Abstract
Transforming growth factor beta (TGF-β) signaling is involved in the regulation of proliferation, differentiation and survival/or apoptosis of many cells, including glioma cells. TGF-β acts via specific receptors activating multiple intracellular pathways resulting in phosphorylation of receptor-regulated Smad2/3 proteins that associate with the common mediator, Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of many genes. Furthermore, TGF-β-activated kinase-1 (TAK1) is a component of TGF-β signaling and activates mitogen-activated protein kinase (MAPK) cascades. Negative regulation of TGF-β/Smad signaling may occur through the inhibitory Smad6/7. While genetic alterations in genes related to TGF-β signaling are relatively rare in gliomas, the altered expression of those genes is a frequent event. The increased expression of TGF-β1–3 correlates with a degree of malignancy of human gliomas. TGF-β may contribute to tumor pathogenesis in many ways: by direct support of tumor growth, by maintaining self-renewal of glioma initiating stem cells and inhibiting anti-tumor immunity. Glioma initiating cells are dedifferentiated cells that retain many stem cell-like properties, play a role in tumor initiation and contribute to its recurrence. TGF-β1,2 stimulate expression of the vascular endothelial growth factor as well as the plasminogen activator inhibitor and some metalloproteinases that are involved in vascular remodeling, angiogenesis and degradation of the extracellular matrix. Inhibitors of TGF-β signaling reduce viability and invasion of gliomas in animal models and show a great promise as novel, potential anti-tumor therapeutics.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- ADAMTS-1:
-
metalloproteinase and disintegrin-like domain
- Akt:
-
protein kinase B/Akt kinase
- ALKs:
-
activin-receptor-like kinases
- AP-1:
-
activator protein 1
- BMPs:
-
bone morphogenetic proteins
- CTLs:
-
cytotoxic T lymphocytes;
- ECM:
-
extracellular matrix
- EGFR:
-
epidermal growth factor receptor
- ERK1/2:
-
extracellular signal-regulated kinases 1/2
- GDFs:
-
growth and differentiation factors
- Id:
-
inhibitor of DNA binding
- JAK:
-
Janus kinase
- JNK:
-
c-Jun N-terminal kinases
- LAP:
-
latency-associated peptide
- LIF:
-
leukemia inhibitory factor
- LTBP:
-
latent TGF-β binding protein
- MMP:
-
metalloproteinase
- MT1-MMP:
-
membrane-type 1 matrix metalloproteinase
- p38 MAPK:
-
P38 mitogen-activated protein kinases
- R-Smads:
-
receptor-Smad proteins
- SARA:
-
Smad anchor for receptor activation
- STAT:
-
signal transducer and activator of transcription
- TAK1:
-
TGF-β-activated kinase-1
- TGF-β:
-
transforming growth factor β
- TMZ:
-
temozolomide
- TNFα:
-
tumor necrosis factor α
- TRAF:
-
TNF receptor associated factor
- TβRI:
-
TGF-β type I receptor
- TβRII:
-
TGF-β type II receptor
- VEGF:
-
vascular endothelial growth factor
References
Alcantara Llaguno S, Chen J, Kwon CH et al (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15:45–56. https://doi.org/10.1016/j.ccr.2008.12.006
Anido J, Saez-Borderias A, Gonzalez-Junca A et al (2010) TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 18:655–668. https://doi.org/10.1016/j.ccr.2010.10.023
Annes JP, Chen Y, Munger JS, Rifkin DB (2004) Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol 165:723–734. https://doi.org/10.1083/jcb.200312172
Arslan F, Bosserhoff AK, Nickl-Jockschat T et al (2007) The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-beta2. Br J Cancer 96:1560–1568. https://doi.org/10.1038/sj.bjc.6603766
Baumann F, Leukel P, Doerfelt A et al (2009) Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2. Neuro-oncology 11:368–380. https://doi.org/10.1215/15228517-2008-106
Beck C, Schreiber H, Rowley D (2001) Role of TGF-beta in immune-evasion of cancer. Microsc Res Tech 52:387–395. https://doi.org/10.1002/1097-0029(20010215)52:4<387::AID-JEMT1023>3.0.CO;2-W
Benigni A, Zoja C, Corna D et al (2003) Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 14:1816–1824. https://doi.org/10.1097/01.asn.0000074238.61967.b7
Bottner M, Krieglstein K, Unsicker K (2000) The transforming growth factor-betas: structure, signaling, and roles in nervous system development and functions. J Neurochem 75:2227–2240. https://doi.org/10.1046/j.1471-4159.2000.0752227.x
Brown KA, Pietenpol JA, Moses HL (2007) A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem 101:9–33. https://doi.org/10.1002/jcb.21255
Bruna A, Darken RS, Rojo F et al (2007) 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 11:147–160. https://doi.org/10.1016/j.ccr.2006.11.023
Budi EH, Duan D, Derynck R (2017) Transforming growth factor-β receptors and Smads: regulatory complexity and functional versatility. Trends Cell Biol 27:658–672. https://doi.org/10.1016/j.tcb.2017.04.005
Cambier S, Gline S, Mu D et al (2005) Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch. Am J Pathol 166:1883–1894. https://doi.org/10.1016/s0002-9440(10)62497-2
Carpentier AF, Brandes AA, Kesari S et al (2013) Safety interim data from a three-arm phase II study evaluating safety and pharmacokinetics of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor LY2157299 monohydrate in patients with glioblastoma at first progression. In: Annual meeting of The American Society of Clinical Oncology, Chicago, IL. Abstract Number 2061
Chen YG, Hata A, Lo RS et al (1998) Determinants of specificity in TGF-beta signal transduction. Genes Dev 12:2144–2152. https://doi.org/10.1101/gad.12.14.2144
Chen CR, Kang Y, Siegel PM, Massague J (2002) E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110:19–32. https://doi.org/10.1016/S0092-8674(02)00801-2
Chen ML, Pittet MJ, Gorelik L et al (2005) Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A 102:419–424. https://doi.org/10.1073/pnas.0408197102
Chen J, Li Y, Yu TS et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526. https://doi.org/10.1038/nature11287
Crane CA, Han SJ, Barry JJ et al (2010) TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro-Oncology 12:7–13. https://doi.org/10.1093/neuonc/nop009
DaCosta BS, Major C, Laping NJ, Roberts AB (2004) SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol 65:744–752. https://doi.org/10.1124/mol.65.3.744
den Hollander MW, Bensch F, Glaudemans AWJM et al (2015) TGF-β antibody uptake in recurrent high-grade glioma imaged with 89Zr-Fresolimumab PET. J Nucl Med 56:1310–1314. https://doi.org/10.2967/jnumed.115.154401
Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584. https://doi.org/10.1038/nature02006
Dieterich LC, Mellberg S, Langenkamp E et al (2012) Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization. J Pathol 228:378–390. https://doi.org/10.1002/path.4072
Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R (1995) Processing of transforming growth factor beta 1 precursor by human furin convertase. J Biol Chem 270:10618–10624. https://doi.org/10.1074/jbc.270.18.10618
Dziembowska M, Danilkiewicz M, Wesolowska A et al (2007) Cross-talk between Smad and p38 MAPK signalling in transforming growth factor beta signal transduction in human glioblastoma cells. Biochem Biophys Res Commun 354:1101–1106. https://doi.org/10.1016/j.bbrc.2007.01.113
Edlund S, Landstrom M, Heldin CH, Aspenstrom P (2002) Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 13:902–914. https://doi.org/10.1091/mbc.01-08-0398
Edlund S, Bu S, Schuster N et al (2003) Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell 14:529–544. https://doi.org/10.1091/mbc.02-03-0037
Fakhrai H, Mantil JC, Liu L et al (2006) Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther 13:1052–1060. https://doi.org/10.1038/sj.cgt.7700975
Ferrer VP, Moura Neto V, Mentlein R (2018) Glioma infiltration and extracellular matrix: key players and modulators. Glia 66:1542–1565. https://doi.org/10.1002/glia.23309
Formenti SC, Lee P, Adams S et al (2018) Focal irradiation and systemic transforming growth factor β blockade in metastatic breast cancer. Clin Cancer Res 24:2493–2504. https://doi.org/10.1158/1078-0432.CCR-17-3322
Friedmann-Morvinski D, Verma IM (2014) Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep 15:244–253. https://doi.org/10.1002/embr.201338254
Friese MA, Wischhusen J, Wick W et al (2004) RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 64:7596–7603. https://doi.org/10.1158/0008-5472.CAN-04-1627
Gaarenstroom T, Hill CS (2014) TGF-β signaling to chromatin: how Smads regulate transcription during self-renewal and differentiation. Semin Cell Dev Biol 32:107–118. https://doi.org/10.1016/j.semcdb.2014.01.009
Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118–1122. https://doi.org/10.1038/nm1001-1118
Goumans MJ, Mummery C (2000) Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol 44:253–265
Goumans MJ, Valdimarsdottir G, Itoh S et al (2002) Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 21:1743–1753. https://doi.org/10.1093/emboj/21.7.1743
Grainger DJ, Wakefield L, Bethell HW, Farndale RW, Metcalfe JC (1995) Release and activation of platelet latent TGF-beta in blood clots during dissolution with plasmin. Nat Med 1:932–937
Groppe J, Hinck CS, Samavarchi-Tehrani P et al (2008) Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell 29:157–168. https://doi.org/10.1016/j.molcel.2007.11.039
Hanafusa H, Ninomiya-Tsuji J, Masuyama N et al (1999) Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J Biol Chem 274:27161–27167. https://doi.org/10.1074/jbc.274.38.27161
Hau P, Kunz-Schughart LA, Rummele P et al (2006) Tenascin-C protein is induced by transforming growth factor-beta1 but does not correlate with time to tumor progression in high-grade gliomas. J Neuro-Oncol 77:1–7. https://doi.org/10.1007/s11060-005-9000-5
Hau P, Jachimczak P, Schlingensiepen R et al (2007) Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17:201–212. https://doi.org/10.1089/oli.2006.0053
Hau P, Jachimczak P, Schlaier J, Bogdahn U (2011) TGF-beta2 signaling in high-grade gliomas. Curr Pharm Biotechnol 12:2150–2157. https://doi.org/10.2174/138920111798808347
Held-Feindt J, Lutjohann B, Ungefroren H, Mehdorn HM, Mentlein R (2003) Interaction of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) in human glioma cells. J Neuro-Oncol 63:117–127. https://doi.org/10.1023/A:1023943405292
Hjelmeland MD, Hjelmeland AB, Sathornsumetee S et al (2004) SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol Cancer Ther 3:737–745
Holmgaard RB, Schaer DA, Li Y et al (2018) Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade. J Immunother Cancer 6:47. https://doi.org/10.1186/s40425-018-0356-4
Hyytiainen M, Penttinen C, Keski-Oja J (2004) Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit Rev Clin Lab Sci 41:233–264. https://doi.org/10.1080/10408360490460933
Ijichi H, Otsuka M, Tateishi K et al (2004) Smad4-independent regulation of p21/WAF1 by transforming growth factor-beta. Oncogene 23:1043–1051. https://doi.org/10.1038/sj.onc.1207222
Ikushima H, Komuro A, Isogaya K et al (2008) An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-beta signalling. EMBO J 27:2955–2965. https://doi.org/10.1038/emboj.2008.218
Ikushima H, Todo T, Ino Y et al (2009) Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5:504–514. https://doi.org/10.1016/j.stem.2009.08.018
Itoh S, ten Dijke P (2007) Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol 19:176–184. https://doi.org/10.1016/j.ceb.2007.02.015
Jachimczak P, Bogdahn U, Schneider J et al (1993) The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J Neurosurg 78:944–951. https://doi.org/10.3171/jns.1993.78.6.0944
Jachimczak P, Hessdorfer B, Fabel-Schulte K et al (1996) Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides. Int J Cancer 65:332–337. https://doi.org/10.1002/(SICI)1097-0215(19960126)65:3<332::AID-IJC10>3.0.CO;2-C
Jennings MT, Maciunas RJ, Carver R et al (1991) TGF beta 1 and TGF beta 2 are potential growth regulators for low-grade and malignant gliomas in vitro: evidence in support of an autocrine hypothesis. Int J Cancer 49:129–139. https://doi.org/10.1002/ijc.2910490124
Jiang J, Zhang Y, Zhang Q et al (2016) Development and validation of an LC-MS/MS method for the determination of SB-505124 in rat plasma: application to pharmacokinetic study. J Pharm Biomed Anal 117:205–209. https://doi.org/10.1016/j.jpba.2015.09.002
Kaminska B (2009) Molecular characterization of inflammation-induced JNK/c-Jun signaling pathway in connection with tumorigenesis. Methods Mol Biol 512:249–264. https://doi.org/10.1007/978-1-60327-530-9_13
Kamiya Y, Miyazono K, Miyazawa K (2010) Smad7 inhibits transforming growth factor-β family type I receptors through two distinct modes of interaction. J Biol Chem 285:30804–30813. https://doi.org/10.1074/jbc.M110.166140
Karsdal MA, Hjorth P, Henriksen K et al (2003) Transforming growth factor-beta controls human osteoclastogenesis through the p38 MAPK and regulation of RANK expression. J Biol Chem 278:44975–44987. https://doi.org/10.1074/jbc.M303905200
Khaw P, Grehn F, Hollo G et al (2007) A phase III study of subconjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy. Ophthalmology 114:1822–1830. https://doi.org/10.1016/j.ophtha.2007.03.050
Kim SJ, Angel P, Lafyatis R et al (1990) Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol 10:1492–1497. https://doi.org/10.1128/mcb.10.4.1492
Kim SI, Kwak JH, Zachariah M et al (2007) TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. Am J Physiol Renal Physiol 292:F1471–F1478. https://doi.org/10.1152/ajprenal.00485.2006
Korkut A, Zaidi S, Kanchi RS et al (2018) A pan-Cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the TGF-β superfamily. Cell Syst 7:422–437. https://doi.org/10.1016/j.cels.2018.08.010
Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN (2015) Cancer stem cells in glioblastoma. Genes Dev 29:1203–1217. https://doi.org/10.1101/gad.261982.115
Laverty HG, Wakefield LM, Occleston NL, O’Kane S, Ferguson MW (2009) TGF-beta3 and cancer: a review. Cytokine Growth Factor Rev 20:305–317. https://doi.org/10.1016/j.cytogfr.2009.07.002
Lee MK, Pardoux C, Hall MC et al (2007) TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 26:3957–3967. https://doi.org/10.1038/sj.emboj.7601818
Levy L, Hill CS (2005) Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol 25:8108–8125. https://doi.org/10.1128/MCB.25.18.8108-8125.2005
Liang H, Yi L, Wang X, Zhou C, Xu L (2014) Interleukin-17 facilitates the immune suppressor capacity of high-grade glioma-derived CD4 (+) CD25 (+) Foxp3 (+) T cells via releasing transforming growth factor beta. Scand J Immunol 80:144–150. https://doi.org/10.1111/sji.12185
Liau LM, Fakhrai H, Black KL (1998) Prolonged survival of rats with intracranial C6 gliomas by treatment with TGF-beta antisense gene. Neurol Res 20:742–747
Lin HK, Bergmann S, Pandolfi PP (2004) Cytoplasmic PML function in TGF-beta signalling. Nature 431:205–211. https://doi.org/10.1038/nature02783
Lindholm D, Castren E, Kiefer R, Zafra F, Thoenen H (1992) Transforming growth factor-beta 1 in the rat brain: increase after injury and inhibition of astrocyte proliferation. J Cell Biol 117:395–400. https://doi.org/10.1083/jcb.117.2.395
Liu Y, Wang Q, Kleinschmidt-DeMasters BK et al (2007) TGF-beta2 inhibition augments the effect of tumor vaccine and improves the survival of animals with pre-established brain tumors. J Neuro-Oncol 81:149–162. https://doi.org/10.1007/s11060-006-9222-1
Lu Y, Jiang F, Zheng X et al (2011) TGF-beta1 promotes motility and invasiveness of glioma cells through activation of ADAM17. Oncol Rep 25:1329–1335. https://doi.org/10.3892/or.2011.1195
Maeda H, Kuwahara H, Ichimura Y et al (1995) TGF-beta enhances macrophage ability to produce IL-10 in normal and tumor-bearing mice. J Immunol 155:4926–4932
Massague J (2008) TGFbeta in Cancer. Cell 134:215–230. https://doi.org/10.1016/j.cell.2008.07.001
Massague J, Wotton D (2000) Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 19:1745–1754. https://doi.org/10.1093/emboj/19.8.1745
Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19:2783–2810. https://doi.org/10.1101/gad.1350705
Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT (2003) Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 44:3394–3401. https://doi.org/10.1167/iovs.02-0978
Melisi D, Ishiyama S, Sclabas GM et al (2008) 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 7:829–840. https://doi.org/10.1158/1535-7163.MCT-07-0337
Miura S, Takeshita T, Asao H et al (2000) Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol Cell Biol 20:9346–9355. https://doi.org/10.1128/mcb.20.24.9346-9355.2000
Miyazawa K, Miyazono K (2017) Regulation of TGF-β family signaling by inhibitory Smads. Cold Spring Harb Perspect Biol 9(3):a022095. https://doi.org/10.1101/cshperspect.a022095
Mohammad KS, Javelaud D, Fournier PGJ et al (2011) TGF-β-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res 71:175–184. https://doi.org/10.1158/0008-5472.CAN-10-2651
Morris JC, Tan AR, Olencki TE et al (2014) Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One 9(3):e90353. https://doi.org/10.1371/journal.pone.0090353
Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118:3573–3584. https://doi.org/10.1242/jcs.02554
Moustakas A, Souchelnytskyi S, Heldin CH (2001) Smad regulation in TGF-beta signal transduction. J Cell Sci 114:4359–4369
Mu Y, Sundar R, Thakur N et al (2011) TRAF6 ubiquitinates TGFbeta type I receptor to promote its cleavage and nuclear translocation in cancer. Nat Commun 2:330. https://doi.org/10.1038/ncomms1332
Mulder KM (2000) Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev 11:23–35. https://doi.org/10.1016/S1359-6101(99)00026-X
Mullen AC, Orlando DA, Newman JJ et al (2011) Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 147:565–576. https://doi.org/10.1016/j.cell.2011.08.050
Nakada M, Miyamori H, Kita D et al (2005) Human glioblastomas overexpress ADAMTS-5 that degrades brevican. Acta Neuropathol 110:239–246. https://doi.org/10.1007/s00401-005-1032-6
Nakao A, Imamura T, Souchelnytskyi S et al (1997) TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J 16:5353–5362. https://doi.org/10.1093/emboj/16.17.5353
Pauklin S, Vallier L (2015) Activin/nodal signalling in stem cells. Development 142:607–619. https://doi.org/10.1242/dev.091769
Pen A, Moreno MJ, Durocher Y, Deb-Rinker P, Stanimirovic DB (2008) Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-beta signaling. Oncogene 27:6834–6844. https://doi.org/10.1038/onc.2008.287
Penheiter SG, Mitchell H, Garamszegi N et al (2002) Internalization-dependent and -independent requirements for transforming growth factor beta receptor signaling via the Smad pathway. Mol Cell Biol 22:4750–4759. https://doi.org/10.1128/mcb.22.13.4750-4759.2002
Penuelas S, Anido J, Prieto-Sanchez RM et al (2009) TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15:315–327. https://doi.org/10.1016/j.ccr.2009.02.011
Pepper MS (1997) Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev 8:21–43. https://doi.org/10.1016/S1359-6101(96)00048-2
Piccirillo SG, Reynolds BA, Zanetti N et al (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765. https://doi.org/10.1038/nature05349
Piek E, Westermark U, Kastemar M et al (1999) Expression of transforming-growth-factor (TGF)-beta receptors and Smad proteins in glioblastoma cell lines with distinct responses to TGF-beta1. Int J Cancer 80:756–763. https://doi.org/10.1002/(SICI)1097-0215(19990301)80:5<756::AID-IJC21>3.0.CO;2-N
Platten M, Wick W, Wild-Bode C et al (2000) Transforming growth factors beta(1) (TGF-beta(1)) and TGF-beta(2) promote glioma cell migration via up-regulation of alpha(V)beta(3) integrin expression. Biochem Biophys Res Commun 268:607–611. https://doi.org/10.1006/bbrc.2000.2176
Platten M, Wick W, Weller M (2001) Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52:401–410. https://doi.org/10.1002/1097-0029(20010215)52:4<401::AID-JEMT1025>3.0.CO;2-C
Ribeiro SM, Poczatek M, Schultz-Cherry S, Villain M, Murphy-Ullrich JE (1999) The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem 274:13586–13593. https://doi.org/10.1074/jbc.274.19.13586
Rich JN (2003) The role of transforming growth factor-beta in primary brain tumors. Front Biosci 8:e245–e260. https://doi.org/10.2741/992
Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF (1999) Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem 274:35053–35058. https://doi.org/10.1074/jbc.274.49.35053
Rider CC, Mulloy B (2010) Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists. Biochem J 429:1–12. https://doi.org/10.1042/BJ20100305
Rodon J, Carducci MA, Sepulveda-Sánchez JM et al (2015) First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res 21:553–560. https://doi.org/10.1158/1078-0432.CCR-14-1380
Rodríguez-García A, Samsó P, Fontova P et al (2017) TGF-β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells. FEBS J 284:3437–3454. https://doi.org/10.1111/febs.14201
Ross S, Cheung E, Petrakis TG et al (2006) Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription. EMBO J 25:4490–4502. https://doi.org/10.1038/sj.emboj.7601332
Sanchez-Elsner T, Botella LM, Velasco B et al (2001) Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276:38527–38535. https://doi.org/10.1074/jbc.M104536200
Sawyer JS, Beight DW, Britt KS et al (2004) Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett 14:3581–3584. https://doi.org/10.1016/j.bmcl.2004.04.007
Schlingensiepen KH, Schlingensiepen R, Steinbrecher A et al (2006) Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. Cytokine Growth Factor Rev 17:129–139. https://doi.org/10.1016/j.cytogfr.2005.09.002
Schlingensiepen KH, Fischer-Blass B, Schmaus S, Ludwig S (2008) Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors. Cancer Res 177:137–150. https://doi.org/10.1007/978-3-540-71279-4_16
Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8:970–982. https://doi.org/10.1038/nrm2297
Seoane J, Pouponnot C, Staller P et al (2001) TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol 3:400–408. https://doi.org/10.1038/35070086
Seoane J, Le HV, Shen L, Anderson SA, Massague J (2004) Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117:211–223. https://doi.org/10.1016/S0092-8674(04)00298-3
Seystahl K, Tritschler I, Szabo E, Tabatabai G, Weller M (2015) Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma. Neuro-Oncology 17:254–265. https://doi.org/10.1093/neuonc/nou218
Seystahl K, Papachristodoulou A, Burghardt I et al (2017) Biological role and therapeutic targeting of TGF-β3 in glioblastoma. Mol Cancer Ther 16:1177–1186. https://doi.org/10.1158/1535-7163.MCT-16-0465
Shen MM (2007) Nodal signaling: developmental roles and regulation. Development 134:1023–1034. https://doi.org/10.1242/dev.000166
Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700. https://doi.org/10.1016/S0092-8674(03)00432-X
Siegel PM, Shu W, Massague J (2003) Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression. J Biol Chem 278:35444–35450. https://doi.org/10.1074/jbc.M301413200
Smyth MJ, Strobl SL, Young HA, Ortaldo JR, Ochoa AC (1991) Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-beta. J Immunol 146:3289–3297
Sorrentino A, Thakur N, Grimsby S et al (2008) The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 10:1199–1207. https://doi.org/10.1038/ncb1780
Tanaka H, Shinto O, Yashiro M et al (2010) Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol Rep 24:1637–1643. https://doi.org/10.3892/or_00001028
Tate CM, Pallini R, Ricci-Vitiani L et al (2012) A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells. Cell Death Differ 19:1644–1654. https://doi.org/10.1038/cdd.2012.44
Tatti O, Vehvilainen P, Lehti K, Keski-Oja J (2008) MT1-MMP releases latent TGF-beta1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1. Exp Cell Res 314:2501–2514. https://doi.org/10.1016/j.yexcr.2008.05.018
Tchaicha JH, Reyes SB, Shin J et al (2011) Glioblastoma angiogenesis and tumor cell invasiveness are differentially regulated by {beta}8 integrin. Cancer Res 71:6371–6381. https://doi.org/10.1158/0008-5472.CAN-11-0991
ten Dijke P, Hill CS (2004) New insights into TGF-beta-Smad signalling. Trends Biochem Sci 29:265–273. https://doi.org/10.1016/j.tibs.2004.03.008
Terabe M, Robertson FC, Clark K et al (2017) Blockade of only TGF-β 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. OncoImmunology 6(5):e130861. https://doi.org/10.1080/2162402X.2017.1308616
Thomas DA, Massagué J (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8:369–380. https://doi.org/10.1016/j.ccr.2005.10.012
Tiemann K, Rossi JJ (2009) RNAi-based therapeutics-current status, challenges and prospects. EMBO Mol Med 1:142–151. https://doi.org/10.1002/emmm.200900023
Tolcher AW, Berlin JD, Cosaert J et al (2017) A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors. Cancer Chemother Pharmacol 79:673–680. https://doi.org/10.1007/s00280-017-3245-5
Trachtman H, Fervenza FC, Gipson DS et al (2011) A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 79(11):1236–1243. https://doi.org/10.1038/ki.2011.33
Tran TT, Uhl M, Ma JY et al (2007) Inhibiting TGF-beta signaling restores immune surveillance in the SMA-560 glioma model. Neuro-Oncology 9:259–270. https://doi.org/10.1215/15228517-2007-010
Tritschler I, Gramatzki D, Capper D et al (2009) Modulation of TGF-beta activity by latent TGF-beta-binding protein 1 in human malignant glioma cells. Int J Cancer 125:530–540. https://doi.org/10.1002/ijc.24443
Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95:779–791. https://doi.org/10.1016/S0092-8674(00)81701-8
Tsuneyoshi N, Tan EK, Sadasivam A et al (2012) The SMAD2/3 corepressor SNON maintains pluripotency through selective repression of mesendodermal genes in human ES cells. Genes Dev 6:2471–2476. https://doi.org/10.1101/gad.201772.112
Ueda R, Fujita M, Zhu X et al (2009) Systemic inhibition of transforming growth factor-beta in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin Cancer Res 15:6551–6559. https://doi.org/10.1158/1078-0432.CCR-09-1067
Uhl M, Aulwurm S, Wischhusen J et al (2004) 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 64:7954–7961. https://doi.org/10.1158/0008-5472.CAN-04-1013
Van Obberghen-Schilling E, Roche NS et al (1988) Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells. J Biol Chem 263:7741–7746
Verrecchia F, Mauviel A (2002) Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol 118:211–215. https://doi.org/10.1046/j.1523-1747.2002.01641.x
Vincenti F, Fervenza FC, Campbell KN et al (2017) A phase 2, double-blind, placebo-controlled, randomized study of Fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis. Kidney Intern Rep 2:800–810. https://doi.org/10.1016/j.ekir.2017.03.011
Vogt J, Traynor R, Sapkota GP (2011) The specificities of small molecule inhibitors of the TGFss and BMP pathways. Cell Signal 23:1831–1842. https://doi.org/10.1016/j.cellsig.2011.06.019
Wang YQ, Qi XW, Wang F et al (2012) Association between TGFBR1 polymorphisms and cancer risk: a meta-analysis of 35 case-control studies. PLoS One 7:e42899. https://doi.org/10.1371/journal.pone.0042899
Wesolowska A, Kwiatkowska A, Slomnicki L et al (2008) Microglia-derived TGF-beta as an important regulator of glioblastoma invasion--an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. Oncogene 27:918–930. https://doi.org/10.1038/sj.onc.1210683
Wick W, Platten M, Weller M (2001) Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta. J Neuro-Oncol 53:177–185. https://doi.org/10.1023/A:1012209518843
Wick W, Suarez C, Rodon J et al (2013) Phase 1b/2a study evaluating safety, pharmacokinetics (PK) and preliminary pharmacodynamics responses of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with chemoradiotherapy in newly diagnosed malignant gliomas. Poster at: 18th annual SNO scientific meeting; November 22, 2013, San Francisco, CA
Wilkes MC, Murphy SJ, Garamszegi N, Leof EB (2003) Cell-type-specific activation of PAK2 by transforming growth factor beta independent of Smad2 and Smad3. Mol Cell Biol 23:8878–8889. https://doi.org/10.1128/mcb.23.23.8878-8889.2003
Won J, Kim H, Park EJ et al (1999) Tumorigenicity of mouse thymoma is suppressed by soluble type II transforming growth factor beta receptor therapy. Cancer Res 59:1273–1277
Wong C, Rougier-Chapman EM, Frederick JP et al (1999) Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta. Mol Cell Biol 19:1821–1830. https://doi.org/10.1128/mcb.19.3.1821
Xi Q, He W, Zhang XH, Le HV, Massagué J (2008) Genome-wide impact of the BRG1 SWI/SNF chromatin remodeler on the transforming growth factor beta transcriptional program. J Biol Chem 283:1146–1155. https://doi.org/10.1074/jbc.M707479200
Yagi K, Furuhashi M, Aoki H et al (2002) C-myc is a downstream target of the Smad pathway. J Biol Chem 277(1):854–861. https://doi.org/10.1074/jbc.M104170200
Yamaguchi K, Shirakabe K, Shibuya H et al (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270:2008–2011. https://doi.org/10.1126/science.270.5244.2008
Ye XZ, Xu SL, Xin YH, Yu SC et al (2012) Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol 189:444–453. https://doi.org/10.4049/jimmunol.1103248
Zagzag D, Salnikow K, Chiriboga L et al (2005) Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain. Lab Investig 85(3):328–341. https://doi.org/10.1038/labinvest.3700233
Zawel L, Dai JL, Buckhaults P et al (1998) Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1:611–617. https://doi.org/10.1016/S1097-2765(00)80061-1
Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19:128–139. https://doi.org/10.1038/cr.2008.328
Zhang L, Sato E, Amagasaki K, Nakao A, Naganuma H (2006) Participation of an abnormality in the transforming growth factor-beta signaling pathway in resistance of malignant glioma cells to growth inhibition induced by that factor. J Neurosurg 105:119–128. https://doi.org/10.3171/jns.2006.105.1.119
Zhang D, Jing Z, Qiu B, Wu A, Wang Y (2011a) Temozolomide decreases invasion of glioma stem cells by down-regulating TGF-beta2. Oncol Rep 26:901–908. https://doi.org/10.3892/or.2011.1362
Zhang M, Herion TW, Timke C et al (2011b) Trimodal glioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-beta receptor I kinase inhibitor LY2109761. Neoplasia 13:537–549. https://doi.org/10.1593/neo.11258
Zhang X, Wu A, Fan Y, Wang Y (2011c) Increased transforming growth factor-beta2 in epidermal growth factor receptor variant III-positive glioblastoma. J Clin Neurosci 18:821–826. https://doi.org/10.1016/j.jocn.2010.09.024
Zhong Z, Carroll KD, Policarpio D et al (2010) Anti-transforming growth factor b receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multi-effects on cancer, stroma, and immune cells. Clin Cancer Res 16:1191–1205. https://doi.org/10.1158/1078-0432.CCR-09-1634
Acknowledgments
The work is supported by a National Science Center grant 017/27/B/NZ3/01605 (BK). SC is a recipient of a scholarship from the National Center of Research and Development project WND-POWR.03.02.00-00-I041/16.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Kaminska, B., Cyranowski, S. (2020). Recent Advances in Understanding Mechanisms of TGF Beta Signaling and Its Role in Glioma Pathogenesis. In: Barańska, J. (eds) Glioma Signaling. Advances in Experimental Medicine and Biology, vol 1202. Springer, Cham. https://doi.org/10.1007/978-3-030-30651-9_9
Download citation
DOI: https://doi.org/10.1007/978-3-030-30651-9_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-30650-2
Online ISBN: 978-3-030-30651-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)