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Pten Haploinsufficiency Accelerates Formation of High-Grade Astrocytomas

Departments of ¹ Developmental Biology, ² Radiology, and ³ Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; ⁴ Department of Developmental and Cell Biology, University of California, Irvine, California; and ⁵ Department of Molecular and Medical Pharmacology, University of California at Los Angeles David Geffen School of Medicine, Los Angeles, California

Requests for reprints: Luis F. Parada, Department of Developmental Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9133. Phone: 214-648-1822; Fax: 214-648-1960; E-mail: luis.parada{at}utsouthwestern.edu.

Key Words: Pten • Nf1 • p53 • neural stem cell • high-grade astrocytomas • mouse

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. [Cancer Res 2008;68(9):3286–94]