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Angiotensinogen Delays Angiogenesis and Tumor Growth of Hepatocarcinoma in Transgenic Mice

¹ Chaire de Médecine Expérimentale, INSERM U833, Collège de France; ² Cardiovascular Research Center, INSERM U689 and ³ Institut des Vaisseaux et du Sang, Hôpital Lariboisière, Paris 7-Denis Diderot, Paris, France and ⁴ Service d'Explorations Fonctionnelles Physiologiques, Centre Hospitalier Universitaire Dupuytren, Limoges, France

Requests for reprints: François Vincent, Collège de France, Laboratoire de Médecine Expérimentale, INSERM U833-11 place Marcelin Berthelot, 75005 Paris, France. Phone: 33-14427-1653; Fax: 33-14427-1691; E-mail: francois.vincent{at}college-de-france.fr.

Key Words: angiotensinogen • angiogenesis • tumor vascular remodeling • hepatocellular carcinoma • transgenic mice

Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo. [Cancer Res 2009;69(7):2853–60]