Journal of Neuro-Oncology

, Volume 110, Issue 1, pp 69–77 | Cite as

Expression of VAV1 in the tumour microenvironment of glioblastoma multiforme

  • Juan Luis GarciaEmail author
  • Jose Couceiro
  • Juan Antonio Gomez-Moreta
  • J. M. Gonzalez Valero
  • Angel Santos Briz
  • Vincent Sauzeau
  • Eva Lumbreras
  • Manuel Delgado
  • Cristina Robledo
  • Monica Lara Almunia
  • Xose R. Bustelo
  • Jesus M. Hernandez
Clinical Study - Patient Study


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.


Glioma Expression profile VAV1 



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.

Supplementary material

11060_2012_936_MOESM1_ESM.xls (52 kb)
Supplementary material 1 (XLS 52 kb)
11060_2012_936_MOESM2_ESM.docx (1.2 mb)
Supplementary material 2 (DOCX 1189 kb)


  1. 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 9:157–173PubMedCrossRefGoogle Scholar
  2. 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 65:1678–1686PubMedCrossRefGoogle Scholar
  3. 3.
    Kitange GJ, Templeton KL, Jenkins RB (2003) Recent advances in the molecular genetics of primary gliomas. Curr Opin Oncol 15:197–203PubMedCrossRefGoogle Scholar
  4. 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 63:6613–6625PubMedGoogle Scholar
  5. 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 64:6503–6510PubMedCrossRefGoogle Scholar
  6. 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 163:1033–1043PubMedCrossRefGoogle Scholar
  7. 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 61:6885–6891PubMedGoogle Scholar
  8. 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 359:1011–1018PubMedCrossRefGoogle Scholar
  9. 9.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507PubMedCrossRefGoogle Scholar
  10. 10.
    Bustelo XR (2000) Regulatory and signaling properties of the Vav family. Mol Cell Biol 20:1461–1477PubMedCrossRefGoogle Scholar
  11. 11.
    Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142PubMedCrossRefGoogle Scholar
  12. 12.
    Symons M, Settleman J (2000) Rho family GTPases: more than simple switches. Trends Cell Biol 10:415–419PubMedCrossRefGoogle Scholar
  13. 13.
    Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 29:356–370PubMedCrossRefGoogle Scholar
  14. 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 12:841–845PubMedCrossRefGoogle Scholar
  15. 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 133:642–645PubMedCrossRefGoogle Scholar
  16. 16.
    Berenjeno IM, Nunez F, Bustelo XR (2007) Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases. Oncogene 26:4295–4305PubMedCrossRefGoogle Scholar
  17. 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 283:36454–36464PubMedCrossRefGoogle Scholar
  18. 18.
    Khalil BD, El-Sibai M (2012) Rho GTPases in primary brain tumor malignancy and invasion. J Neurooncol 108(3):333–339PubMedCrossRefGoogle Scholar
  19. 19.
    Bustelo XR (2001) Vav proteins, adaptors and cell signaling. Oncogene 20:6372–6381PubMedCrossRefGoogle Scholar
  20. 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 308:364–380PubMedCrossRefGoogle Scholar
  21. 21.
    Bustelo XR (2002) Regulation of Vav proteins by intramolecular events. Front Biosci 7:d24–d30PubMedCrossRefGoogle Scholar
  22. 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 9:2405–2413PubMedGoogle Scholar
  23. 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 7:39–49PubMedCrossRefGoogle Scholar
  24. 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 8:158PubMedCrossRefGoogle Scholar
  25. 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 219:25–34PubMedCrossRefGoogle Scholar
  26. 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 173:1828–1838PubMedCrossRefGoogle Scholar
  27. 27.
    Nathoo N, Prayson RA, Bondar J, Vargo L, Arrigain S et al (2006) Increased expression of 5-lipoxygenase in high-grade astrocytomas. Neurosurgery 58:347–354PubMedCrossRefGoogle Scholar
  28. 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 60:1353–1360PubMedGoogle Scholar
  29. 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 336:1227–1233PubMedCrossRefGoogle Scholar
  30. 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 62:1103–1109PubMedGoogle Scholar
  31. 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 65:5535–5543PubMedCrossRefGoogle Scholar
  32. 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 33:623–626PubMedCrossRefGoogle Scholar
  33. 33.
    Lin Q, Fuji RN, Yang W, Cerione RA (2003) RhoGDI is required for Cdc42-mediated cellular transformation. Curr Biol 13:1469–1479PubMedCrossRefGoogle Scholar
  34. 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 22:2361–2373PubMedCrossRefGoogle Scholar
  35. 35.
    Chiang AC, Massague J (2008) Molecular basis of metastasis. N Engl J Med 359:2814–2823PubMedCrossRefGoogle Scholar
  36. 36.
    Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868PubMedCrossRefGoogle Scholar
  37. 37.
    Borg I, Groenen PM (1997) Modern multidimensional scaling: theory and applications. Springer, New YorkGoogle Scholar
  38. 38.
    Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116–5121PubMedCrossRefGoogle Scholar
  39. 39.
    Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437:1032–1037PubMedCrossRefGoogle Scholar
  40. 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 93:147–151PubMedCrossRefGoogle Scholar
  41. 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 145:1301–1308PubMedGoogle Scholar
  42. 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 13:718–725PubMedCrossRefGoogle Scholar
  43. 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 85:481–485PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Juan Luis Garcia
    • 1
    Email author
  • Jose Couceiro
    • 5
  • Juan Antonio Gomez-Moreta
    • 3
  • J. M. Gonzalez Valero
    • 2
  • Angel Santos Briz
    • 4
  • Vincent Sauzeau
    • 5
  • Eva Lumbreras
    • 5
  • Manuel Delgado
    • 5
  • Cristina Robledo
    • 5
  • Monica Lara Almunia
    • 3
  • Xose R. Bustelo
    • 5
  • Jesus M. Hernandez
    • 6
  1. 1.Research UnitIECSCYL-Hospital Universitario de Salamanca. IBSAL, IBMCC (USALCSIC)SalamancaSpain
  2. 2.Research UnitIECSCYL-Hospital Universitario de SalamancaSalamancaSpain
  3. 3.Neurosurgery ServiceHospital Universitario de SalamancaSalamancaSpain
  4. 4.Department of PathologyHospital Universitario de SalamancaSalamancaSpain
  5. 5.Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del CáncerUniversidad de Salamanca-CSICSalamancaSpain
  6. 6.Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer IBSAL, IBMCC (USALCSIC) Department of HaematologyHospital Universitario de SalamancaSalamancaSpain

Personalised recommendations