title: Pten haploinsufficiency accelerates formation of high-grade astrocytomas.
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.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133, USA.
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
authors.forename: Dawen
authors.initials: D
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Sheila
authors.initials: S
authors.lastname: Alcantara
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Li
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Mason
authors.forename: Eva Y-H P
authors.initials: EY
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival; D018450:Disease Progression; D005260:Female; D016514:Genes, Neurofibromatosis 1; D016158:Genes, p53; D019656:Loss of Heterozygosity / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D013234:Stem Cells / Q000502:physiology
chemical_list: D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse