TGF beta signalling and its role in tumour pathogenesis.

• Authors: Bozena Kaminska , Aleksandra Wesolowska , Malgorzata Danilkiewicz
• Languages of publication: EN

Abstracts

EN

Transforming growth factor beta (TGF-β) is a multifunctional cytokine involved in the regulation of cell proliferation, differentiation and survival/or apoptosis of many cells. Knock-out experiments in mice for the three isoforms of TGF-β have demonstrated their importance in regulating inflammation and tissue repair. TGF-β is implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis. TGF-β receptors act through multiple intracellular pathways. Upon binding of TGF-β with its receptor, receptor-regulated Smad2/3 proteins become phosphorylated and associate with Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of specific genes. Negative regulation of TGF-β/Smad signalling may occur through the inhibitory Smad6/7. Furthermore, TGF-β-activated kinase-1 (TAK1) is a component of TGF-β signalling and activates stress-activated kinases: p38 through MKK6 or MKK3 and c-Jun N-terminal kinases (JNKs) via MKK4. In the brain TGF-β, normally expressed at the very low level, increases dramatically after injury. Increased mRNA levels of the three TGF-β isoforms correlate with the degree of malignancy of human gliomas. TGF-βs are secreted as latent precursors requiring activation into the mature form. TGF-β may contribute to tumour pathogenesis by direct support of tumour growth and influence on local microenvironment, resulting in immunosuppression, induction of angiogenesis, and modification of the extracellular matrix. TGF-β1,2 may stimulate production of vascular endothelial growth factor (VEGF) as well as plasminogen activator inhibitor (PAI-I), that are involved in vascular remodelling occurring during angiogenesis. Blocking of TGF-β action inhibits tumour viability, migration, metastases in mammary cancer, melanoma and prostate cancer model. Reduction of TGF-β production and activity may be a promising target of therapeutic strategies to control tumour growth.

Keywords

EN

Smad propteins; RNA interference.; TGF beta signal transduction; tumour invasion; cancer therapy; MAP kinases

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2005
• Volume: 52
• Issue: 2
• Pages: 329-337

Dates

published

2005

received

2005-04-05

revised

2005-05-09

accepted

2005-05-31

Contributors

author

Bozena Kaminska

• Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warszawa, Poland

author

Aleksandra Wesolowska

• Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warszawa, Poland

author

Malgorzata Danilkiewicz

• Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warszawa, Poland

References

• An DS, Xie Y, Mao SH, Morizono K, Kung SK, Chen IS (2003) Efficient lentiviral vectors for short hairpin RNA delivery into human cells. Hum Gene Ther 14: 1207-1212.
• Attisano L, Wrana JL (2002) Signal transduction by TGF-β superfamily. Science 296: 1646-1647.
• Batuman OA, Ferrero A, Cupp C, Jimenez SA, Khalili K (1995) Differential regulation of transforming growth factor β-1 gene expression by glucocorticoids in human T and glial cells. J Immunol 155: 4397-4405.
• Beck C, Schreiber H, Rowley D (2001) Role of TGF-β in immune-evasion of cancer. Microsc Res Tech 52: 387-395.
• Benckert C, Jonas S, Cramer T, Von Marschall Z, Schafer G, Peters M, Wagner K, Radke C, Wiedenmann B, Neuhaus P, Hocker M, Rosewicz S (2003) Transforming growth factor β 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells. Cancer Res 63: 1083-1092.
• Benigni A, Zoja C, Corna D, Zatelli C, Conti S, Campana M, Gagliardini E, Rottoli D, Zanchi C, Abbate M, Ledbetter S, Remuzzi G (2003) Add-on anti-TGF-β antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 14: 1816-1824.
• Birchenall-Roberts MC, Ruscetti FW, Kasper J, Lee HD, Friedman R, Geiser A, Sporn MB, Roberts AB, Kim SJ (1990) Transcriptional regulation of the transforming growth factor β 1 promoter by v-src gene products is mediated through the AP-1 complex. Mol Cell Biol 10: 4978-4983.
• Biswas S, Chytil A, Washington K, Romero-Gallo J, Gorska AE, Wirth PS, Gautam S, Moses HL, Grady WM (2004) Transforming growth factor β receptor Type II inactivation promotes the establishment and progression of colon cancer. Cancer Res 64: 4687-4692.
• Bogdahn U, Hau P, Brawanski A, Schlaier J, Mehdorn M, Wurm G, Pichler J, Kunst M, Stauder G, Schlingensiepen KH (2004) Specific therapy for high-grade glioma by convection-enhanced delivery of the TGF-β2 specific antisense oligonucleotide AP 12009. Am Soc Clin Oncol Ann Meet. Abstract 1514.
• Bollard CM, Rossig C, Calonge MJ, Huls MH, Wagner HJ, Massague J, Brenner MK, Heslop HE, Rooney CM (2002) Adapting of transforming growth factor β- related tumor protection strategy to enhance antitumor immunity. Blood 99: 3179-3187.
• Bottner M, Krieglstein K, Unsicker K (2000) The transforming growth factor-βs: structure, signaling, and roles in nervous system development and functions. J Neurochem 75: 2227-2240.
• Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, Khazaie K (2005) Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proc Natl Acad Sci USA 102: 419-424.
• Dai C, Yang J, Liu Y (2003) Transforming growth factor-β1 potentiates renal tubular epithelial cell death by a mechanism independent of Smad signaling, J Biol Chem 278: 12537-12545.
• DaCosta Byfield S, Major C, Laping NJ, Roberts AB (2004) SB-505124 is a selective inhibitor of transforming growth factor β type I receptors ALK4, ALK5 and ALK7. Mol Pharmacol 65: 744-752.
• Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425: 577-584.
• Dong Y, Tang L, Letterio JJ, Benveniste EN (2001) The Smad3 protein is involved in TGF-β inhibition of class II transactivator and class II MHC expression. J Immunol 167: 311-319.
• Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R (1995) Processing of transforming growth factor β 1 precursor by human furin convertase. J Biol Chem 270: 10618-10624.
• Friese MA, Wischhusen J, Wick W, Weiler M, Eisele G, Steinle A, Weller M (2004) RNA interference targeting transforming growth factor β enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness and abrogates tumorigenicity in vivo. Cancer Res 64: 7596-7603.
• Geiser AG, Busam KJ, Kim SJ, Lafyatis R, O’Reilly MA, Webbink R, Roberts AB, Sporn MB (1993) Regulation of the transforming growth factor-β 1 and -β 3 promoters by transcription factor Sp1. Gene 129: 223-228.
• Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor β. Nat Med 7: 1118-1122.
• Grainger DJ, Wakefield L, Bethell HW, Farndale RW, Metcalfe JC (1995) Release and activation of platelet latent TGF-β in blood clots during dissolution with plasmin. Nat Med 1: 932-937.
• Grimm D, Pandey K, Kay MA (2005) Adeno-associated virus vectors for short hairpin RNA expression. Methods Enzymol 392: 381-405.
• Hanafusa H, Ninomiya-Tsuji J, Masuyama N, Nishita M, Fujisawa J, Shibuya H, Matsumoto K, Nishida E (1999) Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-β-induced gene expression. J Biol Chem 274: 27161-27167.
• Hjelmeland MD, Hjelmeland AB, Sathornsumetee S, Reese ED, Herbstreith MH, Laping NJ, Friedman HS, Bigner DD, Wang XF, Rich JN (2003) SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol Cancer Ther 3: 737-745.
• Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M (1999) Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397: 530-534.
• Hyytiainen M, Penttinen C, Keski-Oja J (2004) Latent TGF-β binding proteins: extracellular matrix association and roles in TGF-β activation. Crit Rev Clin Lab Sci 41: 233-264.
• Inge TH, Hoover SK, Susskind BM, Barrett SK, Bear HD (1992) Inhibition of tumor-specific cytotoxic T-lymphocyte responses by transforming growth factor β 1. Cancer Res 52: 1386-1392.
• Inman GJ, Nicolas FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS (2001) SB-431542 is a potent and specific inhibitor of transforming growth factor β superfamily Type I activin receptor-like kinase (ALK) receptors ALK4, ALK5 and ALK7. Mol Pharmacol 62: 65-74.
• Jachimczak P, Bogdahn U, Schneider J, Behl C, Meixensberger J, Apfel R, Dorries R, Schlingensiepen KH, Brysch W (1993) The effect of transforming growth factor-β 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J Neurosurg 78: 944-951.
• Jachimczak P, Hessdorfer B, Fabel-Schulte K, Wismeth C, Brysch W, Schlingensiepen KH, Bauer A, Blesch A, Bogdahn U (1996) Transforming growth factor-β-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides. Int J Cancer 65: 332-337.
• Jennings MT, Pietenpol JA (1998) The role of transforming growth factor β in glioma progression. J Neurooncol 36: 123-140.
• Jennings MT, Maciunas RJ, Carver R, Bascom CC, Juneau P, Misulis K, Moses HL (1991) TGF β 1 and TGF β 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.
• Johansson N, Ala-aho R, Uitto V, Grenman R, Fusenig NE, Lopez-Otin C, Kahari VM (2000) Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. J Cell Sci 113: 227-235.
• Kaklamani VG, Hou N, Bian Y, Reich J, Offit K, Michel LS, Rubinstein WS, Rademaker A, Pasche B (2003) TGFβR1*6A and cancer risk: a meta-analysis of seven case-control studies. J Clin Oncol 21: 3236-3243.
• Karsdal MA, Hjorth P, Henriksen K, Kirkegaard T, Nielsen KL, Lou H, Delaisse JM, Foged NT (2003) Transforming growth factor-β controls human osteoclastogenesis through the p38 MAPK and regulation of RANK expression. J Biol Chem 278: 44975-44987.
• Kaur B, Tan C, Brat DJ, Post DE, Van Meir EG (2004) Genetic and hypoxic regulation of angiogenesis in gliomas. J Neurooncol 70: 229-243.
• Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB, Karin M, Roberts AB (1990) Autoinduction of transforming growth factor β 1 is mediated by the AP-1 complex. Mol Cell Biol 10: 1492-1497.
• Kim SJ, Park K, Koeller D, Kim KY, Wakefield LM, Sporn MB, Roberts AB (1992) Post-transcriptional regulation of the human transforming growth factor-β 1 gene. J Biol Chem 267: 13702-13707.
• Kim ES, Kim MS, Moon A (2004) TGF-β-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 25: 1375-1382.
• Kuppner MC, Hamou MF, Bodmer S, Fontana A, de Tribolet N (1988) The glioblastoma-derived T-cell suppressor factor/ transforming growth factor β2 inhibits the generation of lymphokine-activated killer (LAK) cells. Int J Cancer 42: 562-567.
• Kutz SM, Hordines J, McKeown-Longo PJ, Higgins PJ (2001) TGF-β1-induced PAI-1 gene expression requires MEK activity and cell-to-substrate adhesion. J Cell Sci 114: 3905-3914.
• Lee YJ, Han Y, Lu HT, Nguyen V, Qin H, Howe PH, Hocevar BA, Boss JM, Ransohoff RM, Benveniste EN (1997) TGF-β suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression. J. Immunol 158: 2065-2075.
• Lindholm D, Castren E, Kiefer R, Zafra F, Thoenen H (1992) Transforming growth factor-β 1 in the rat brain: increase after injury and inhibition of astrocyte proliferation. J Cell Biol 117: 395-400.
• Massague J, Wotton D (2000) Transcriptional control by the TGFβ/Smad signaling system. EMBO J 19: 1745-1754.
• Maeda H, Kuwahara H, Ichimura Y, Ohtsuki M, Kurakata S, Shiraishi A (1995) TGF-β enhances macrophage ability to produce IL-10 in normal and tumor-bearing mice. J Immunol 155: 4926-4932.
• Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT (2003) Evaluation of anti-TGF-β2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 44: 3394-3401
• Mulder KM (2000) Role of Ras and Mapks in TGFβ signaling. Cytokine Growth Factor Rev 11: 23-35.
• Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, Easterly E, Roebuck LR, Ryan S, Gotwals PJ, Koteliansky V, Arteaga CL (2002) Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 109: 1551-1559.
• Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, Ten Dijke P (1997) Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389: 631-635.
• Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, Ten Dijke P (1997) TGF-β receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J 16: 5353-5362.
• Oft M, Heider KH, Beug H (1998) TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8: 1243-1252.
• Platten M, Wick W, Weller M (2001) Malignant glioma biology: role for TGF-β in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52: 401-410.
• Piek E, Heldin CH, Ten Dijke P (1999) Specificity, diversity, and regulation in TGF-β superfamily signaling. FASEB J 13: 2105-2124.
• Prashar Y, Khanna A, Sehajpal P, Sharma VK, Suthanthiran M (1995) Stimulation of transforming growth factor-β 1 transcription by cyclosporine. FEBS Lett 358: 109-112.
• Ranges GE, Figari IS, Espevik T, Palladino MA Jr (1987) Inhibition of cytotoxic T cell development by transforming growth factor β and reversal by recombinant tumor necrosis factor α. J Exp Med 166: 991-998.
• Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3: 489-501.
• 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-β. J Biol Chem 274: 13586-13593.
• Sanchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C ( 2001) Synergistic cooperation between hypoxia and transforming growth factor-β pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276: 38527-38535.
• Sawyer JS, Beight DW, Britt KS, Anderson BD, Campbell RM, Goodson T Jr, Herron DK, Li HY, McMillen WT, Mort N, Parsons S, Smith EC, Wagner JR, Yan L, Zhang F, Yingling JM (2004) Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrollo[1,2-b]pyrozole inhibitors of the transforming growth factor β- type I receptor kinase domain. Bioorg Med Chem Lett 14: 3581-3584.
• Schlingensiepen KH, Bischof A, Egger T, Hafner M, Herrmuth H, Jachimczak P, Kielmanowicz M, Niewel M, Zavadova E, Stauder G (2004) The TGF-β1 antisense oligonucleotide AP 11014 for the treatment of non-small cell lung, colorectal and prostate cancer: Preclinical studies. Am Soc Clin Oncol Ann Meeting Abstract 3132.
• Shah AH, Tabayoyong WB, Kundu SD, Kim SJ, Van Parijs L, Liu VC, Kwon E, Greenberg NM, Lee C (2002) Suppression of tumor metastasis by blockade of transforming growth factor β signaling in bone marrow cells through a retroviral-mediated gene therapy in mice. Cancer Res 62: 7135-7138.
• Shi Y, Massague J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113: 685-700.
• 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 β. J Immunol 146: 3289-3297.
• Souchelnytskyi S, Tamaki K, Engstrom U, Wernstedt C, Ten Dijke P, Heldin CH (1997) Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-β signalling. J Biol Chem 272: 28107-28115.
• Sugano Y, Matsuzaki K, Tahashi Y, Furukawa F, Mori S, Yamagata H, Yoshida K, Matsushita M, Nishizawa M, Fujisawa J, Inoue K (2003) Distortion of autocrine transforming growth factor β signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells. Oncogene 22: 2309-2321.
• Tiscornia G, Singer O, Ikawa M, Verma IM (2003) A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA 100: 1844-1848.
• Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, Mangadu R, Liu YW, Platten M, Herrlinger U, Murphy A, Wong DH, Wick W, Higgins LS, Weller M (2004) SD-208, a novel of transforming growth factor β receptor 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.
• Ungefroren H, Lenschow W, Chen WB, Faendrich F, Kalthoff H (2003) Regulation of biglycan gene expression by transforming growth factor-β requires MKK6-p38 mitogen-activated protein kinase signaling downstream of Smad signaling. J Biol Chem 278: 11041-11049.
• Van Obberghen-Schilling E, Roche NS, Flanders KC, Sporn MB, Roberts AB (1988) Transforming growth factor β 1 positively regulates its own expression in normal and transformed cells. J Biol Chem 263: 7741-7746.
• Ventura JJ, Kennedy NJ, Flavell RA, Davis RJ (2004) JNK regulates autocrine expression of TGF-β1. Mol Cell 15: 269-278.
• Wang L, Zhu Y, Sharma K (1998) Transforming growth factor-β1 stimulates protein kinase A in mesangial cells. J Biol Chem 273: 8522-8527.
• Wang L, Kwak JH, Kim SI, He Y, Choi ME (2004) Transforming growth factor-β1 stimulates vascular endothelial growth factor 164 via mitogen-activated protein kinase kinase 3-p38α and p38δ mitogen-activated protein kinase-dependent pathway in murine mesangial cells. J Biol Chem 279: 33213-33219.
• Wick W, Platten M, Weller M (2001) Glioma cell invasion: regulation of metalloproteinase activity by TGF-β. J Neurooncol 53: 177-185.
• Won J, Kim H, Park EJ, Hong Y, Kim SJ, Yun Y (1999) Tumorigenicity of mouse thymoma is suppressed by soluble Type II transforming growth factor β receptor therapy. Cancer Res 59: 1273-1277.
• Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270: 2008-2011.
• Yoo Y, Ghiassi M, Jirmanova L, Balliet AG, Hoffman B, Fornace AJ Jr, Liebermann DA, Bottinger EP, Roberts AB (2003) Transforming growth factor-β-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J Biol Chem 278: 43001-43007.
• Yue J, Sun B, Liu G, Mulder KM (2004) Requirement of TGF-β receptor-dependent activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (Sapks) for TGF-β up-regulation of the urokinase-type plasminogen activator receptor. J Cell Physiol 199: 284-292.
• Zagzag D, Salnikow K, Chiriboga L, Yee H, Lan L, Ali MA, Garcia R, Demaria S, Newcomb EW (2005) Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain. Lab Invest 85: 328-341.