Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice.
Tumor vasculature is hyperpermeable to macromolecules compared to normal vasculature; however, the relationship between tumor hyperpermeability and tumor progression is poorly understood. Here we show that a cell-permeable peptide derived from caveolin-1, termed cavtratin, reduces microvascular hyperpermeability and delays tumor progression in mice. These antipermeability and antitumor actions of cavtratin occur in the absence of direct cytostatic or antiangiogenic effects. Cavtratin blocks microvascular permeability by inhibiting endothelial nitric oxide synthase (eNOS), as the antipermeability and antitumor actions of cavtratin are markedly diminished in eNOS knockout mice. Our results support the concepts that hyperpermeability of tumor blood vessels contributes to tumor progression and that blockade of eNOS may be exploited as a novel target for antitumor therapy.
Gratton
Jean Philippe
JP
Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Lin
Michelle I
MI
Yu
Jun
J
Weiss
Erik D
ED
Jiang
Zao Li
ZL
Fairchild
Todd A
TA
Iwakiri
Yasuko
Y
Groszmann
Roberto
R
Claffey
Kevin P
KP
Cheng
Yung Chi
YC
Sessa
William C
WC
D000818:Animals; D002199:Capillary Permeability; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D051242:Caveolin 1; D022461:Caveolins / Q000627:therapeutic use*; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010446:Peptide Fragments / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse