Skip to main content

Advertisement

SpringerLink
Log in

Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas

  • Original Article
  • Published:
Brain Tumor Pathology Aims and scope Submit manuscript

Abstract

Bevacizumab (BV), a monoclonal antibody against vascular endothelial growth factor (VEGF), is currently used in the treatment of malignant glioma. To understand mechanisms of resistance to BV, we investigated morphological changes in tumor vessels and expression of angiogenic factors, such as VEGF, Flt-1, basic fibroblast growth factor (bFGF), and platelet-derived growth factor-BB (PDGF-BB), in four autopsied tumors after BV treatment. Three patients had glioblastomas; the fourth had a secondary glioblastoma that developed from a diffuse astrocytoma. BV was administered because of recurrence following the use of the Stupp regimen in these four patients. We compared the initial surgical specimen with that obtained after death following BV treatment. Immunohistochemical staining of the autopsied tumors showed that Flt-1 expression increased while VEGF expression was significantly reduced. Additionally, other angiogenic factors, particularly bFGF, were enhanced. Interestingly, the proliferation of endothelial cells was reduced, but remarkable proliferation of pericytes was observed. These results suggest that following BV treatment, glioblastomas can grow tumor vessels by expressing various angiogenic factors. These mechanisms might be important for rapid regrowth and blood brain barrier repair after BV treatment. Inhibition of multiple angiogenic factors will be required to control tumor vessels in glioblastoma.

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

Similar content being viewed by others

References

  1. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  CAS  PubMed  Google Scholar 

  2. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  3. Presta LG, Chen H, O’Connor SJ et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599

    CAS  PubMed  Google Scholar 

  4. Willett CG, Boucher Y, di Tomaso E et al (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nagane M, Nishikawa R, Narita Y et al (2012) Phase II study of single-agent bevacizumab in Japanese patients with recurrent malignant glioma. Jpn J Clin Oncol 42:887–895

    Article  PubMed  PubMed Central  Google Scholar 

  6. Furuta T, Nakada M, Misaki K et al (2014) Molecular analysis of a recurrent glioblastoma treated with bevacizumab. Brain Tumor Pathol 31:32–39

    Article  CAS  PubMed  Google Scholar 

  7. Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol. 7:452–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Takeuchi H, Hashimoto N, Kitai R et al (2010) Proliferation of vascular smooth muscle cells in glioblastoma multiforme. J Neurosurg 113:218–224

    Article  PubMed  Google Scholar 

  9. Sato S, Sato Y, Hatakeyama K et al (2011) Quantitative analysis of vessels with smooth muscle layer in astrocytic tumors: correlation with histological grade and prognostic significance. Histol Histopathol 26:497–504

    PubMed  Google Scholar 

  10. Lu X, Dunn J, Dickinson AM et al (2004) Smooth muscle alpha-actin expression in endothelial cells derived from CD34+ human cord blood cells. Stem Cells Dev 13:521–527

    Article  CAS  PubMed  Google Scholar 

  11. Muragaki Y, Maruyama T, Iseki H et al (2011) Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma. Clinical article. J Neurosurg 115:248–255

    Article  PubMed  Google Scholar 

  12. di Tomaso E, Snuderl M, Kamoun WS et al (2011) Glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res 71:19–28

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sun H, Guo D, Su Y et al (2014) Hyperplasia of pericytes is one of the main characteristics of microvascular architecture in malignant glioma. PLoS One 9:e114246

    Article  PubMed  PubMed Central  Google Scholar 

  14. Takeuchi H, Hashimoto N, Kitai R et al (2010) Proliferation of vascular smooth muscle cells in glioblastoma multiforme. J Neurosurg 113:218–224

    Article  PubMed  Google Scholar 

  15. Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed  PubMed Central  Google Scholar 

  16. Shepro D, Morel NM (1993) Pericyte physiology. FASEB J 7:1031–1038

    CAS  PubMed  Google Scholar 

  17. Arimura K, Ago T, Kamouchi M et al (2012) PDGF receptor β signaling in pericytes following ischemic brain injury. Curr Neurovasc Res 9:1–9

    Article  CAS  PubMed  Google Scholar 

  18. Cheng L, Huang Z, Zhou W et al (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153:139–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Seystahl K, Tritschler I, Szabo E et al (2015) Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma. Neuro Oncol 17:254–265

    Article  PubMed  PubMed Central  Google Scholar 

  20. Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740

    Article  CAS  PubMed  Google Scholar 

  21. Parliament E, Allalunis-Turner MJ, Franko AJ et al (2000) Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours. Br J Cancer 82:635–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stefanik DF, Fellows WK, Rizkalla LR et al (2001) Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor; FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. J Neurooncol 55:91–100

    Article  CAS  PubMed  Google Scholar 

  23. Lu-Emerson C, Snuderl M, Kirkpatrick ND et al (2013) Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma. Neuro Oncol. 15:1079–1087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Yoichiro Kato, Hideyuki Takeiri, Noriko Sakayori, and Takashi Sakayori for their help with immunohistochemistry and their scientific suggestions.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Saori Okamoto, Masayuki Nitta, Takashi Maruyama, Yoshikazu Okada & Yoshihiro Muragaki

  2. Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan

    Saori Okamoto, Masayuki Nitta, Takashi Maruyama & Yoshihiro Muragaki

  3. Department of Pathology, Tokyo Women’s Medical University, Tokyo, Japan

    Tatsuo Sawada

  4. Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Takashi Komori

Authors
  1. Saori Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masayuki Nitta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatsuo Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takashi Komori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoshikazu Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshihiro Muragaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Saori Okamoto.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10014_2016_248_MOESM1_ESM.pdf

Hematoxylin and eosin, alpha-smooth muscle actin (αSMA), and CD31 immunohistochemical staining of the surgical and autopsied samples (scale bar, 50 µm) in Case2 and Case4. (PDF 290 kb)

10014_2016_248_MOESM2_ESM.pdf

Staining for vascular endothelial growth factor A (VEGF-A), Flt-1, basic fibroblast growth factor (bFGF), and platelet-derived growth factor-BB (PDGF-BB) Scale bar, 100 µm. Compared with the surgical samples, the expression of bFGF (I–L) were especially highly expressed in the autopsied samples (PDF 388 kb)

10014_2016_248_MOESM3_ESM.pdf

Hematoxylin and eosin, alpha-smooth muscle actin (αSMA), and CD31 immunohistochemical staining of the surgical and autopsied samples (scale bar, 50 µm) in case without BV treatment. Proliferation of pericytes around the vessels was not observed, in difference with tumor specimens obtained after Bevacizumab administration. (PDF 283 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okamoto, S., Nitta, M., Maruyama, T. et al. Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas. Brain Tumor Pathol 33, 129–136 (2016). https://doi.org/10.1007/s10014-016-0248-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10014-016-0248-6

Keywords

Search

Navigation