Somatic induction of Pten loss in a preclinical astrocytoma model reveals major roles in disease progression and avenues for target discovery and validation

Andrew Xiao, Chaoying Yin, Chunyu Yang, Antonio Di Cristofano, Pier Paolo Pandolfi, Terry Van Dyke

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

High-grade astrocytomas are invariably deadly and minimally responsive to therapy. Pten is frequently mutated in aggressive astrocytoma but not in low-grade astrocytoma. However, the Pten astrocytoma suppression mechanisms are unknown. Here we introduced conditional null alleles of Pten (Pten loxp/loxp) into a genetically engineered mouse astrocytoma model [TgG(ΔZ)T121] in which the pRb family proteins are inactivated specifically in astrocytes. Pten inactivation was induced by localized somatic retroviral (MSCV)-Cre delivery. Depletion of Pten function in adult astrocytoma cells alleviated the apoptosis evoked by pRb family protein inactivation and also induced tumor cell invasion. In primary astrocytes derived from TgG(ΔZ)T121; Ptenloxp/loxp mice, Pten deficiency resulted in a marked increase in cell invasiveness that was suppressed by inhibitors of protein kinase C (PKC) or of PKC-ζ, specifically. Finally, focal induction of Pten deficiency in vivo promoted angiogenesis in affected brains. Thus, we show that Pten deficiency in pRb-deficient astrocytoma cells contributes to tumor progression via multiple mechanisms, including suppression of apoptosis, increased cell invasion, and angiogenesis, all of which are hallmarks of high-grade astrocytoma. These studies not only provide mechanistic insight into the role of Pten in astrocytoma suppression but also describe a valuable animal model for preclinical testing that is coupled with a primary cell-based system for target discovery and drug screening.

Original languageEnglish (US)
Pages (from-to)5172-5180
Number of pages9
JournalCancer research
Volume65
Issue number12
DOIs
StatePublished - Jun 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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