HBEGF promotes gliomagenesis in the context of Ink4a/Arf and Pten loss

Oncogene. 2017 Aug 10;36(32):4610-4618. doi: 10.1038/onc.2017.83. Epub 2017 Apr 3.

Abstract

Heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) is a ligand for the EGF receptor (EGFR), one of the most commonly amplified receptor tyrosine kinases (RTKs) in glioblastoma (GBM). While HBEGF has been found to be expressed in a subset of malignant gliomas, its sufficiency for glioma initiation has not been evaluated. In this study, we demonstrate that HBEGF can initiate GBM in mice in the context of Ink4a/Arf and Pten loss, and that these tumors are similar to the classical GBM subtype observed in patients. Isogenic astrocytes from these mice showed activation not only of Egfr but also the RTK Axl in response to HBEGF stimulation. Deletion of either Egfr or Axl decreased the tumorigenic properties of HBEGF-transformed cells; however, only EGFR was able to rescue the phenotype in cells lacking both RTKs indicating that Egfr is required for activation of Axl in this context. Silencing of HBEGF in vivo resulted in tumor regression and significantly increased survival, suggesting that HBEGF may be a clinically relevant target.

MeSH terms

  • ADP-Ribosylation Factor 1 / genetics*
  • ADP-Ribosylation Factor 1 / metabolism
  • Animals
  • Astrocytes / pathology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Cohort Studies
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Heparin-binding EGF-like Growth Factor / genetics
  • Heparin-binding EGF-like Growth Factor / metabolism*
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • EGFR protein, mouse
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • PTEN Phosphohydrolase
  • ADP-Ribosylation Factor 1