Anti-angiogenic Barriers to Tumor Development

Summary

Principal Investigator: Susan Crawford
Abstract: Pigment epithelium-derived factor (PEDF) is a 50 kD secreted glycoprotein made by many cell types. It has been shown to be a potent inhibitor of pathologic angiogenesis by inducing endothelial cell apoptosis. We developed a mouse null for PEDF that spontaneously remodels the liver matrix, accumulates lipid, and demonstrates progressive fibrosis with increased vascularity. All animals develop dysplastic lesions or hepatocellular carcinoma (HCC). These changes were associated with activated hepatic stellate cells and increased levels of angiogenic inducers, VEGF, and leptin in the PEDF null liver. Moreover, a significant decrease in PEDF mRNA was evident when PPAR gamma was over-expressed in rodent livers and PEDF interacted with nuclear receptors suggesting that PEDF may be a new target gene for a hormone receptor family known to be important regulators of lipid metabolism. Preliminary testing of PEDF gene therapy in a xenograft rodent model appeared promising when hepatoma tumors were found to have markedly reduced levels of VEGF and increased tumor necrosis. These results led us to the hypothesis that loss of multifunctional PEDF in the liver triggers an imbalance in hepatocyte and stellate cell-derived extracellular factors, thus, promoting a highly angiogenic environment capable of supporting the growth of tumors. Using cultured hepatocytes, stellate cells and the PEDF null mouse model, we will explore changes in angiogenic activity, epithelial growth, and elucidate mechanisms by which tumor cells down-regulate PEDF. PEDF null mice will be crossed with leptin-deficient mice to better characterize the signaling pathways between PEDF, leptin, and VEGF. PEDF expression levels will be examined in human HCC to assess its utility as a tumor prognostic marker. Xenograft models of HCC will be treated with recombinant PEDF protein or with PEDF gene therapy to characterize the actions of PEDF on tumor growth. The interaction of PEDF and PPARgamma will be investigated by evaluating the functional activity of PPAR response elements in the PEDF gene and the nuclear signaling pathways explored. This proposed study has the potential to identify a novel signaling pathway in the pathogenesis of liver disease and it may validate PEDF gene therapy as a potent new agent to combat liver cancer.
Funding Period: ----------------1994 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model
    Marybeth Browne
    Department of Surgery, Children s Memorial Hospital, Chicago, Illinois 60614, USA
    Pediatr Res 60:282-7. 2006
  2. ncbi Pigment epithelium-derived factor targets endothelial and epithelial cells in Wilms' tumor
    Lisa P Abramson
    Division of Pediatric Surgery, Children s Memorial Hospital, Chicago, IL 60614, USA
    J Pediatr Surg 41:1351-6. 2006
  3. ncbi Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL)
    Chuhan Chung
    Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
    J Hepatol 48:471-8. 2008
  4. pmc Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-beta activation
    Philip P Fitchev
    Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA
    Lab Invest 90:1078-90. 2010
  5. ncbi Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice
    Paul J Grippo
    Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
    Gut 61:1454-64. 2012
  6. pmc FOXO3 growth inhibition of colonic cells is dependent on intraepithelial lipid droplet density
    Wentao Qi
    Department of Medicine, Division of Gastroenterology, NorthShore University HealthSystem Research Institute, Evanston, Illinois 60201, USA
    J Biol Chem 288:16274-81. 2013
  7. pmc Pigment epithelium-derived factor regulates early pancreatic fibrotic responses and suppresses the profibrotic cytokine thrombospondin-1
    John C Schmitz
    Section of Digestive Diseases, VA Connecticut Healthcare System, New Haven, Connecticut, USA
    Am J Pathol 179:2990-9. 2011

Detail Information

Publications7

  1. ncbi Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model
    Marybeth Browne
    Department of Surgery, Children s Memorial Hospital, Chicago, Illinois 60614, USA
    Pediatr Res 60:282-7. 2006
    ..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...
  2. ncbi Pigment epithelium-derived factor targets endothelial and epithelial cells in Wilms' tumor
    Lisa P Abramson
    Division of Pediatric Surgery, Children s Memorial Hospital, Chicago, IL 60614, USA
    J Pediatr Surg 41:1351-6. 2006
    ..We postulated that decreased levels of endogenous PEDF in the kidney creates a tumor permissive environment for Wilms' tumor...
  3. ncbi Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL)
    Chuhan Chung
    Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
    J Hepatol 48:471-8. 2008
    ..We postulated that hepatocyte triglyceride metabolism was dependent on interactions between PEDF and ATGL, and loss of PEDF would impair mobilization of triglycerides in the liver...
  4. pmc Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-beta activation
    Philip P Fitchev
    Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA
    Lab Invest 90:1078-90. 2010
    ..Therefore, loss of TSP-1 during tumorigenesis would eliminate two barriers to cancer progression...
  5. ncbi Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice
    Paul J Grippo
    Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
    Gut 61:1454-64. 2012
    ..Oncogenic Ras, the most common mutation in pancreatic ductal adenocarcinoma (PDAC), has similarly been shown to promote adipogenesis and premalignant lesions...
  6. pmc FOXO3 growth inhibition of colonic cells is dependent on intraepithelial lipid droplet density
    Wentao Qi
    Department of Medicine, Division of Gastroenterology, NorthShore University HealthSystem Research Institute, Evanston, Illinois 60201, USA
    J Biol Chem 288:16274-81. 2013
    ..Taken together, FOXO3 and LDs might serve as new targets for therapeutic intervention of colon cancer...
  7. pmc Pigment epithelium-derived factor regulates early pancreatic fibrotic responses and suppresses the profibrotic cytokine thrombospondin-1
    John C Schmitz
    Section of Digestive Diseases, VA Connecticut Healthcare System, New Haven, Connecticut, USA
    Am J Pathol 179:2990-9. 2011
    ..PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wild-type mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in pancreatitis...