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Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The small leucine-rich proteoglycan (SLRP) biglycan is a major constituent of many extracellular matrices and is overexpressed in stroma-rich tumors such as pancreatic carcinoma. Here, biglycan is produced by both stromal cells and tumor cells and through its ability to act as a binding protein for TGF-β and other growth factors, and to directly inhibit proliferation of tumor cells, this SLRP is involved in various aspects of tumor biology. Biglycan expression itself is controlled by TGF-β and represents an established marker of TGF-β activity. The focus of our work during the past years has been to elucidate the molecular mechanisms and signaling pathways involved in TGF-β regulation of biglycan using pancreatic tumor cells as the principal cellular model. In this chapter, we review some of the most significant observations published previously and, in addition, present data on the role of intracellular mediators which have not been implicated in TGF-β control of biglycan so far. Besides providing a basis for pharmacologic interference with TGF-β-induced fibrotic tissue formation through specific inhibition of biglycan. TGF-β regulation of biglycan represents a paradigm of how specificity and complexity in TGF-β signaling is achieved at both the cellular and gene level.

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References

  1. Massagué J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 2000;103:295–309.

    Article  PubMed  Google Scholar 

  2. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001;29:117–129.

    Article  CAS  PubMed  Google Scholar 

  3. Moustakas A, Pardali K, Gaal A, Heldin C-H. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett 2002;82:85–91.

    Article  CAS  PubMed  Google Scholar 

  4. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 2003;425:577–584.

    Article  CAS  PubMed  Google Scholar 

  5. ten Dijke P, Ichijo H, Franzen P, et al. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 1993;8:2879–2887.

    CAS  PubMed  Google Scholar 

  6. Ebner R, Chen RH, Lawler S, Zioncheck T, Lee A, Lopez AR, Derynck R. Cloning of a type I TGFβ receptor and its effect on TGFβ binding to the type II receptor. Science 1993;260:1344–1348.

    Article  CAS  PubMed  Google Scholar 

  7. Franzén P, ten Dijke P, Ichijo H, et al. Cloning of a TGFβ type I receptor that forms a heteromeric complex with the TGFβ type II receptor. Cell 1993;75:681–692.

    Article  PubMed  Google Scholar 

  8. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–353.

    Article  CAS  PubMed  Google Scholar 

  9. Yu L, Hebert MC, Zhang YE. TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J 2002;21:3749–3737.

    Article  CAS  PubMed  Google Scholar 

  10. Takekawa M, Tatebayashi K, Itoh F, Adachi M, Imai K, Saito H. Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β. EMBO J 2002;21:6473–6482.

    Article  CAS  PubMed  Google Scholar 

  11. Javelaud D, Mauviel A. Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene 2005;24:5742–5750

    Article  CAS  PubMed  Google Scholar 

  12. Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 2004;35:83–92.

    Article  CAS  PubMed  Google Scholar 

  13. Iozzo RV, Murdoch AD. Proteoglycans of the extracellular environment: clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J 1996;10:598–614.

    CAS  PubMed  Google Scholar 

  14. Iozzo RV. The biology of the small leucine-rich proteoglycans. Functional network of interactive proteins. J Biol Chem 1999;274:18,843–18,846.

    Article  CAS  PubMed  Google Scholar 

  15. Iozzo RV. The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit Rev Biochem Mol Biol 1997;32:141–174.

    Article  CAS  PubMed  Google Scholar 

  16. Wadhwa S, Embree MC, Bi Y, Young MF. Regulation, regulatory activities, and function of biglycan. Crit Rev Eukaryot Gene Expr 2004;14:301–315.

    Article  CAS  PubMed  Google Scholar 

  17. Kinsella MG, Bressler SL, Wight TN. The regulated synthesis of versican, decorin, and biglycan: extracellular matrix proteoglycans that influence cellular phenotype. Crit Rev Eukaryot Gene Expr 2004;14:203–234.

    Article  CAS  PubMed  Google Scholar 

  18. Bachman KE, Park BH. Duel nature of TGF-beta signaling: tumor suppressor vs. tumor promoter. Curr Opin Oncol 2005;17:49–54.

    Article  CAS  PubMed  Google Scholar 

  19. Muraoka-Cook RS, Dumont N, Arteaga CL. Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin Cancer Res 2005;11:937s–943s.

    CAS  PubMed  Google Scholar 

  20. Friess H, Yamanaka Y, Buchler M, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993;105:1846–1856.

    CAS  PubMed  Google Scholar 

  21. Weber CK, Sommer G, Michl P, et al. Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines. Gastroenterology 2001;121:657–667.

    Article  CAS  PubMed  Google Scholar 

  22. Lohr M, Schmidt C, Ringel J, et al. Transforming growth factor-betal induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 2001;61:550–555.

    CAS  PubMed  Google Scholar 

  23. Chen WB, Lenschow W, Tiede K, Fischer JW, Kalthoff H, Ungefroren H. Smad4/DPC4-dependent regulation of biglycan gene expression by transforming growth factor-beta in pancreatic tumor cells. J Biol Chem 2002;277:36,118–36,128.

    Article  CAS  PubMed  Google Scholar 

  24. Moore PS, Sipos B, Orlandini S, et al. Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Wirchows Arch 2001;439:798–802.

    CAS  Google Scholar 

  25. Hunzelmann N, Schonherr E, Bonnekoh B, Hartmann C, Kresse H, Krieg T. Altered immunohistochemical expression of small proteoglycans in the tumor tissue and stroma of basal cell carcinoma. J Invest Dermatol 1995;104:509–513.

    Article  CAS  PubMed  Google Scholar 

  26. Leivo I, Jee KJ, Heikinheimo K, et al. Characterization of gene expression in major types of salivary gland carcinomas with epithelial differentiation. Cancer Genet Cytogenet 2005;156:104–113.

    Article  CAS  PubMed  Google Scholar 

  27. Strauss LG, Dimitrakopoulou-Strauss A, Koczan D, et al. 18F-FDG kinetics and gene expression in giant cell tumors. J Nucl Med 2004;45:1528–1535.

    CAS  PubMed  Google Scholar 

  28. Koninger J, Giese NA, di Mola FF, et al. Overexpressed decorin in pancreatic cancer: potential tumor growth inhibition and attenuation of chemotherapeutic action. Clin Cancer Res 2004;10:4776–4783.

    Article  PubMed  Google Scholar 

  29. Csordas G, Santra M, Reed CC, et al. Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo. J Biol Chem 2000;275:32,879–32,887.

    Article  CAS  PubMed  Google Scholar 

  30. Reed CC, Gauldie J, Iozzo RV. Suppression of tumorigenicity by adenovirus-mediated gene transfer of decorin. Oncogene 2002;21:3688–3695.

    Article  CAS  PubMed  Google Scholar 

  31. Grant DS, Yenisey C, Rose RW, Tootell M, Santra M, Iozzo RV. Decorin suppresses tumor cell-mediated angiogenesis. Oncogene 2002;21:4765–4777.

    Article  CAS  PubMed  Google Scholar 

  32. Reed CC, Waterhouse A, Kirby S, et al. Decorin prevents metastatic spreading of breast cancer. Oncogene 2005;24:1104–1110.

    Article  CAS  PubMed  Google Scholar 

  33. Hildebrand A, Romaris M, Rasmussen LM, et al. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J 1994;302:527–534.

    CAS  PubMed  Google Scholar 

  34. Fukushima D, Butzow R, Hildebrand A, Ruoslahti E. Localization of transforming growth factor beta binding site in betaglycan. Comparison with small extracellular matrix proteoglycans. J Biol Chem 1993;268:22,710–22,715.

    CAS  PubMed  Google Scholar 

  35. Bi Y, Stuelten CH, Kilts T, et al. Extracellular matrix proteoglycans control the fate of bone marrow stromal cells. J Biol Chem 2005;280:30,481–30,489.

    Article  CAS  PubMed  Google Scholar 

  36. Heegaard AM, Gehron Robey P, Vogel W, et al. Functional characterization of the human biglycan 5′-flanking DNA and binding of the transcription factor c-Krox. J Bone Miner Res 1997;12:2050–2060.

    Article  CAS  PubMed  Google Scholar 

  37. Heegaard AM, Xie Z, Young MF, Nielsen KL. Transforming growth factor beta stimulation of biglycan gene expression is potentially mediated by Sp1 binding factors. J Cell Biochem 2004;93:463–475.

    Article  CAS  PubMed  Google Scholar 

  38. Ungefroren H, Krull NB. Transcriptional regulation of the human biglycan gene. J Biol Chem 1996;271:15,787–15,795.

    Article  CAS  PubMed  Google Scholar 

  39. Soyal SM, Seelos C, Lin-Lee YC, et al. Thyroid hormone influences the maturation of apolipoprotein A-I messenger RNA in rat liver. J Biol Chem 1995;270:3996–4004.

    Article  CAS  PubMed  Google Scholar 

  40. Ungefroren H, Groth S, Ruhnke M, Kalthoff H, Fandrich F. Transforming growth factor-beta (TGF-beta) type I receptor/ALK5-dependent activation of the GADD45beta gene mediates the induction of biglycan expression by TGF-beta. J Biol Chem 2005;280:2644–2652.

    Article  CAS  PubMed  Google Scholar 

  41. Knaus PI, Lindemann D, DeCoteau JF, et al. A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol 1996;16:3480–3489.

    CAS  PubMed  Google Scholar 

  42. Sorkina T, Huang F, Beguinot L, Sorkin A. Effect of tyrosine kinase inhibitors on clathrin-coated pit recruitment and internalization of epidermal growth factor receptor. J Biol Chem 2002;277:27,433–27,441.

    Article  CAS  PubMed  Google Scholar 

  43. Inman GJ, Nicolas FJ, Callahan JF, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-β superfamily type I receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2002;62:65–74.

    Article  CAS  PubMed  Google Scholar 

  44. Baldwin RL, Friess H, Yokoyama M, et al. Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition. Int J Cancer 1996;67:283–288.

    Article  CAS  PubMed  Google Scholar 

  45. Jonson T, Albrechtsson E, Axelson J, et al. Altered expression of TGFβ receptors and mitogenic effects of TGFβ in pancreatic carcinomas. Int J Oncol 2001;19:71–81.

    CAS  PubMed  Google Scholar 

  46. Major MB, Jones DA. Identification of a Gadd45β 3-prime enhancer that mediates SMAD3 and SMAD4 dependent transcriptional induction by TGFβ. J Biol Chem 2003;279:5278–5287.

    Article  PubMed  Google Scholar 

  47. Ungefroren H, Lenschow W, Chen WB, Faendrich F, Kalthoff H. 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 2003;278:11,041–11,049.

    Article  CAS  PubMed  Google Scholar 

  48. Ellenrieder V, Hendler SF, Boeck W, et al. Transforming growth factor betal treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signalregulated kinase 2 activation. Cancer Res 2001;61:4222–4228.

    CAS  PubMed  Google Scholar 

  49. Yoo J, Ghiassi M, Jirmanova L, et al. Transforming growth factor-β-induced apoptosis is mediated by Smad-dependent expression of GADD45β through p38 activation. J Biol Chem 2003;278:43,001–43,007.

    Article  CAS  PubMed  Google Scholar 

  50. Dean JL, Sully G, Clark AR, Saklatvala J. The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. Cell Signal 2004;16:1113–1121.

    Article  CAS  PubMed  Google Scholar 

  51. Kotlyarov A, Gaestel M. Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? Biochem Soc Trans 2002;30:959–963.

    Article  CAS  PubMed  Google Scholar 

  52. Kinsella MG, Tsoi CK, Jarvelainen HT, Wight TN. Selective expression and processing of biglycan during migration of bovine aortic endothelial cells. The role of endogenous basic fibroblast growth factor. J Biol Chem 1997;272:318–325.

    Article  CAS  PubMed  Google Scholar 

  53. Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HL. Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J Biol Chem 2001;276:46,707–46,713.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang S, Han J, Sells MA, et al. Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem 1995;270:23,934–23,936.

    Article  CAS  PubMed  Google Scholar 

  55. Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 2002;115:3139–3206.

    Google Scholar 

  56. Groth S, Schulze M, Kalthoff H, Fandrich F, Ungefroren H. Adhesion and Rac1-dependent regulation of biglycan gene expression by transforming growth factor-beta. Evidence for oxidative signaling through NADPH oxidase. J Biol Chem 2005;280:33,190–33,199.

    Article  CAS  PubMed  Google Scholar 

  57. Tufvesson E, Westergren-Thorsson G. Biglycan and decorin induce morphological and cytoskeletal changes involving signalling by the small GTPases RhoA and Rac1 resulting in lung fibroblast migration. J Cell Sci 2003;116:4857–4864.

    Article  CAS  PubMed  Google Scholar 

  58. Koivunen J, Aaltonen V, Peltonen J. Protein kinase C (PKC) family in cancer progression. Cancer Lett 2006;235:1–10.

    Article  CAS  PubMed  Google Scholar 

  59. Yakymovych I, ten Dijke P, Heldin C-H, Souchelnytskyi S. Regulation of Smad signaling by protein kinase C. FASEB J 2001;15:553–555.

    CAS  PubMed  Google Scholar 

  60. Storz P, Doppler H, Toker A. Protein kinase Cdelta selectively regulates protein kinase D-dependent activation of NF-kappaB in oxidative stress signaling. Mol Cell Biol 2004;24:2614–2626.

    Article  CAS  PubMed  Google Scholar 

  61. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000;351:95–105.

    Article  CAS  PubMed  Google Scholar 

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© 2008 Humana Press Inc., Totowa, NJ

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Ungefroren, H. (2008). TGF-β Signaling and Biglycan in Pancreatic Cancer. In: Jakowlew, S.B. (eds) Transforming Growth Factor-β in Cancer Therapy, Volume II. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-293-9_4

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  • DOI: https://doi.org/10.1007/978-1-59745-293-9_4

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-715-0

  • Online ISBN: 978-1-59745-293-9

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