Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model

Marybeth Browne, Veronica Stellmach, Mona Cornwell, Chuhan Chung, Jennifer A. Doll, Eun Jig Lee, J. Larry Jameson, Marleta Reynolds, Riccardo A. Superina, Lisa P. Abramson, Susan E. Crawford*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 β-galactosidase (Hyb-βgal, 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-βgal-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.

Original languageEnglish (US)
Pages (from-to)282-287
Number of pages6
JournalPediatric Research
Volume60
Issue number3
DOIs
StatePublished - Sep 1 2006

Fingerprint

Hepatoblastoma
Heterografts
Growth
Genes
Neoplasms
Vascular Endothelial Growth Factor A
pigment epithelium-derived factor
Cell Migration Assays
Galactosidases
Angiogenesis Inhibitors

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Browne, Marybeth ; Stellmach, Veronica ; Cornwell, Mona ; Chung, Chuhan ; Doll, Jennifer A. ; Lee, Eun Jig ; Jameson, J. Larry ; Reynolds, Marleta ; Superina, Riccardo A. ; Abramson, Lisa P. ; Crawford, Susan E. / Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model. In: Pediatric Research. 2006 ; Vol. 60, No. 3. pp. 282-287.
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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 β-galactosidase (Hyb-βgal, 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-βgal-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.",
author = "Marybeth Browne and Veronica Stellmach and Mona Cornwell and Chuhan Chung and Doll, {Jennifer A.} and Lee, {Eun Jig} and Jameson, {J. Larry} and Marleta Reynolds and Superina, {Riccardo A.} and Abramson, {Lisa P.} and Crawford, {Susan E.}",
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Browne, M, Stellmach, V, Cornwell, M, Chung, C, Doll, JA, Lee, EJ, Jameson, JL, Reynolds, M, Superina, RA, Abramson, LP & Crawford, SE 2006, 'Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model', Pediatric Research, vol. 60, no. 3, pp. 282-287. https://doi.org/10.1203/01.pdr.0000232789.86632.91

Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model. / Browne, Marybeth; Stellmach, Veronica; Cornwell, Mona; Chung, Chuhan; Doll, Jennifer A.; Lee, Eun Jig; Jameson, J. Larry; Reynolds, Marleta; Superina, Riccardo A.; Abramson, Lisa P.; Crawford, Susan E.

In: Pediatric Research, Vol. 60, No. 3, 01.09.2006, p. 282-287.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model

AU - Browne, Marybeth

AU - Stellmach, Veronica

AU - Cornwell, Mona

AU - Chung, Chuhan

AU - Doll, Jennifer A.

AU - Lee, Eun Jig

AU - Jameson, J. Larry

AU - Reynolds, Marleta

AU - Superina, Riccardo A.

AU - Abramson, Lisa P.

AU - Crawford, Susan E.

PY - 2006/9/1

Y1 - 2006/9/1

N2 - 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 β-galactosidase (Hyb-βgal, 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-βgal-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.

AB - 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 β-galactosidase (Hyb-βgal, 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-βgal-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.

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