Pten haploinsufficiency accelerates formation of high-grade astrocytomas

Cancer Res. 2008 May 1;68(9):3286-94. doi: 10.1158/0008-5472.CAN-07-6867.


We previously reported that central nervous system (CNS) inactivation of Nf1 and p53 tumor suppressor genes in mice results in the development of low-grade to high-grade progressive astrocytomas. When the tumors achieve high grade, they are frequently accompanied by Akt activation, reminiscent of the frequent association of PTEN mutations in human high-grade glioma. In the present study, we introduced CNS heterozygosity of Pten into the Nf1/p53 astrocytoma model. Resulting mice had accelerated morbidity, shortened survival, and full penetrance of high-grade astrocytomas. Haploinsufficiency of Pten accelerated formation of grade 3 astrocytomas, whereas loss of Pten heterozygosity and Akt activation coincided with progression into grade 4 tumors. These data suggest that successive loss of each Pten allele may contribute to de novo formation of high-grade astrocytoma and progression into glioblastoma, respectively, thus providing insight into the etiology of primary glioblastoma. The presence of ectopically migrating neural stem/progenitor lineage cells in presymptomatic Pten-deficient mutant brains supports the notion that these tumors may arise from stem/progenitor cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytoma / genetics
  • Astrocytoma / pathology*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Cell Movement / genetics
  • Cell Survival
  • Disease Progression
  • Female
  • Genes, Neurofibromatosis 1
  • Genes, p53
  • Loss of Heterozygosity / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Neurons / pathology
  • Oncogene Protein v-akt / metabolism
  • PTEN Phosphohydrolase / genetics*
  • Stem Cells / physiology


  • Oncogene Protein v-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse