Caveolin-1-deficient mice have increased tumor microvascular permeability, angiogenesis, and growth.
Caveolin-1 (Cav-1) is a major structural protein that is essential to the formation of the organelle, caveolae. Cav-1 knockout (KO) mice were observed to be completely devoid of caveolae yet they exhibit a hyperpermeable vasculature. Given the nature of the hyperpermeable Cav-1 KO endothelium, we sought to investigate if tumors grown in Cav-1 KO mice would be leaky and grow faster. Indeed, Lewis lung carcinoma cells implanted into Cav-1 KO mice had increased tumor vascular permeability, measured by Evans blue extravasation and fibrinogen deposition compared with tumors implanted into wild-type (WT) mice. Cav-1 KO mice also had significantly higher tumor growth rates, attributable to increased tumor angiogenesis and decreased tumor cell death. Furthermore, administration of an antipermeability peptide, cavtratin, was able to correct the tumor hyperpermeability as well as attenuate the increased tumor growth. Mechanistically, endothelial cells isolated from Cav-1 KO mice exhibited increased tyrosine phosphorylation on vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and decreased association with the adherens junction protein, VE-cadherin. Thus, the loss of Cav-1 increases tumor permeability and growth and that may relate to enhanced VEGF signaling due to lack of Cav-1 inhibition of VEGFR-2 or decreased VE-cadherin mediated VEGFR-2 phosphorylation.
Lin
Michelle I
MI
Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University, New Haven, Connecticut 06536, USA.
Yu
Jun
J
Murata
Takahisa
T
Sessa
William C
WC
D022005:Adherens Junctions / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002199:Capillary Permeability; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000473:pathology; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D051242:Caveolin 1; D040301:Vascular Endothelial Growth Factor Receptor-2