title: Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model.
abstract: Normal hepatocytes express pigment epithelium-derived factor (PEDF), an endogenous antiangiogenic factor. We hypothesized that decreased PEDF expression may be one mechanism driving hepatoblastoma growth, and in vivo gene transfer of PEDF could suppress neovascularization and limit tumor growth. PEDF functional activity was determined in vitro using endothelial cell migration assays and in vivo using a subcutaneous tumor model. HUH-6 human hepatoblastoma tumors were treated with hybrid adenoviral/adeno-associated viral expression vectors for PEDF (Hyb-PEDF, n = 4) or beta-galactosidase (Hyb-betagal, n = 4) daily for 4 d. Mitotic figures, microvascular density (MVD), PEDF, and VEGF expression were assessed. Hyb-PEDF treatment inhibited in vivo tumor growth (p < 0.008) and decreased MVD (p < 0.001), the number of mitotic figures (p < 0.001), and VEGF expression when compared with Hyb-betagal-treated tumors. HUH-6 expression of PEDF was dramatically reduced when cultured under hypoxic conditions and also when grown in vivo, and the addition of neutralizing anti-PEDF antibody increased the already high baseline angiogenic activity of the HUH-6 cell secretions in vitro (p < 0.04). PEDF is an important endogenous regulator of the liver vasculature. Augmenting intra-tumoral PEDF levels inhibits tumor growth by reducing angiogenesis and VEGF expression. Potent inhibitors of angiogenesis, such as PEDF, may be an effective alternative treatment for children with hepatoblastoma.
authors.affiliation: Department of Surgery, Children's Memorial Hospital, Chicago, Illinois 60614, USA.
authors.forename: Marybeth
authors.initials: M
authors.lastname: Browne
authors.forename: Veronica
authors.initials: V
authors.lastname: Stellmach
authors.forename: Mona
authors.initials: M
authors.lastname: Cornwell
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doll
authors.forename: Eun-Jig
authors.initials: EJ
authors.lastname: Lee
authors.forename: J Larry
authors.initials: JL
authors.lastname: Jameson
authors.forename: Marleta
authors.initials: M
authors.lastname: Reynolds
authors.forename: Riccardo A
authors.initials: RA
authors.lastname: Superina
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Abramson
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D018197:Hepatoblastoma / Q000628:therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000628:therapy*; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor