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. [Cancer Res 2008;68(9):3286-94]

Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats

“…Taken together, these results suggest that Pten is likely involved in tumorigenesis of BDII rat EAC. Similar conclusions regarding Pten functioning in a Endocrine-Related Cancer (2009) 16 99-111 www.endocrinology-journals.org haploinsufficient mode has been drawn in several other reports (Di Cristofano et al 1998, Kwabi-Addo et al 2001, Sjöling et al 2002, Kolasa et al 2006, Kwon et al 2008. Decreasing level of PTEN expression was shown to correlate with the progressive outcome of solid cancers, including ovarian, prostate, and cervical cancers (Harima et al 2001, Jiang & Liu 2008.…”

Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage

“…mTOR knockout mice (mTOR −/− mice) die in utero (21,22), and brainspecific deletion of the mTORC1 up-stream regulators Tsc1 or Pten results in death within the first postnatal weeks (15,23). Thus, the study of mTORC1 signaling in adult animals has been limited.…”

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

“…NF1 is a human glioblastoma suppressor gene-Although somatic mutations in NF1 have been reported in a small series of human GBM tumors 21, their role remains controversial 22, despite strong genetic data in mouse model systems 19,20. Here, 19 NF1 somatic mutations were identified in 13 samples (14% of 91), including six nonsense mutations, four splice site mutations, five missense changes, and four frameshift indels (Fig.…”