Pten haploinsufficiency accelerates formation of high-grade astrocytomas.
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.
Kwon
Chang-Hyuk
CH
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133, USA.
Zhao
Dawen
D
Chen
Jian
J
Alcantara
Sheila
S
Li
Yanjiao
Y
Burns
Dennis K
DK
Mason
Ralph P
RP
Lee
Eva Y-H P
EY
Wu
Hong
H
Parada
Luis F
LF
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
D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse