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Modeling Astrocytoma Pathogenesis In Vitro and In Vivo Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice
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A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an

S Fernández1, L Genis1, I Torres-Alemán1

  • 1Department Systems Neuroscience, Cajal Institute, CSIC, and CIBERNED, Madrid, Spain.

Oncogene
|September 24, 2013
PubMed

Insights

Mutations in PTEN (phosphatase and tensin homolog deleted on chromosome 10) can promote astrocyte tumors by activating growth pathways. A specific PTEN truncation acts as a tumor promoter, not a loss-of-function, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Loss-of-function mutations in PTEN (phosphatase and tensin homolog deleted on chromosome 10) are linked to abnormal cell growth via the IGF-1/PI3K/Akt pathway.
  • This pathway normally provides feedback regulation on PTEN, but its disruption contributes to tumor development.

Purpose of the Study:

  • To investigate the impact of mutual control between PTEN and the IGF-1/PI3K/Akt pathway on astrocyte growth.
  • To explore the functional consequences of PTEN C-terminal truncation (PTENΔ51), a region frequently altered in human gliomas.

Main Methods:

  • Mutagenesis analysis was employed to create and study PTEN variants.
  • NFκB activity, IGF-1 synthesis, Akt activation, and astrocyte proliferation were assessed.
  • In vitro colony formation and in vivo tumor generation assays were performed.

Main Results:

  • PTENΔ51 truncation exhibited neomorphic (gain-of-function) activity, independent of its phosphatase function.
  • This gain-of-function involved stimulating IGF-1 synthesis via protein kinase A activation of the IGF-1 promoter.
  • PTENΔ51 induced an autocrine loop, activating Akt and NFκB, leading to aberrant astrocyte growth, colony formation, and tumor development.

Conclusions:

  • PTEN mutations can convert this tumor suppressor into a tumor promoter through gain-of-function mechanisms.
  • The PTENΔ51-mediated IGF-1 production highlights a role for this growth factor in glioma progression.
  • Understanding this mechanism may identify druggable targets for personalized glioma therapy.

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