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

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169 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

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kwon, C. H., Zhao, D., Chen, J., Alcantara, S., Li, Y., Burns, D. K., Mason, R. P., Lee, E. Y. H. P., Wu, H., & Parada, L. F. (2008). Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Research, 68(9), 3286-3294. https://doi.org/10.1158/0008-5472.CAN-07-6867