Advertisement

Tumor Biology

, Volume 36, Issue 3, pp 1613–1618 | Cite as

TGFβ signaling in pancreatic ductal adenocarcinoma

  • Hui Zhang
  • Chengli Liu
  • Yalin Kong
  • Hui Huang
  • Cheng Wang
  • Hongyi Zhang
Research Article

Abstract

Transforming growth factor β (TGFβ) receptor signaling plays a paradoxical effect in the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC), in which its tumor-inhibitory role at early stages turns into a tumor-promoting role at later stages. The underlying mechanism remains far from clear. Here we provide strong evidence that the activation of TGFβ receptor signaling in PDAC cells increased SMAD3 phosphorylation and nuclear translocation to inhibit cell growth. Meanwhile, it also activated SMAD7 to induce nuclear translocation and retention of β-catenin, which not only attenuated the inhibition of cell growth by nuclear SMAD3 but also activated vascular endothelial growth factor A (VEGF-A) to promote vascularization. Our data thus support a model involving crosstalk of the TGFβ and Wnt signaling pathways, for regulating the complicated effect of TGFβ signaling on the tumorigenesis of PDAC.

Keywords

Pancreatic ductal adenocarcinoma Transforming growth factor β receptor signaling SMAD3 β-Catenin Wnt signaling pathway Vascular endothelial growth factor 

Notes

Acknowledgments

This study was supported by the National Science Foundation of China (grant no. 81273955).

Conflicts of interest

None

References

  1. 1.
    Han H, Von Hoff DD. Snapshot: pancreatic cancer. Cancer Cell. 2013;23:424–424 e421.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Massague J. TGFbeta in cancer. Cell. 2008;134:215–30.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A. 2014;111:E1211–1220.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yi JJ, Barnes AP, Hand R, Polleux F, Ehlers MD. TGF-beta signaling specifies axons during brain development. Cell. 2010;142:144–57.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ewen ME, Sluss HK, Whitehouse LL, Livingston DM. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell. 1993;74:1009–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463:676–80.CrossRefPubMedGoogle Scholar
  7. 7.
    Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, Paredes J, et al. TGFbeta receptor signaling is essential for inflammation-induced but not beta-cell workload-induced beta-cell proliferation. Diabetes. 2013;62:1217–26.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology. 2007;7:423–35.CrossRefPubMedGoogle Scholar
  9. 9.
    Kleeff J, Ishiwata T, Maruyama H, Friess H, Truong P, Buchler MW, et al. The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene. 1999;18:5363–72.CrossRefPubMedGoogle Scholar
  10. 10.
    Villanueva A, Garcia C, Paules AB, Vicente M, Megias M, Reyes G, et al. Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene. 1998;17:1969–78.CrossRefPubMedGoogle Scholar
  11. 11.
    Afrakhte M, Moren A, Jossan S, Itoh S, Sampath K, Westermark B, et al. Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members. Biochem Biophys Res Commun. 1998;249:505–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Yan X, Chen YG. Smad7: not only a regulator, but also a cross-talk mediator of TGF-beta signalling. Biochem J. 2011;434:1–10.CrossRefPubMedGoogle Scholar
  13. 13.
    Itoh S, ten Dijke P. Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol. 2007;19:176–84.CrossRefPubMedGoogle Scholar
  14. 14.
    Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89:1165–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.CrossRefPubMedGoogle Scholar
  16. 16.
    Zhang S, Fei T, Zhang L, Zhang R, Chen F, Ning Y, et al. Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol Cell Biol. 2007;27:4488–99.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2009;29:789–91.CrossRefPubMedGoogle Scholar
  18. 18.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.CrossRefPubMedGoogle Scholar
  19. 19.
    Xiao X, Prasadan K, Guo P, El-Gohary Y, Fischbach S, Wiersch J, et al. Pancreatic duct cells as a source of VEGF in mice. Diabetologia. 2014;57:991–1000.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Xiao X, Guo P, Chen Z, El-Gohary Y, Wiersch J, Gaffar I, et al. Hypoglycemia reduces vascular endothelial growth factor a production by pancreatic beta cells as a regulator of beta cell mass. J Biol Chem. 2013;288:8636–46.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ma J, Sawai H, Ochi N, Matsuo Y, Xu D, Yasuda A, et al. PTEN regulates angiogenesis through PI3K/Akt/VEGF signaling pathway in human pancreatic cancer cells. Mol Cell Biochem. 2009;331:161–71.CrossRefPubMedGoogle Scholar
  22. 22.
    Cabebe E, Fisher GA. Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer. Expert Opin Investig Drugs. 2007;16:467–76.CrossRefPubMedGoogle Scholar
  23. 23.
    Hotz HG, Hines OJ, Masood R, Hotz B, Foitzik T, Buhr HJ, et al. VEGF antisense therapy inhibits tumor growth and improves survival in experimental pancreatic cancer. Surgery. 2005;137:192–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Mao D, Zhang Y, Lu H, Zhang H. Molecular basis underlying inhibition of metastasis of gastric cancer by anti-VEGFa treatment. Tumour Biol. 2014;35:8217–23.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhou X, Qi Y. PLGF inhibition impairs metastasis of larynx carcinoma through MMP3 downregulation. Tumour Biol. 2014;35:9381–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Teraoka H, Sawada T, Nishihara T, Yashiro M, Ohira M, Ishikawa T, et al. Enhanced VEGF production and decreased immunogenicity induced by TGF-beta 1 promote liver metastasis of pancreatic cancer. Br J Cancer. 2001;85:612–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lieber M, Mazzetta J, Nelson-Rees W, Kaplan M, Todaro G. Establishment of a continuous tumor-cell line (PANC-1) from a human carcinoma of the exocrine pancreas. Int J Cancer. 1975;15:741–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Takatani T, Minagawa M, Takatani R, Kinoshita K, Kohno Y. AMP-activated protein kinase attenuates Wnt/beta-catenin signaling in human osteoblastic Saos-2 cells. Mol Cell Endocrinol. 2011;339:114–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Hui Zhang
    • 1
  • Chengli Liu
    • 1
  • Yalin Kong
    • 1
  • Hui Huang
    • 2
  • Cheng Wang
    • 1
  • Hongyi Zhang
    • 1
  1. 1.Department of Hepatobiliary SurgeryAir Force General Hospital of PLABeijingChina
  2. 2.Department of Hepatobiliary Surgery309 Hospital of PLABeijingChina

Personalised recommendations