Skip to main content

Advertisement

SpringerLink
Log in

Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Glioblastoma multiforme (GBM) is an aggressive cancer with a poor survival rate. A key component that contributes to the poor prognosis is the capacity of glioma cells to invade local brain tissue in a diffuse manner. Among various proteases that aid in the process of invasion, matrix metalloproteinase-1 (MMP-1) has been identified as an important contributory factor in various cancers. Apart from its traditional role in cleaving its primary extracellular matrix (ECM) substrates, and like other members of the matrix metalloproteinase family, MMP-1 can activate latent forms of bio-active molecules initiating downstream pro-invasive and pro-oncogenic signaling mechanisms. MMP-1 expression is regulated by several growth factors including epidermal growth factor (EGF). Due to the fact that the epidermal growth factor receptor (EGFR) is aberrantly overexpressed in GBM, we wanted to examine in greater detail the signaling mechanisms by which MMP-1 expression and invasion is driven by EGF in GBM cells. T98G cells treated with EGF resulted in an induction of MMP-1 expression following EGFR activation. Inhibition of EGFR by both pharmacologic and genetic approaches abrogated this induction. Repression of the mitogen activated protein kinase (MAPK) signaling led to the inhibition of EGF-induced MMP-1 whereas the PI3-kinase/AKT signaling was not associated with EGFR-mediated MMP-1 induction. Inhibition of EGFR signaling also led to a decrease in T98G invasion. These data suggest that EGFR mediated MMP-1 regulation is mainly via the MAPK pathway in T98G cells and inhibition of EGFR and MMP-1 results in a decrease in T98G cell invasion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. CBTRUS (2010) 2009–2010 CBTRUS Statistical Report: Primary brain and central nervous system tumors diagnosed in the United States in 2004–2006. Source: Central Brain Tumor Registry of the United States, Hinsdale, IL. website: www.cbtrus.org

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  3. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174

    Article  PubMed  CAS  Google Scholar 

  4. Libermann TA, Nusbaum HR, Razon N (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313:144–147

    Article  PubMed  CAS  Google Scholar 

  5. Wong AJ, Ruppert JM, Bigner SH (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89:2965–2969

    Article  PubMed  CAS  Google Scholar 

  6. Frederick L (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60:1383–1387

    PubMed  CAS  Google Scholar 

  7. Zandi R, Larsen AB, Andersen P, Stockhausen MT, Poulsen HS (2007) Mechanisms for oncogenic activation of epidermal growth factor receptor. Cell Signal 19:2013–2023

    Article  PubMed  CAS  Google Scholar 

  8. Ekstrand AJ, Longo N, Hamid ML (1994) Functional characterization of a EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGF-R gene amplification. Oncogene 9:2313–2320

    PubMed  CAS  Google Scholar 

  9. Chu CT, Everiss KD, Wikstrand CJ, Batra SK, Kung HJ, Bigner DD (1997) Receptor dimerization is not a factor in the signaling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem J 324:855–861

    PubMed  CAS  Google Scholar 

  10. Grandal MV, Zandi R, Pedersen MW, Willumsen BM, van Deurs B, Poulsen HS (2007) EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes. Carcinogenesis 28:1408–1417

    Article  PubMed  CAS  Google Scholar 

  11. Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19:3159–3167

    Article  PubMed  CAS  Google Scholar 

  12. Stojic J, Hagemann C, Haas S, Herbold C, Kühnel S, Gerngras S, Roggendorf W, Roosen K, Vince GH (2008) Expression of matrix metalloproteinases MMP-1, MMP-11 and MMP-19 is correlated with the WHO-grading of human malignant gliomas. Neurosci Res 60:40–49

    Article  PubMed  CAS  Google Scholar 

  13. McCready J, Broaddus WC, Sykes V, Fillmore HL (2005) Association of a single nucleotide polymorphism in the matrix metalloproteinase-1 promoter with glioblastoma. Int J Cancer 117:781–785

    Article  PubMed  CAS  Google Scholar 

  14. Gondi CS, Dinh DH, Klopfenstein JD, Gujrati M, Rao JS (2009) MMP-2 downregulation mediates differential regulation of cell death via ErbB-2 in glioma xenografts. Int J Oncol 35:257–263

    PubMed  CAS  Google Scholar 

  15. Vince GH, Wagner S, Pietsch T, Klein R, Goldbrunner RH, Roosen K, Tonn JC (1999) Heterogeneous regional expression patterns of matrix metalloproteinases in human malignant gliomas. Int J Dev Neurosci 17:437–445

    Article  PubMed  CAS  Google Scholar 

  16. Ezhilarasan R, Jadhav U, Mohanam I, Rao JS, Gujrati M, Mohanam S (2009) The hemopexin domain of MMP-9 inhibits angiogenesis and retards the growth of intracranial glioblastoma xenograft in nude mice. Int J Cancer 124:306–315

    Article  PubMed  CAS  Google Scholar 

  17. Lakka SS, Jasti SL, Gondi C, Boyd D, Chandrasekar N, Dinh DH, Olivero WC, Gujrati M, Rao JS (2002) Downregulation of MMP-9 in ERK-mutated stable transfectants inhibits glioma invasion in vitro. Oncogene 21:5601–5608

    Article  PubMed  CAS  Google Scholar 

  18. Van Meter TE, Broaddus WC, Rooprai HK, Pilkington GJ, Fillmore HL (2004) Induction of membrane–type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas. Neuro Oncol 6:188–199

    Article  PubMed  Google Scholar 

  19. Zhang J, Sarkar S, Yong VW (2005) The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. Carcinogenesis 26:2069–2077

    Article  PubMed  CAS  Google Scholar 

  20. Fillmore HL, VanMeter TE, Broaddus WC (2001) Membrane-type matrix metalloproteinases (MTMMPs): expression and function during glioma invasion. J Neuro oncol 53:187–202

    Article  CAS  Google Scholar 

  21. Xia H, Qi Y, Ng SS, Chen X, Li D, Chen S, Ge R, Jiang S, Li G, Chen Y, He ML, Kung HF, Lai L, Lin MC (2009) MicroRNA-146b inhibits glioma cell migration and invasion by targeting MMPs. Brain Res 1269:158–165

    Article  PubMed  CAS  Google Scholar 

  22. Hodgson JG, Yeh RF, Ray A, Wang NJ, Smirnov I, Yu M, Hariono S, Silber J, Feiler HS, Gray JW, Spellman PT, Vandenberg SR, Berger MS, James CD (2009) Comparative analyses of gene copy number and mRNA expression in glioblastoma multiforme tumors and xenografts. Neuro Oncol 11:477–487

    Article  PubMed  CAS  Google Scholar 

  23. Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We extend our sincere thanks to the Hord family for funding this work through the Hord Foundation, MCV. We are grateful to Dr Harold Young and Dr. William Broaddus for support of these studies. We also thank Dr. Paul Dent for the adenoviral constructs and Dr. Adly Yacoub for his technical advice concerning the adenoviral transfections.

Author information

Author notes

  1. H. L. Fillmore

    Present address: Office of Research, Old Dominion University, 4111 Monarch Way, Suite 203, Norfolk, VA, 23508, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA

    M. Anand & H. L. Fillmore

  2. Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA

    T. E. Van Meter & H. L. Fillmore

Authors
  1. M. Anand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. E. Van Meter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. L. Fillmore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. L. Fillmore.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anand, M., Van Meter, T.E. & Fillmore, H.L. Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway. J Neurooncol 104, 679–687 (2011). https://doi.org/10.1007/s11060-011-0549-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-011-0549-x

Keywords

Search

Navigation