Artikel
Implication of PTEN loss in the neoangiogenesis of cerebral cavernous malformations (CCMs)
Der Verlust von PTEN trägt zur Neoangiogenese von zerebralen Kavernomen bei
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Autoren
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Y. Zhu
- Klinik für Neurochirurgie, Universitätsklinikum Gießen und Marburg, Standort Marburg
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C. Peters
- Klinik für Neurochirurgie, Universitätsklinikum Gießen und Marburg, Standort Marburg
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M. Hallier-Nelsen
- Klinik für Neurochirurgie, Universitätsklinikum Gießen und Marburg, Standort Marburg
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M. Fass
- Klinik für Neurochirurgie, Universitätsklinikum Gießen und Marburg, Standort Marburg
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H. Bertalanffy
- Klinik für Neurochirurgie, Universitätsklinikum Gießen und Marburg, Standort Marburg
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U. Sure
- Klinik für Neurochirurgie, Universitätsklinikum Gießen und Marburg, Standort Marburg
| Veröffentlicht: | 11. April 2007 |
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Gliederung
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Objective: Increasing evidence shows growth and de novo formation of lesions in CCMs, which may relate to the abnormal angiogenetic bioactivity. However, the molecular mechanisms underlying the neoangiogenesis in CCM are poorly understood. PTEN, a tumor suppressor, is frequently mutated in various types of cancers. PTEN/PI3K/Akt pathway plays a crucial role in tumor- and hypoxia-induced angiogenesis. The present study aimed to identify whether PTEN is implicated in the angiogenesis of CCM.
Methods: To study the expression profile of PTEN, 78 cases of CCM patients were collected. Double immunostaining of PTEN/vWF, PTEN/PCNA and PTEN/HIF-1α was performed. The immunoreactivity of PTEN was scored as normal (+++/++) and low (+/-). To explore the role of PTEN in angiogenesis, PTEN was knocked down by siRNA in endothelial culture. PCNA protein expression was detected by Western blot. The proliferation of endothelial cells (ECs) was measured by Coulter Counter.
Results: Analysis of 3082 vessels in immunostained CCM brain tissues revealed a significantly high percentage of vessels expressing low PTEN (35%) in comparison with the controls (2%) (p<0.001). Interestingly, a significant higher numbers of vessels expressing low PTEN was found in multiple (44%) and in big lesions (<10 mm, 40%) in comparison to the single (27%, p<0.05) and small (<10 mm, 28%, p<0.01) lesions, respectively, suggesting an implication of PTEN loss in the progression of CCM. Double staining showed a negative correlation between PTEN expression and PCNA and HIF-1α. Furthermore, in vitro study demonstrated that knockdown of PTEN by siRNA significantly increased PCNA protein expression and the proliferation of ECs.
Conclusions: We demonstrated for the first time a significant loss of PTEN in intrinsic CCM vessels. Our in vitro results proved a crucial role of PTEN in the angiogenesis of ECs. These findings point out a novel angiogenesis mechanism in CCM progression.
