Skip to main content

Cellular and Molecular Characterization of Anti-VEGF and IL-6 Therapy in Experimental Glioma

  • Chapter
  • First Online:
  • 1756 Accesses

Part of the book series: Tumors of the Central Nervous System ((TCNS,volume 2))

Abstract

Vascular endothelial growth factor (VEGF) and interleukin 6 (IL6) play central roles in various angiogenesis-dependent diseases, including malignant brain tumors. VEGF-blocking agents are increasingly used against glioblastoma, but the potential of IL6 pathway inhibition is little explored in this pathology. Here we resume recent work performed in our recently developed experimental glioma model grown on the chick chorio-allantoic membrane (CAM) showing that (1) VEGF-inhibition leads to avascular tumors which up-regulate genes associated with poor survival in glioblastoma patients, (2) single inhibition of VEGF or IL6 is equally effective in regard to angiogenesis inhibition, activates different molecular responses in tumor cells but increases invasion and (3) combined inhibition of IL6 and VEGF prevents tumor development without inducing invasion. Different treatment and transcriptomic profiling strategies are discussed with emphasis to alternative tumor models such as the chicken CAM experimental glioma.

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309

    Article  PubMed  CAS  Google Scholar 

  • Chang CY, Li MC, Liao SL, Huang YL, Shen CC, Pan HC (2005) Prognostic and clinical implication of IL-6 expression in glioblastoma multiforme. J Clin Neurosci 12:930–933

    Article  PubMed  CAS  Google Scholar 

  • Cheng SY, Huang HJ, Nagane M, Ji XD, Wang D, Shih CC, Arap W, Huang CM, Cavenee WK (1996) Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc Natl Acad Sci USA 93:8502–8507

    Article  PubMed  CAS  Google Scholar 

  • Clauss A, Ng V, Liu J, Piao H, Russo M, Vena N, Sheng Q, Hirsch MS, Bonome T, Matulonis U, Ligon AH, Birrer MJ, Drapkin R (2010) Overexpression of elafin in ovarian carcinoma is driven by genomic gains and activation of the nuclear factor kappaB pathway and is associated with poor overall survival. Neoplasia 12:161–172

    PubMed  CAS  Google Scholar 

  • Dai C, Holland EC (2001) Glioma models. Biochim Biophys Acta 1551:M19–M27

    PubMed  CAS  Google Scholar 

  • de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, Conrad CA (2010) Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 12:233–242

    PubMed  Google Scholar 

  • Dumartin L, Quemener C, Laklai H, Herbert J, Bicknell R, Bousquet C, Pyronnet S, Castronovo V, Schilling MK, Bikfalvi A, Hagedorn M (2010) Netrin-1 mediates early events in pancreatic adenocarcinoma progression, acting on tumor and endothelial cells. Gastroenterology 138:1595–1606

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N (2010) Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev 21:21–26

    Article  PubMed  CAS  Google Scholar 

  • Hagedorn M, Javerzat S, Gilges D, Meyre A, de Lafarge B, Eichmann A, Bikfalvi A (2005) Accessing key steps of human tumor progression in vivo by using an avian embryo model. Proc Natl Acad Sci USA 102:1643–1648

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  • Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57

    Article  PubMed  CAS  Google Scholar 

  • Huang J, Frischer JS, Serur A, Kadenhe A, Yokoi A, McCrudden KW, New T, O’Toole K, Zabski S, Rudge JS, Holash J, Yancopoulos GD, Yamashiro DJ, Kandel JJ (2003) Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc Natl Acad Sci USA 100:7785–7790

    Article  PubMed  CAS  Google Scholar 

  • Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D (2002) VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1:193–202

    Article  PubMed  CAS  Google Scholar 

  • Jendreyko N, Popkov M, Rader C, Barbas CF 3rd (2005) Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo. Proc Natl Acad Sci USA 102:8293–8298

    Article  PubMed  CAS  Google Scholar 

  • Jensen RL (2009) Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol 92:317–335

    Article  PubMed  CAS  Google Scholar 

  • Knisely JP, Rockwell S (2002) Importance of hypoxia in the biology and treatment of brain tumors. Neuroimaging Clin N Am 12:525–536

    Article  PubMed  Google Scholar 

  • Kunkel P, Ulbricht U, Bohlen P, Brockmann MA, Fillbrandt R, Stavrou D, Westphal M, Lamszus K (2001) Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 61:6624–6628

    PubMed  CAS  Google Scholar 

  • Lamour V, Le Mercier M, Lefranc F, Hagedorn M, Javerzat S, Bikfalvi A, Kiss R, Castronovo V, Bellahcene A (2010) Selective osteopontin knockdown exerts anti-tumoral activity in a human glioblastoma model. Int J Cancer 126:1797–1805

    PubMed  CAS  Google Scholar 

  • Loeffler S, Fayard B, Weis J, Weissenberger J (2005) Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. Int J Cancer 115:202–213

    Article  PubMed  CAS  Google Scholar 

  • Mottet D, Pirotte S, Lamour V, Hagedorn M, Javerzat S, Bikfalvi A, Bellahcene A, Verdin E, Castronovo V (2009) HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism. Oncogene 28:243–256

    Article  PubMed  CAS  Google Scholar 

  • Niola F, Evangelisti C, Campagnolo L, Massalini S, Bue MC, Mangiola A, Masotti A, Maira G, Farace MG, Ciafre SA (2006) A plasmid-encoded VEGF siRNA reduces glioblastoma angiogenesis and its combination with interleukin-4 blocks tumor growth in a xenograft mouse model. Cancer Biol Ther 5:174–179

    Article  PubMed  CAS  Google Scholar 

  • Pelloski CE, Mahajan A, Maor M, Chang EL, Woo S, Gilbert M, Colman H, Yang H, Ledoux A, Blair H, Passe S, Jenkins RB, Aldape KD (2005) YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res 11:3326–3334

    Article  PubMed  CAS  Google Scholar 

  • Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T (2000) Nf1; Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26:109–113

    Article  PubMed  CAS  Google Scholar 

  • Saidi A, Hagedorn M, Allain N, Verpelli C, Sala C, Bello L, Bikfalvi A, Javerzat S (2009) Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int J Cancer 125:1054–1064

    Article  PubMed  CAS  Google Scholar 

  • Saidi A, Javerzat S, Bellahcene A, De Vos J, Bello L, Castronovo V, Deprez M, Loiseau H, Bikfalvi A, Hagedorn M (2008) Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma. Int J Cancer 122:2187–2198

    Article  PubMed  CAS  Google Scholar 

  • Strieth S, Eichhorn ME, Sutter A, Jonczyk A, Berghaus A, Dellian M (2006) Antiangiogenic combination tumor therapy blocking alpha(v)-integrins and VEGF-receptor-2 increases therapeutic effects in vivo. Int J Cancer 119:423–431

    Article  PubMed  CAS  Google Scholar 

  • Tchirkov A, Rolhion C, Bertrand S, Dore JF, Dubost JJ, Verrelle P (2001) IL-6 gene amplification and expression in human glioblastomas. Br J Cancer 85:518–522

    Article  PubMed  CAS  Google Scholar 

  • Tu H, Zhou Z, Liang Q, Li Z, Li D, Qing J, Wang H, Zhang L (2009) CXCR4 and SDF-1 production are stimulated by hepatocyte growth factor and promote glioma cell invasion. Onkologie 32:331–336

    Article  PubMed  CAS  Google Scholar 

  • Van Meir E, Sawamura Y, Diserens AC, Hamou MF, de Tribolet N (1990) Human glioblastoma cells release interleukin 6 in vivo and in vitro. Cancer Res 50:6683–6688

    PubMed  Google Scholar 

  • Weissenberger J, Loeffler S, Kappeler A, Kopf M, Lukes A, Afanasieva TA, Aguzzi A, Weis J (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23:3308–3316

    Article  PubMed  CAS  Google Scholar 

  • Wicki A, Christofori G (2007) The potential role of podoplanin in tumour invasion. Br J Cancer 96:1–5

    Article  PubMed  CAS  Google Scholar 

  • Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported La Ligue Contre le Cancer, Comitée de la Dordogne (to SJ) and l’Agence Nationale de la Recherche, ANR (“Glioma Model”, JC05_0060, to MH).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin Hagedorn .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Javerzat, S., Hagedorn, M. (2011). Cellular and Molecular Characterization of Anti-VEGF and IL-6 Therapy in Experimental Glioma. In: Hayat, M. (eds) Tumors of the Central Nervous System, Volume 2. Tumors of the Central Nervous System, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0618-7_35

Download citation

  • DOI: https://doi.org/10.1007/978-94-007-0618-7_35

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-007-0617-0

  • Online ISBN: 978-94-007-0618-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics