Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Nodal promotes growth and invasion in human gliomas

Oncogene volume 29, pages 3110–3123 (2010)Cite this article

Subjects

Abstract

Uncontrolled growth and diffused invasion are major causes of mortality in patients with malignant gliomas. Nodal has been shown to have a central role in the tumorigenic signaling pathways of malignant melanoma. In this study, we show that grade IV human glioma cell lines expressed different levels of Nodal, paralleled to the potential for cell invasiveness. Treatment of glioma cell lines with recombinant Nodal (rNodal) increased matrix metalloproteinase 2 (MMP-2) secretion and cell invasiveness. The ectopic expression of Nodal in GBM glioma cells that expressed Nodal at low level resulted in increased MMP-2 secretion, enhanced cell invasiveness, raised cell proliferation rates in vitro, increased tumor growth in vivo, and was associated with poor survival in a mice xenograft model. In contrast, the knockdown of Nodal expression in U87MG glioma cells with high Nodal expression level had reduced MMP-2 secretion, less cell invasiveness, lower tumor growth in vivo and longer lifespan in mice with U87MG/shNodal cell xenografts. In addition, Nodal knockdown promoted the reversion of malignant glioma cells toward a differentiated astrocytic phenotype. Furthermore, our data support the notion that Nodal may regulate glioma progression through the induction of the leukemia inhibitory factor (LIF) and Cripto-1 through activated Smad.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Bennett JT, Stickney HL, Choi WY, Ciruna B, Talbot WS, Schier AF . (2007). Maternal nodal and zebrafish embryogenesis. Nature 450: E1–E2; discussion E2-4.

    Article  CAS  Google Scholar 

  • Besser D . (2004). Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. J Biol Chem 279: 45076–45084.

    Article  CAS  Google Scholar 

  • Brennan J, Norris DP, Robertson EJ . (2002). Nodal activity in the node governs left-right asymmetry. Genes Dev 16: 2339–2344.

    Article  CAS  Google Scholar 

  • Bruna A, Darken RS, Rojo F, Ocana A, Penuelas S, Arias A 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.

    Article  CAS  Google Scholar 

  • Candolfi M, Curtin JF, Nichols WS, Muhammad AG, King GD, Pluhar GE et al. (2007). Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression. J Neurooncol 85: 133–148.

    Article  Google Scholar 

  • Chakravarti A, Palanichamy K . (2008). Overcoming therapeutic resistance in malignant gliomas: current practices and future directions. Cancer Treat Res 139: 173–189.

    CAS  PubMed  Google Scholar 

  • Christiansen JJ, Rajasekaran AK . (2006). Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66: 8319–8326.

    Article  CAS  Google Scholar 

  • Hendrix MJ, Seftor EA, Seftor RE, Kasemeier-Kulesa J, Kulesa PM, Postovit LM . (2007). Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 7: 246–255.

    Article  CAS  Google Scholar 

  • Hjelmeland MD, Hjelmeland AB, Sathornsumetee S, Reese ED, Herbstreith MH, Laping NJ 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.

    CAS  PubMed  Google Scholar 

  • Jan HJ, Lee CC, Shih YL, Hueng DY, Ma HI, Lai JH et al. (2010). Osteopontin regulates human glioma cell invasiveness and tumor growth in mice. Neuro-Oncology 12: 58–70.

    Article  CAS  Google Scholar 

  • Kargiotis O, Chetty C, Gondi CS, Tsung AJ, Dinh DH, Gujrati M et al. (2008). Adenovirus-mediated transfer of siRNA against MMP-2 mRNA results in impaired invasion and tumor-induced angiogenesis, induces apoptosis in vitro and inhibits tumor growth in vivo in glioblastoma. Oncogene 27: 4830–4840.

    Article  CAS  Google Scholar 

  • Koul D, Parthasarathy R, Shen R, Davies MA, Jasser SA, Chintala SK et al. (2001). Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20: 6669–6678.

    Article  CAS  Google Scholar 

  • Ma HI, Guo P, Li J, Lin SZ, Chiang YH, Xiao X et al. (2002a). Suppression of intracranial human glioma growth after intramuscular administration of an adeno-associated viral vector expressing angiostatin. Cancer Res 62: 756–763.

    CAS  PubMed  Google Scholar 

  • Ma HI, Lin SZ, Chiang YH, Li J, Chen SL, Tsao YP et al. (2002b). Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adeno-associated viral (AAV) vector. Gene Therapy 9: 2–11.

    Article  CAS  Google Scholar 

  • Mancino M, Strizzi L, Wechselberger C, Watanabe K, Gonzales M, Hamada S et al. (2008). Regulation of human Cripto-1 gene expression by TGF-beta1 and BMP-4 in embryonal and colon cancer cells. J Cell Physiol 215: 192–203.

    Article  CAS  Google Scholar 

  • Nonaka S, Shiratori H, Saijoh Y, Hamada H . (2002). Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418: 96–99.

    Article  CAS  Google Scholar 

  • Penuelas S, Anido J, Prieto-Sanchez RM, Folch G, Barba I, Cuartas I et al. (2009). TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15: 315–327.

    Article  CAS  Google Scholar 

  • Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD et al. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9: 157–173.

    Article  CAS  Google Scholar 

  • Postovit LM, Margaryan NV, Seftor EA, Hendrix MJ . (2008a). Role of nodal signaling and the microenvironment underlying melanoma plasticity. Pigment Cell Melanoma Res 21: 348–357.

    Article  CAS  Google Scholar 

  • Postovit LM, Margaryan NV, Seftor EA, Kirschmann DA, Lipavsky A, Wheaton WW et al. (2008b). Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells. Proc Natl Acad Sci USA 105: 4329–4334.

    Article  CAS  Google Scholar 

  • Rooprai HK, Rucklidge GJ, Panou C, Pilkington GJ . (2000). The effects of exogenous growth factors on matrix metalloproteinase secretion by human brain tumour cells. Br J Cancer 82: 52–55.

    Article  CAS  Google Scholar 

  • Rutka JT, Murakami M, Dirks PB, Hubbard SL, Becker LE, Fukuyama K et al. (1997). Role of glial filaments in cells and tumors of glial origin: a review. J Neurosurg 87: 420–430.

    Article  CAS  Google Scholar 

  • Saha S, Ji L, de Pablo JJ, Palecek SP . (2008). TGFbeta/activin/Nodal pathway in inhibition of human embryonic stem cell differentiation by mechanical strain. Biophys J 94: 4123–4133.

    Article  CAS  Google Scholar 

  • Smith JR, Vallier L, Lupo G, Alexander M, Harris WA, Pedersen RA . (2008). Inhibition of activin/Nodal signaling promotes specification of human embryonic stem cells into neuroectoderm. Dev Biol 313: 107–117.

    Article  CAS  Google Scholar 

  • Strizzi L, Hardy KM, Seftor EA, Costa FF, Kirschmann DA, Seftor RE et al. (2009). Development and cancer: at the crossroads of Nodal and Notch signaling. Cancer Res 69: 7131–7134.

    Article  CAS  Google Scholar 

  • Strizzi L, Postovit LM, Margaryan NV, Seftor EA, Abbott DE, Seftor RE et al. (2008). Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression. Breast Dis 29: 91–103.

    Article  Google Scholar 

  • Strojnik T, Kavalar R, Lah TT . (2006). Experimental model and immunohistochemical analyses of U87 human glioblastoma cell xenografts in immunosuppressed rat brains. Anticancer Res 26: 2887–2900.

    CAS  PubMed  Google Scholar 

  • Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S et al. (2006). Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9: 287–300.

    Article  CAS  Google Scholar 

  • Svechnikova I, Almqvist PM, Ekstrom TJ . (2008). HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin. Int J Oncol 32: 821–827.

    CAS  PubMed  Google Scholar 

  • Topczewska JM, Postovit LM, Margaryan NV, Sam A, Hess AR, Wheaton WW et al. (2006). Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nat Med 12: 925–932.

    Article  CAS  Google Scholar 

  • Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R 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.

    Article  CAS  Google Scholar 

  • Vallier L, Alexander M, Pedersen RA . (2005). Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci 118: 4495–4509.

    Article  CAS  Google Scholar 

  • Vallier L, Reynolds D, Pedersen RA . (2004). Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev Biol 275: 403–421.

    Article  CAS  Google Scholar 

  • Wick W, Naumann U, Weller M . (2006). Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 12: 341–349.

    Article  CAS  Google Scholar 

  • Zhou R, Skalli O . (2000). TGF-alpha differentially regulates GFAP, vimentin, and nestin gene expression in U-373 MG glioblastoma cells: correlation with cell shape and motility. Exp Cell Res 254: 269–278.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Shin Kong Memorial Hospital, Taipei, Taiwan

    C-C Lee

  2. Department of Pathology, Taipei Medical University, Taipei, Taiwan

    C-C Lee

  3. School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan

    C-C Lee

  4. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

    H-J Jan, J-H Lai, Y-Y Cheng, L-W Liu & H-M Lee

  5. Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    H-I Ma & D-Y Hueng

  6. Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan

    Y-C Gladys Lee

  7. Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan

    H-W Wei

  8. Institute of Pharmaceutical Science and Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan

    H-M Lee

  9. Department of Medical Laboratory Sciences and Biotechnology, College of Medicine, Taipei Medical University, Taipei, Taiwan

    H-M Lee

Authors
  1. C-C Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H-J Jan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J-H Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H-I Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D-Y Hueng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y-C Gladys Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y-Y Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L-W Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H-W Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H-M Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H-M Lee.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, CC., Jan, HJ., Lai, JH. et al. Nodal promotes growth and invasion in human gliomas. Oncogene 29, 3110–3123 (2010). https://doi.org/10.1038/onc.2010.55

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.55

Keywords

This article is cited by

Search

Advanced search

Quick links