Pten haploinsufficiency accelerates formation of high-grade astrocytomas

Chang Hyuk Kwon, Dawen Zhao, Jian Chen, Sheila Alcantara, Yanjiao Li, Dennis K. Burns, Ralph P. Mason, Eva Y H P Lee, Hong Wu, Luis F. Parada

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3286-3294
Number of pages9
JournalCancer research
Volume68
Issue number9
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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