Complementary effects of platelet-derived growth factor autocrine stimulation and p53 or Ink4a-Arf deletion in a
Göran Hesselager1, Lene Uhrbom, Bengt Westermark
1Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, SE-75185 Uppsala, Sweden. goran.hesselager@genpat.uu.se
Abstract:
INK4a-ARF and p53 inactivation are common but rarely concurrent findings in glioblastoma multiforme. Here we demonstrate that experimental deletion of either tumor suppressor gene cooperates with retrovirally expressed platelet-derived growth factor (PDGF)-B regarding both tumor latency and frequency in a mouse brain tumor model. We find indications of PTEN down-regulation and increased Akt phosphorylation in both types of null tumors (although more prominent in p53-/- tumors) suggesting a possible mechanism for this synergism. This is the first time that the cooperative tumorigenic effects of PDGF-B stimulation and p53 loss of function are demonstrated in an in vivo model, establishing a functional link between two common molecular changes of human secondary glioblastoma multiforme.
Insights
Loss of tumor suppressor genes INK4a-ARF or p53 accelerates glioblastoma development in mice when combined with platelet-derived growth factor (PDGF)-B. This study links common glioblastoma molecular changes in a novel in vivo model.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma multiforme frequently exhibits inactivation of INK4a-ARF and p53 tumor suppressor genes, but rarely concurrently.
- Platelet-derived growth factor (PDGF)-B signaling is implicated in various cancers, including glioblastoma.
Purpose of the Study:
- To investigate the cooperative effect of PDGF-B stimulation with the loss of either INK4a-ARF or p53 tumor suppressor genes in glioblastoma development.
- To establish a functional link between common molecular alterations in human secondary glioblastoma multiforme using an in vivo model.
Main Methods:
- Utilized a mouse brain tumor model.
- Experimentally deleted either the INK4a-ARF or p53 tumor suppressor gene.
- Expressed platelet-derived growth factor (PDGF)-B retrovirally.
- Analyzed tumor latency and frequency.
- Assessed PTEN down-regulation and Akt phosphorylation.
Main Results:
- Experimental deletion of INK4a-ARF or p53 cooperated with PDGF-B, reducing tumor latency and increasing tumor frequency.
- PTEN down-regulation and increased Akt phosphorylation were observed in both INK4a-ARF- and p53-deficient tumors, suggesting a synergistic mechanism.
- These effects were more pronounced in p53-deficient tumors.
Conclusions:
- Demonstrated the cooperative tumorigenic effects of PDGF-B stimulation and p53 loss of function in an in vivo model for the first time.
- Established a functional link between PDGF-B signaling and p53 inactivation, two common molecular changes in human secondary glioblastoma multiforme.
- Indicated a potential role for PTEN/Akt pathway alterations in mediating the observed synergism.
