Suppression of angiogenesis and tumor growth by adenoviral-mediated gene transfer of pigment epithelium-derived factor.
Pigment epithelium-derived factor (PEDF) was identified from retinal pigment epithelial cells and has been shown to display neurotrophic effects. In addition it has been found to induce a potent inhibition of angiogenesis. In this study we have explored whether overexpression of PEDF by a gene transfer approach can block tumor angiogenesis and reduce tumor growth. We found that cells infected with an adenovirus encoding PEDF under the control of the CMV promoter (AdPEDF) secreted PEDF protein into the medium that exhibited strong inhibitory effects on migration and tube formation of endothelial cells cultured in the presence of vascular endothelial growth factor. Moreover, the systemic administration of AdPEDF was able to inhibit angiogenesis in Matrigel assay in vivo, and treatment with this adenovirus of established hepatocellular carcinoma tumor in nude mice resulted in strong suppression of tumor growth. This anti-tumor effect could also be seen in a mouse lung carcinoma model by systemic administration of vector. In that model, treatment of tumor by intratumoral injection of AdPEDF also caused significant inhibition of tumor growth. The anti-tumor effect was related to a decrease in density of microvessels in tumors after treatment with AdPEDF. These data suggest that the antiangiogenic properties of PEDF can be exploited to inhibit the establishment of tumor neovasculature and reduce tumor growth.
Wang
Lin
L
Division of Hepatology and Gene Therapy, Department of Medicine, Pamplona, Spain.
Schmitz
Volker
V
Perez-Mediavilla
Alberto
A
Izal
Iñigo
I
Prieto
Jesus
J
Qian
Cheng
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004195:Disease Models, Animal; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000473:pathology; D005136:Eye Proteins; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008833:Microcirculation; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D009389:Neovascularization, Pathologic; D009414:Nerve Growth Factors; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D011509:Proteoglycans / Q000494:pharmacology; D015843:Serpins / Q000235:genetics*; D013997:Time Factors; D000099174:Pigment Epithelium-Derived Factor
D003094:Collagen; D004338:Drug Combinations; D005136:Eye Proteins; D007797:Laminin; D009414:Nerve Growth Factors; D011506:Proteins; D011509:Proteoglycans; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C059485:matrigel