| Angiogenesis, the formation of new blood vessels from preexisting ones, is tightly controlled under physiological conditions, and deregulated angiogenesis contributes to many pathological situations. This study investigates the role of PI3K/Akt pathway in both physiological and pathological angiogenesis. Angiopoietin-1 (Ang1) is an endothelial specific growth factor that plays a critical role in vessel maturation and stabilization during angiogenesis. We found that Ang1 potently induced p70S6K1 activation in human umbilical vein endothelial cells (HUVECs). p70S6K1 is a downstream target of PI3K, but its role in angiogenesis has not be defined. In the work shown in Chapter 2, p70S6K1 activity in HUVECs was modified by adenovirus-mediated gene transfer, and we provided first evidence that p70S6K1 is directly involved in Ang1-induced angiogenic endothelial responses, including cell migration, invasion, survival, and capillary morphogenesis. We also examined the effect and mechanisms of action of insulin-like growth factor-I (IGF-I) on the expression of cyclooxygenase-2 (COX-2), which is a crucial player in angiogenesis and tumorigenesis. In Chapter 3, we showed that IGF-I efficiently upregulated COX-2 expression in human ovarian cancer cells, which was differentially regulated by PI3K, MAPK, and PKC signaling pathways at transcriptional and/or post-transcriptional levels. In the study shown in Chapter 4, we selectively modulated PI3K/Akt signaling in either human microvascular endothelial cells or cancer cells, and examined the effects on tumor angiogenesis using a chimeric tumor model. We found that PI3K and Akt activities in both endothelial cells and tumor cells contributed to tumor growth and angiogenesis, suggesting that targeting PI3K/Akt signaling in both cellular compartments may be more effective for anti-cancer therapy. In Chapter 5, we demonstrated that resveratrol has a strong inhibitory effects on hypoxiainducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression in human ovarian cancer cells. The effects are associated with suppression of PI3K/Akt and MAPK pathways, interference with protein translational machinery, and enhancement of HIF-1alpha protein degradation through the proteasome. This work provides a better understanding of the molecular basis of angiogenesis, which we hope may facilitate the identification of novel therapeutic targets in the future. |
