Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1

M.L. Falchetti, Q.G. D'Alessandris, S. Pacioni, M. Buccarelli, L. Morgante, S. Giannetti, V. Lulli, M. Martini, L.M. Larocca, E. Vakana, L. Stancato, L. Ricci-Vitiani, R. Pallini

Research output: Contribution to journalArticle

Abstract

Bevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t-test), however, bands of tumor cells spread through the brain farther than controls (p <0.001; Student t-test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over-expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. Our study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells. © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
Original languageEnglish
Pages (from-to)1331-1344
Number of pages14
JournalInternational Journal of Cancer
Volume144
Issue number6
DOIs
Publication statusPublished - 2019

Keywords

  • antiangiogenic therapy
  • bevacizumab
  • brain infiltration
  • glioblastoma
  • PLXDC1
  • cell marker
  • cell receptor
  • Plexin Domain Containing 1 receptor
  • tumor marker
  • unclassified drug
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • astrocyte
  • blood brain barrier
  • cancer infiltration
  • cancer inhibition
  • cancer stem cell
  • cell invasion
  • controlled study
  • drug effect
  • epithelial mesenchymal transition
  • glioblastoma cell line
  • human
  • human cell
  • in vitro study
  • male
  • metastasis
  • nonhuman
  • nuclear magnetic resonance imaging
  • perivascular space
  • priority journal
  • rat
  • tropism
  • tumor growth
  • tumor xenograft
  • U87MG cell line
  • vascular endothelial cell

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  • Cite this

    Falchetti, M. L., D'Alessandris, Q. G., Pacioni, S., Buccarelli, M., Morgante, L., Giannetti, S., Lulli, V., Martini, M., Larocca, L. M., Vakana, E., Stancato, L., Ricci-Vitiani, L., & Pallini, R. (2019). Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1. International Journal of Cancer, 144(6), 1331-1344. https://doi.org/10.1002/ijc.31983