Chapter 2 PI3K/PTEN Signaling in Angiogenesis and Tumorigenesis

Abstract

Phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway play an important role in multiple cellular functions such as cell metabolism, proliferation, cell-cycle progression, and survival. PI3K is activated by growth factors and angiogenesis inducers such as vascular endothelial growth factor (VEGF) and angiopoietins. The amplification and mutations of PI3K and the loss of the tumor suppressor PTEN are common in various kinds of human solid tumors. The genetic alterations of upstream and downstream of PI3K signaling molecules such as receptor tyrosine kinases and AKT, respectively, are also frequently altered in human cancer. PI3K signaling regulates tumor growth and angiogenesis by activating AKT and other targets, and by inducing HIF-1 and VEGF expression. Angiogenesis is required for tumor growth and metastasis. In this review, we highlight the recent studies on the roles and mechanisms of PI3K and PTEN in regulating tumorigenesis and angiogenesis, and the roles of the downstream targets of PI3K for transmitting the signals. We also discuss the crosstalk of these signaling molecules and cellular events during tumor growth, metastasis, and tumor angiogenesis. Finally, we summarize the potential applications of PI3K, AKT, and mTOR inhibitors and their outcome in clinical trials for cancer treatment.

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

“…[14][15][16] NFκB induces EMT via regulation of the expression of multiple matrix proteases, adhesion molecules and both angiogenic and invasive factors. 14,[17][18][19][20][21] In contrast, inhibition of NFκB by various means suppresses EMT and inhibits tumor cell metastasis.…”

Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer

“…Therefore, PI3K/Akt has emerged as a key target for cancer treatment strategies [5] Activation of Akt1 is a multistep process initiated primarily through the binding of exogenous growth factors to receptors having intrinsic tyrosine-kinase activity. Such binding phosphorylates, and activates the intracellular tyrosine-kinasecontaining moiety of the receptor [6]. One of the several proteins recruited to and activated by the tyrosine phosphorylated growth factor receptor is PI3-kinase, which converts phosphatidyl inositol-4, 5-bisphosphate (PIP2) at the 3′ position of the inositol ring to PIP3, leading to recruitment of Akt1 via its pleckstrin homology (PH) domain to the plasma membrane.…”

From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas

“…[14][15][16] Both pathways have been implicated in tumorigenesis. 17,18 In our study, we will focus more specifically on PTEN gene alterations and protein expression in sarcomas with complex genomics, with emphasis on its consequences in activating downstream pathways.…”