Modulation of the tumor vasculature functionality by ionizing radiation accounts for tumor radiosensitization and promotes gene delivery.
The ultimate goal of radiotherapy is to induce irreversible damages in genetically unstable, fast-growing cancer cells while minimizing the cytotoxic effects on host tissues. The satus of the tumor vasculature is particular because it is located within the tumor but mostly arises from host cells. The aim of this study was to characterize the effects of low-dose irradiation on the function of endothelial cells lining tumor vessels. Using isolated arterioles mounted on a pressure myograph, we first documented that the nitric oxide (NO)-mediated vasorelaxation that was defective in tumor vessels was completely restored following local tumor irradiation. Immunoblot analyses revealed that this was attributable to an increase in the abundance of the endothelial NO synthase while the expression of its physiological inhibitor, caveolin-1, was reduced. We further showed that the potentiation of the NO-dependent pathway induced a marked increase in tumor blood flow and oxygenation that determined the higher sensitivity of the tumor to further irradiation. Finally, we documented that the NO-mediated effects of irradiation on the tumor vasculature increased the delivery and expression of a reporter gene into the tumor. Thus, low-dose irradiation of endothelial cells within a tumor is a key determinant of the effectiveness of radiotherapy and may offer a new strategy to increase gene and/or drug delivery to the tumor.
Sonveaux
Pierre
P
University of Louvain Medical School, Pharmacology and Therapeutics Unit (FATH 5349), B-1200 Brussels, Belgium.
Dessy
Chantal
C
Brouet
Agnès
A
Jordan
Bénédicte F
BF
Grégoire
Vincent
V
Gallez
Bernard
B
Balligand
Jean-Luc
JL
Feron
Olivier
O
D000818:Animals; D001160:Arterioles / Q000503:physiopathology / Q000528:radiation effects; D001775:Blood Circulation / Q000528:radiation effects; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism / Q000528:radiation effects; D015316:Genetic Therapy; D008081:Liposomes; D051379:Mice; D008833:Microcirculation / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D018714:Radiotherapy, Adjuvant; D014162:Transfection; D014664:Vasodilation / Q000528:radiation effects
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D008081:Liposomes; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D010100:Oxygen