Objective: Hypoxia is known to be a prevalent stress stimulus and increases the transcription of vascular endothelial growth factor (VEGF) mediated by hypoxia inducible factor-1alpha (HIF-1alpha). We investigated the role of phosphatidyl inositol-3 OH kinase (PI3K)-Akt signaling in the regulation of HIF-1alpha and VEGF expression in human gastric adenocarcinoma.
Methods: The growth-inhibitory and apoptosis-inducing effects of the LY294002 PI3K inhibitor were analyzed in four gastric cancer cell lines and in vivo. The regulatory mechanism of VEGF and HIF-1alpha expression under hypoxic conditions was examined in the cell cultures. In 88 gastric cancer tissue samples, phosphorylated Akt and VEGF expression were analyzed immunohistochemically.
Results: LY294002 suppressed cell proliferation but induced apoptosis with decreased levels of phosphorylated Akt. HIF-1alpha expression and VEGF secretion were induced under hypoxic conditions and VEGF protein secretion was significantly decreased by treatment with LY294002. In tumor samples, phosphorylated Akt expression was detected in 57% of the tumors, which was correlated with high VEGF expression, angiogenesis, clinicopathological parameters as well as a poor outcome.
Conclusions: These findings suggest that phosphorylated Akt (Ser473) reflects the grade of malignancy in human gastric adenocarcinomas, not only in terms of tumor growth but also with respect to tumor angiogenesis.