Suppression of angiogenesis, tumor growth, and metastasis by adenovirus-mediated gene transfer of human angiotensinogen.
Angiogenesis is essential for tumor growth and metastatic dissemination. We have previously shown that human angiotensinogen (AGT) can in vitro inhibit endothelial cell proliferation and migration, capillary-like tube formation, and neovascularization. To determine whether AGT can exert an antitumoral effect through its antiangiogenic properties, we constructed a recombinant adenovirus carrying the human angiotensinogen gene under the control of the cytomegalovirus promoter (AdAGT). In vitro studies showed that AdAGT selectively inhibited endothelial cell proliferation. In vivo, injections of AdAGT into preestablished human MDA-MB-231 mammary carcinomas in nude mice inhibited tumor growth by 70% compared to controls, with 21% total regression. This effect was associated with the suppression of intratumoral vascularization and marked necrosis. Furthermore, in vitroAdAGT infection of MDA-MB-231 and murine melanoma B16F10 cells strongly blocked their in vivo tumorigenicity. Then, in mice expressing high levels of AGT (i.e., either iv injected with AdAGT or HuAGT transgenic mice), the number of B16F10 pulmonary metastases was 85% lower than in control C57BL/6 mice. Our data demonstrate that AGT is a very potent antiangiogenic factor in vivo, independent of angiotensin II generation. Its delivery by gene transfer represents a promising new strategy to block primary tumor growth and to prevent metastasis.
Bouquet
Céline
C
CNRS UMR8121 Univ Paris Sud Vectorologie et Transfert de Gènes, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France. bouquet@igr.fr
Lamandé
Noël
N
Brand
Marcus
M
Gasc
Jean-Marie
JM
Jullienne
Betsy
B
Faure
Gabrielle
G
Griscelli
Franck
F
Opolon
Paule
P
Connault
Elisabeth
E
Perricaudet
Michel
M
Corvol
Pierre
P
D000256:Adenoviridae / Q000235:genetics*; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000628:therapy*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy*; D014183:Transplantation, Heterologous
D000808:Angiotensinogen