PI3K/AKT/PTEN pathway is important in the regulation of angiogenesis mediated by vascular endothelial growth factor in many tumors including leukemia. The signaling pathway is activated in leukemia patients as well as leukemia cell lines together with a decrease in the expression of PTEN gene. The mechanism by which the signaling pathway regulates angiogenesis remains to be further elucidated. However, it has become an attractive target for drug therapy against leukemia, because angiogenesis is a key process in malignant cell growth. In this paper, we will focus on the roles and mechanisms of PI3K/AKT/PTEN pathway in regulating angiogenesis. 1. Introduction Angiogenesis is the process by which new blood capillaries are generated from the preexisting blood vessels [1, 2]. Tumor angiogenesis is essential for tumor growth, invasion, and metastasis [3, 4]. This process can be triggered by a series of signal pathways including extracellular signals such as growth factors (Figure 1). It is a complex process that is also regulated by pro- and antiangiogenic factors. In other words, the angiogenesis and vasculature are regulated through the change of balance between the collective actions of proangiogenic factors such as vascular endothelial growth factor (VEGF) and angiogenic inhibitors such as thrombospondin-1(TSP-1). These factors can be derived from different sources such as stromal cells, extracellular matrix, and cancer cells. Their relative contribution is likely to be different according to the difference in tumor types. The interaction btween cancer cells and vascular endothelial cells in the tumor microenvironment affects the angiogenesis [5, 6]. Leukemia is an aggressive malignancy characterized by the accumulation of immature leukemia blasts in the bone marrow. Bone marrow angiogenesis is therefore important for both leukemogenesis, and the leukemic bone marrow shows increased microvascular density [7]. Figure 1: Schematic representation of PI3K/AKT/PTEN signaling. Examples of molecules known to act on angiogenesis via PI3K/AKT regulatory pathways are shown. VEGF and VEGF receptor (VEGFR) are major angiogenesis inducer associated with tumor angiogenesis in numerous solid or hematological malignancies. VEGF binds to VEGF receptor, which leads to the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. In addition to the PI3K/Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) play an important role as a molecular inhibitor of PI3K/Akt signaling in multiple cellular functions such as cell proliferation,
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