Class 1A PI3K regulates vessel integrity during development and tumorigenesis.
PI3K is important in the regulation of growth, proliferation, and survival of tumor cells. We show that class 1A PI3K is also critical in the tumor microenvironment by regulating the integrity of the tumor vasculature. Using Tie2Cre-mediated deletion of the PI3K regulatory subunits (p85alpha, p55alpha, p50alpha, and p85beta), we generated mice with endothelial cell-specific loss of class 1A PI3K. Complete loss of all subunits caused acute embryonic lethality at E11.5 due to hemorrhaging, whereas retention of a single p85alpha allele yielded viable mice that survived to adulthood. These heterozygous mice exhibited no vascular defects until challenged with a pathological insult, such as tumor cells or high levels of VEGF. Under these pathological conditions, heterozygous mice exhibited localized vascular abnormalities, including vessel leakage and the inability to maintain large vessels, which caused a deceleration of tumorigenesis. Furthermore, we show that a PI3K inhibitor can mimic the effects of class 1A PI3K loss, which suggests that targeting class 1A PI3K may be a promising therapy for blocking tumor angiogenesis.
Yuan
Tina L
TL
Departments of Systems Biology and Genetics, Harvard Medical School, Boston, MA 02115, USA.
Choi
Hak Soo
HS
Matsui
Aya
A
Benes
Cyril
C
Lifshits
Eugene
E
Luo
Ji
J
Frangioni
John V
JV
Cantley
Lewis C
LC
D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000473:pathology; D002199:Capillary Permeability; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D006579:Heterozygote; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D021122:Protein Subunits
D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases