the TGF-β signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-β receptor type II. PLoS One 2013; 8(6):e67109; PMID:23826206
130. Zhang M, Herion TW, Timke C, Han N, Hauser K, Weber KJ, Peschke P, Wirkner U, Lahn M, Huber PE. Trimodal glioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-beta receptor I kinase inhibitor LY2109761. Neoplasia 2011; 13(6):537-49; PMID:21677877
131. Zhang M, Kleber S, Rohrich M, Timke C, Han N, Tuettenberg J, Martin-Villalba A, Debus J, Peschke P, Wirkner U, et al. Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res 2011; 71(23):7155-67; PMID:22006998
132. Bouquet F, Pal A, Pilones KA, Demaria S, Hann B, Akhurst RJ, Babb JS, Lonning SM, DeWyngaert JK, Formenti SC, et al. TGFbeta1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res 2011; 17(21):6754-65; PMID:22028490
133. Wan X, Li ZG, Yingling JM, Yang J, Starbuck MW, Ravoori MK, Kundra V, Vazquez E, Navone NM. Effect of transforming growth factor beta (TGF-beta) receptor I kinase inhibitor on prostate cancer bone growth. Bone 2012; 50(3):695-703; PMID:22173053
134. Connolly EC, Freimuth J, Akhurst RJ. Complexities of TGF-beta targeted cancer therapy. Int J Biol Sci 2012; 8(7):964-78; PMID:22811618
135. Maier A, Peille AL, Vuaroqueaux V, Lahn M. Anti-tumor activity of the TGF-beta receptor kinase inhibitor galunisertib (LY2157299 monohydrate) in patient-derived tumor xenografts. Cell Oncol (Dordr) 2015; 38(2):131-44; PMID:25573078
136. Lee GT, Hong JH, Mueller TJ, Watson JA, Kwak C, Sheen YY, Kim DK, Kim SJ, Kim IY. Effect of IN-1130, a small molecule inhibitor of transforming growth factor-beta type I receptor/activin receptor-like kinase-5, on prostate cancer cells. J Urol 2008; 180(6):2660-7; PMID:18951571
137. Park CY, Min KN, Son JY, Park SY, Nam JS, Kim DK, Sheen YY. An novel inhibitor of TGF-beta type I receptor, IN-1130, blocks breast cancer lung metastasis through inhibition of epithelial-mesenchymal transition. Cancer Lett 2014; 351(1):72-80; PMID:24887560
138. Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S, Trocóniz IF. Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer 2008; 44(1):142-50; PMID:18039567
139. Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther 2015; 9:4479-99; PMID:26309397
140. Gueorguieva I, Cleverly AL, Stauber A, Sada Pillay N, Rodon JA, Miles CP, Yingling JM, Lahn MM. Defining a therapeutic window for the novel TGF-beta inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol 2014; 77(5):796-807; PMID:24868575
141. Fujiwara Y, Nokihara H, Yamada Y, Yamamoto N, Sunami K, Utsumi H, Asou H, TakahashI O, Ogasawara K, Gueorguieva I, et al. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2015; 76(6):1143-52; PMID:26526984
142. Rodon J, Carducci M, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, Braña I, Sicart E, Gueorguieva I, Cleverly A, et al. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-beta receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs 2015; 33(2):357-70; PMID:25529192
143. Cui Q, Lim SK, Zhao B, Hoffmann FM. Selective inhibition of TGF-beta responsive genes by Smad-interacting peptide aptamers from FoxH1, Lef1 and CBP. Oncogene 2005; 24(24):3864-74; PMID:15750622
144. Zhao BM, Hoffmann FM. Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Mol Biol Cell 2006; 17(9):3819-31; PMID:16775010