Skip to main content
SpringerLink
Log in

Expression of VAV1 in the tumour microenvironment of glioblastoma multiforme

  • Clinical Study - Patient Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Even though much progress has been made towards understanding the molecular nature of glioma, the survival rates of patients affected by this tumour have not changed significantly over recent years. Better knowledge of this malignancy is still needed in order to predict its outcome and improve patient treatment. VAV1 is an GDP/GTP exchange factor for Rho/Rac proteins with oncogenic potential that is involved in the regulation of cytoskeletal dynamics and cell migration. Here we report its overexpression in 59 patients diagnosed with high-grade glioma, and the associated upregulation of a number of genes coding for proteins also involved in cell invasion- and migration-related processes. Unexpectedly, immunohistochemical experiments revealed that VAV1 is not expressed in glioma cells. Instead, VAV1 is found in non-tumoural astrocyte-like cells that are located either peritumouraly or perivascularly. We propose that the expression of VAV1 is linked to synergistic signalling cross-talk between cancer and infiltrating cells. Interestingly, we show that the pattern of expression of VAV1 could have a role in the neoplastic process in glioblastoma tumours.

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

Similar content being viewed by others

References

  1. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH 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  PubMed  CAS  Google Scholar 

  2. Nigro JM, Misra A, Zhang L, Smirnov I, Colman H et al (2005) Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res 65:1678–1686

    Article  PubMed  CAS  Google Scholar 

  3. Kitange GJ, Templeton KL, Jenkins RB (2003) Recent advances in the molecular genetics of primary gliomas. Curr Opin Oncol 15:197–203

    Article  PubMed  CAS  Google Scholar 

  4. Godard S, Getz G, Delorenzi M, Farmer P, Kobayashi H et al (2003) Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res 63:6613–6625

    PubMed  CAS  Google Scholar 

  5. Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T et al (2004) Gene expression profiling of gliomas strongly predicts survival. Cancer Res 64:6503–6510

    Article  PubMed  CAS  Google Scholar 

  6. van den Boom J, Wolter M, Kuick R, Misek DE, Youkilis AS et al (2003) Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. Am J Pathol 163:1033–1043

    Article  PubMed  Google Scholar 

  7. Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M et al (2001) Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res 61:6885–6891

    PubMed  CAS  Google Scholar 

  8. Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018

    Article  PubMed  CAS  Google Scholar 

  9. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    Article  PubMed  CAS  Google Scholar 

  10. Bustelo XR (2000) Regulatory and signaling properties of the Vav family. Mol Cell Biol 20:1461–1477

    Article  PubMed  CAS  Google Scholar 

  11. Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142

    Article  PubMed  Google Scholar 

  12. Symons M, Settleman J (2000) Rho family GTPases: more than simple switches. Trends Cell Biol 10:415–419

    Article  PubMed  CAS  Google Scholar 

  13. Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 29:356–370

    Article  PubMed  CAS  Google Scholar 

  14. Sauzeau V, Sevilla MA, Rivas-Elena JV, de Alava E, Montero MJ et al (2006) Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction. Nat Med 12:841–845

    Article  PubMed  CAS  Google Scholar 

  15. Prieto-Sanchez RM, Hernandez JA, Garcia JL, Gutierrez NC, San Miguel J et al (2006) Overexpression of the VAV proto-oncogene product is associated with B-cell chronic lymphocytic leukaemia displaying loss on 13q. Br J Haematol 133:642–645

    Article  PubMed  CAS  Google Scholar 

  16. Berenjeno IM, Nunez F, Bustelo XR (2007) Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases. Oncogene 26:4295–4305

    Article  PubMed  CAS  Google Scholar 

  17. Caloca MJ, Zugaza JL, Bustelo XR (2008) Mechanistic analysis of the amplification and diversification events induced by Vav proteins in B-lymphocytes. J Biol Chem 283:36454–36464

    Article  PubMed  CAS  Google Scholar 

  18. Khalil BD, El-Sibai M (2012) Rho GTPases in primary brain tumor malignancy and invasion. J Neurooncol 108(3):333–339

    Article  PubMed  CAS  Google Scholar 

  19. Bustelo XR (2001) Vav proteins, adaptors and cell signaling. Oncogene 20:6372–6381

    Article  PubMed  CAS  Google Scholar 

  20. Couceiro JR, Martin-Bermudo MD, Bustelo XR (2005) Phylogenetic conservation of the regulatory and functional properties of the Vav oncoprotein family. Exp Cell Res 308:364–380

    Article  PubMed  CAS  Google Scholar 

  21. Bustelo XR (2002) Regulation of Vav proteins by intramolecular events. Front Biosci 7:d24–d30

    Article  PubMed  CAS  Google Scholar 

  22. Bustelo XR, Suen KL, Leftheris K, Meyers CA, Barbacid M (1994) Vav cooperates with Ras to transform rodent fibroblasts but is not a Ras GDP/GTP exchange factor. Oncogene 9:2405–2413

    PubMed  CAS  Google Scholar 

  23. Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR et al (2005) Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Cell 7:39–49

    Article  PubMed  CAS  Google Scholar 

  24. Lee K, Liu Y, Mo JQ, Zhang J, Dong Z et al (2008) Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer. BMC Cancer 8:158

    Article  PubMed  Google Scholar 

  25. Lazer G, Idelchuk Y, Schapira V, Pikarsky E, Katzav S (2009) The haematopoietic specific signal transducer Vav1 is aberrantly expressed in lung cancer and plays a role in tumourigenesis. J Pathol 219:25–34

    Article  PubMed  CAS  Google Scholar 

  26. Salhia B, Tran NL, Chan A, Wolf A, Nakada M et al (2008) The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am J Pathol 173:1828–1838

    Article  PubMed  CAS  Google Scholar 

  27. Nathoo N, Prayson RA, Bondar J, Vargo L, Arrigain S et al (2006) Increased expression of 5-lipoxygenase in high-grade astrocytomas. Neurosurgery 58:347–354

    Article  PubMed  Google Scholar 

  28. Liau LM, Lallone RL, Seitz RS, Buznikov A, Gregg JP et al (2000) Identification of a human glioma-associated growth factor gene, granulin, using differential immuno-absorption. Cancer Res 60:1353–1360

    PubMed  CAS  Google Scholar 

  29. Holtkamp N, Afanasieva A, Elstner A, van Landeghem FK, Konneker M et al (2005) Brain slice invasion model reveals genes differentially regulated in glioma invasion. Biochem Biophys Res Commun 336:1227–1233

    Article  PubMed  CAS  Google Scholar 

  30. Rahaman SO, Sharma P, Harbor PC, Aman MJ, Vogelbaum MA et al (2002) IL-13R{alpha}2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells. Cancer Res 62:1103–1109

    PubMed  CAS  Google Scholar 

  31. Stettner MR, Wang W, Nabors LB, Bharara S, Flynn DC et al (2005) Lyn kinase activity is the predominant cellular SRC kinase activity in glioblastoma tumor cells. Cancer Res 65:5535–5543

    Article  PubMed  CAS  Google Scholar 

  32. Dransart E, Morin A, Cherfils J, Olofsson B (2005) RhoGDI-3, a promising system to investigate the regulatory function of rhoGDIs: uncoupling of inhibitory and shuttling functions of rhoGDIs. Biochem Soc Trans 33:623–626

    Article  PubMed  CAS  Google Scholar 

  33. Lin Q, Fuji RN, Yang W, Cerione RA (2003) RhoGDI is required for Cdc42-mediated cellular transformation. Curr Biol 13:1469–1479

    Article  PubMed  CAS  Google Scholar 

  34. Mischel PS, Shai R, Shi T, Horvath S, Lu KV et al (2003) Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 22:2361–2373

    Article  PubMed  CAS  Google Scholar 

  35. Chiang AC, Massague J (2008) Molecular basis of metastasis. N Engl J Med 359:2814–2823

    Article  PubMed  CAS  Google Scholar 

  36. Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868

    Article  PubMed  CAS  Google Scholar 

  37. Borg I, Groenen PM (1997) Modern multidimensional scaling: theory and applications. Springer, New York

    Google Scholar 

  38. Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116–5121

    Article  PubMed  CAS  Google Scholar 

  39. Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437:1032–1037

    Article  PubMed  CAS  Google Scholar 

  40. Hernandez JM, Mecucci C, Michaux L, Criel A, Stul M et al (1997) del(7q) in chronic B-cell lymphoid malignancies. Cancer Genet Cytogenet 93:147–151

    Article  PubMed  CAS  Google Scholar 

  41. Isola J, DeVries S, Chu L, Ghazvini S, Waldman F (1994) Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples. Am J Pathol 145:1301–1308

    PubMed  CAS  Google Scholar 

  42. Telenius H, Carter NP, Bebb CE, Nordenskjold M, Ponder BA et al (1992) Degenerate oligonucleotide-primed PCR: general amplification of target DNA by a single degenerate primer. Genomics 13:718–725

    Article  PubMed  CAS  Google Scholar 

  43. Hernandez JM, Gonzalez MB, Granada I, Gutierrez N, Chillon C et al (2000) Detection of inv(16) and t(16;16) by fluorescence in situ hybridization in acute myeloid leukemia M4Eo. Haematologica 85:481–485

    PubMed  Google Scholar 

Download references

Acknowledgments

We thank T. Prieto, I. Rodríguez, S. González and M.A. Hernández of the Centro de Investigación del Cáncer, Salamanca, and the IECSCYL-Hospital Universitario Research Unit for their excellent technical assistance. We also thank Dr. E. Fermiñán (Genomics and Proteomics Unit) for microarray analyses.

Author information

Authors and Affiliations

  1. Research Unit, IECSCYL-Hospital Universitario de Salamanca. IBSAL, IBMCC (USALCSIC), Paseo San Vicente 58, 37007, Salamanca, Spain

    Juan Luis Garcia

  2. Research Unit, IECSCYL-Hospital Universitario de Salamanca, Paseo San Vicente 58, 37007, Salamanca, Spain

    J. M. Gonzalez Valero

  3. Neurosurgery Service, Hospital Universitario de Salamanca, Salamanca, Spain

    Juan Antonio Gomez-Moreta & Monica Lara Almunia

  4. Department of Pathology, Hospital Universitario de Salamanca, Salamanca, Spain

    Angel Santos Briz

  5. Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain

    Jose Couceiro, Vincent Sauzeau, Eva Lumbreras, Manuel Delgado, Cristina Robledo & Xose R. Bustelo

  6. Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer IBSAL, IBMCC (USALCSIC) Department of Haematology, Hospital Universitario de Salamanca, Paseo San Vicente 58, 37007, Salamanca, Spain

    Jesus M. Hernandez

Authors
  1. Juan Luis Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jose Couceiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juan Antonio Gomez-Moreta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. M. Gonzalez Valero
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angel Santos Briz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vincent Sauzeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eva Lumbreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuel Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cristina Robledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Monica Lara Almunia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xose R. Bustelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jesus M. Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan Luis Garcia.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLS 52 kb)

Supplementary material 2 (DOCX 1189 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garcia, J.L., Couceiro, J., Gomez-Moreta, J.A. et al. Expression of VAV1 in the tumour microenvironment of glioblastoma multiforme. J Neurooncol 110, 69–77 (2012). https://doi.org/10.1007/s11060-012-0936-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-012-0936-y

Keywords

Search

Navigation