PTEN controls tumor-induced angiogenesis

Mutations of the tumor suppressor PTEN, a phosphatase with specificity for 3-phosphorylated inositol phospholipids, accompany progression of brain tum ors from benign to the most malignant forms. Tumor progression, particularl y in aggressive and malignant tumors, is associated with the induction of a ngiogenesis, a process termed the angiogenic switch. Therefore, we tested w hether PTEN regulates tumor progression by modulating angiogenesis. U87MG g lioma cells stably reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model. We observed that the reconstituti on of wild-type PTEN had no effect on in vitro proliferation but dramatical ly decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these tumor cells. PTEN reconstitution diminished phosp horylation of AKT within the PTEN-reconstituted tumor, induced thrombospond in 1 expression, and suppressed angiogenic activity. These effects were not observed in tumors reconstituted with a lipid phosphatase inactive G129E m utant of PTEN, a result that provides evidence that the lipid phosphatase a ctivity of PTEN regulates the angiogenic response in vivo. These data provi de evidence that PTEN regulates tumor-induced angiogenesis and the progress ion of gliomas to a malignant phenotype via the regulation of phosphoinosit ide-dependent signals.