PTEN controls tumor-induced angiogenesis

Abstract

Mutations of the tumor suppressor PTEN, a phosphatase with specificity for 3-phosphorylated inositol phospholipids, accompany progression of brain tumors from benign to the most malignant forms. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of angiogenesis, a process termed the angiogenic switch. Therefore, we tested whether PTEN regulates tumor progression by modulating angiogenesis. U87MG glioma cells stably reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model. We observed that the reconstitution of wild-type PTEN had no effect on in vitro proliferation but dramatically decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these tumor cells. PTEN reconstitution diminished phosphorylation of AKT within the PTEN-reconstituted tumor, induced thrombospondin 1 expression, and suppressed angiogenic activity. These effects were not observed in tumors reconstituted with a lipid phosphatase inactive G129E mutant of PTEN, a result that provides evidence that the lipid phosphatase activity of PTEN regulates the angiogenic response in vivo. These data provide evidence that PTEN regulates tumor-induced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositide-dependent signals.

Functional roles of Akt signaling in mouse skin tumorigenesis

“…These functions might be associated with increased proliferation or decreased apoptosis of tumor cells (Furnari et al, 1998(Furnari et al, , 1997Paramio et al, 1999a). More recently, it has been shown that PTEN may also control the angiogenic switch (Wen et al, 2001). The elucidation of such mechanisms in mouse skin carcinogenesis requires further investigation.…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…Reintroduction of PTEN into the PTEN-deficient U87MG glioblastoma cell line caused dramatically decreased tumor growth when implanted subcutaneously into mice without having a significant effect on the proliferation of these cells in vitro. This study suggested that this was due to decreased recruitment of blood vessels to the tumor and showed that these cells had increased expression of a negative regulator of angiogenesis, thrombospondin 1 (Wen et al, 2001).…”

Gene Therapy Progress and Prospects: cancer gene therapy using tumour suppressor genes

“…In the presence of PTEN expression, in vivo growth is reduced, with marked reduction in angiogenic activity. 61 Even in the presence of proangiogenic signals such as constitutive EGFR activation and/or p53 inactivation, Ad PTEN delivery to glioma xenografts in mice produces a marked reduction in tumour vascularity. 62 Therefore, there may be a differential role for PTEN in different tumour types, reducing invasion and metastatic potential in some models and inhibiting tumour vascularization in others.…”