PEDF: a potential molecular therapeutic target with multiple anti-cancer activities.

Pigment epithelium-derived factor (PEDF) is an endogenously produced protein that is widely expressed throughout the human body, and exhibits multiple and varied biological activities. Already established as a potent anti-angiogenic molecule, PEDF has recently shown promise as a potential anti-tumour agent, causing both direct and indirect tumour suppression. Here, we explore the unique anti-tumour properties of PEDF and discuss its role as an effective anti-angiogenic, anti-proliferative and pro-differentiation factor. We also discuss the prospects for PEDF therapy and the need for a closer evaluation of issues such as delivery, stability and potential toxicity.

[1]  H. Shimizu,et al.  Overexpression of pigment epithelium-derived factor decreases angiogenesis and inhibits the growth of human malignant melanoma cells in vivo. , 2004, The American journal of pathology.

[2]  E. Alberdi,et al.  Pigment epithelium-derived factor (PEDF) binds to glycosaminoglycans: analysis of the binding site. , 1998, Biochemistry.

[3]  Marta García,et al.  Inhibition of Xenografted Human Melanoma Growth and Prevention of Metastasis Development by Dual Antiangiogenic/Antitumor Activities of Pigment Epithelium-Derived Factor , 2004, Cancer Research.

[4]  A. Vincent,et al.  Identification of the Neuroprotective Molecular Region of Pigment Epithelium-Derived Factor and Its Binding Sites on Motor Neurons , 2002, The Journal of Neuroscience.

[5]  H. Yamashita,et al.  Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor are related to diabetic macular edema. , 2006, Ophthalmology.

[6]  F. McCormick,et al.  Killing time for cancer cells , 2005, Nature Reviews Cancer.

[7]  RPGR: part one of the X-linked retinitis pigmentosa story. , 1996, Molecular vision.

[8]  R. Kuncl,et al.  Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. , 1999, Journal of neuropathology and experimental neurology.

[9]  N. Bouck.  PEDF: anti-angiogenic guardian of ocular function. , 2002, Trends in molecular medicine.

[10]  Christina Meyer,et al.  Mapping the Type I Collagen-binding Site on Pigment Epithelium-derived Factor , 2002, The Journal of Biological Chemistry.

[11]  H. Kourai,et al.  Dual-site recognition of different extracellular matrix components by anti-angiogenic/neurotrophic serpin, PEDF. , 2003, Biochemistry.

[12]  C. Barnstable,et al.  Regulation of factors controlling angiogenesis in liver development: a role for PEDF in the formation and maintenance of normal vasculature. , 2004, Biochemical and biophysical research communications.

[13]  R. Kuncl,et al.  Pigment epithelium‐derived factor is elevated in CSF of patients with amyotrophic lateral sclerosis , 2002, Journal of neurochemistry.

[14]  C. Barnstable,et al.  A PEDF N-terminal peptide protects the retina from ischemic injury when delivered in PLGA nanospheres. , 2006, Experimental eye research.

[15]  S. Crawford,et al.  Wilms' tumor growth is suppressed by antiangiogenic pigment epithelium-derived factor in a xenograft model. , 2003, Journal of pediatric surgery.

[16]  W. Benedict,et al.  Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. , 1999, Science.

[17]  A. Jimeno,et al.  Multitargeted therapy: can promiscuity be praised in an era of political correctness? , 2006, Critical reviews in oncology/hematology.

[18]  N. Bouck,et al.  Pigment epithelium–derived factor regulates the vasculature and mass of the prostate and pancreas , 2003, Nature Medicine.

[19]  N Jo,et al.  Upregulation of pigment epithelium-derived factor after laser photocoagulation. , 2001, American journal of ophthalmology.

[20]  J. Tombran-Tink,et al.  Neuronal differentiation of retinoblastoma cells induced by medium conditioned by human RPE cells. , 1989, Investigative ophthalmology & visual science.

[21]  O. Volpert,et al.  Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. , 2002, American journal of ophthalmology.

[22]  I. Fariñas,et al.  Pigment epithelium–derived factor is a niche signal for neural stem cell renewal , 2006, Nature Neuroscience.

[23]  P. Choong,et al.  Resistance of Epiphyseal Cartilage to Invasion by Osteosarcoma Is Likely to Be Due to Expression of Antiangiogenic Factors , 2003, Pathobiology.

[24]  R. Mansel,et al.  Down-regulation of PEDF expression by ribozyme transgene in endothelial and lung cancer cells and its impact on angiogenesis in vitro. , 2005, Oncology reports.

[25]  R. Mott,et al.  Pigment epithelium‐derived factor (PEDF) is an endogenous antiinflammatory factor , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  A. Martínez,et al.  Evidence for pigment epithelium-derived factor receptors in the neural retina. , 2001, Investigative ophthalmology & visual science.

[27]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[28]  G. Chader,et al.  Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  B. Su,et al.  Loss of pigment epithelium derived factor expression in glioma progression , 2003, Journal of clinical pathology.

[30]  Emelyn H. Shroff,et al.  Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. , 2005, Cancer research.

[31]  J. P. Schwartz,et al.  Pigment epithelium‐derived factor induces the production of chemokines by rat microglia , 2005, Glia.

[32]  W. Jiang,et al.  Pigment Epithelium-derived Factor Inhibits Angiogenesis via Regulated Intracellular Proteolysis of Vascular Endothelial Growth Factor Receptor 1* , 2006, Journal of Biological Chemistry.

[33]  P. Stattin,et al.  Decreased Pigment Epithelium-Derived Factor Is Associated with Metastatic Phenotype in Human and Rat Prostate Tumors , 2004, Cancer Research.

[34]  E. Alberdi,et al.  Binding of Pigment Epithelium-derived Factor (PEDF) to Retinoblastoma Cells and Cerebellar Granule Neurons , 1999, The Journal of Biological Chemistry.

[35]  Raymond P Perez,et al.  New targets and challenges in the molecular therapeutics of cancer. , 2006, British journal of clinical pharmacology.

[36]  Y. Tsao,et al.  Pigment epithelium-derived factor inhibits oxidative stress-induced cell death by activation of extracellular signal-regulated kinases in cultured retinal pigment epithelial cells. , 2006, Life sciences.

[37]  O. Volpert,et al.  Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium–derived factor , 2002, Nature Medicine.

[38]  S. Becerra.  Focus on Molecules: Pigment epithelium-derived factor (PEDF). , 2006, Experimental eye research.

[39]  J. Sebolt-Leopold,et al.  Mechanisms of drug inhibition of signalling molecules , 2006, Nature.

[40]  Douglas M Sidle,et al.  Altered pigment epithelium-derived factor and vascular endothelial growth factor levels in lymphangioma pathogenesis and clinical recurrence. , 2005, Archives of otolaryngology--head & neck surgery.

[41]  C. Barnstable,et al.  PEDF: a multifaceted neurotrophic factor , 2003, Nature Reviews Neuroscience.

[42]  S. Okushiba,et al.  Expression of Pigment Epithelium-Derived Factor Decreases Liver Metastasis and Correlates with Favorable Prognosis for Patients with Ductal Pancreatic Adenocarcinoma , 2004, Cancer Research.

[43]  S. Kondo,et al.  Pigment Epithelium–Derived Factor Gene Therapy Inhibits Human Pancreatic Cancer in Mice , 2005, Clinical Cancer Research.

[44]  R. Mansel,et al.  Expression of pigment epithelial derived factor is reduced in non-small cell lung cancer and is linked to clinical outcome. , 2006, International journal of molecular medicine.

[45]  T. Imaizumi,et al.  Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: a novel anti-oxidative mechanism of PEDF , 2005, Cell and Tissue Research.

[46]  J. Tombran-Tink,et al.  PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. , 1991, Experimental eye research.

[47]  A. Davidoff,et al.  Adeno-associated virus vector-mediated delivery of pigment epithelium-derived factor restricts neuroblastoma angiogenesis and growth. , 2005, Journal of pediatric surgery.

[48]  I. Rodriguez,et al.  Organization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium-derived factor, a unique neurotrophic serpin. , 1996, Molecular vision.

[49]  J. Folkman.  Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[50]  E. T. Ek,et al.  The role of high-dose therapy and autologous stem cell transplantation for pediatric bone and soft tissue sarcomas , 2006, Expert review of anticancer therapy.

[51]  P. Choong,et al.  Localization of Pigment Epithelium-Derived Factor in Growing Mouse Bone , 2005, Calcified Tissue International.

[52]  T. Imaizumi,et al.  Pigment epithelium-derived factor (PEDF)-induced apoptosis and inhibition of vascular endothelial growth factor (VEGF) expression in MG63 human osteosarcoma cells. , 2005, Life sciences.

[53]  I. Morita,et al.  Involvement of the collagen I-binding motif in the anti-angiogenic activity of pigment epithelium-derived factor. , 2005, Biochemical and biophysical research communications.

[54]  O. Volpert,et al.  Pigment epithelium-derived factor (PEDF) in neuroblastoma: a multifunctional mediator of Schwann cell antitumor activity. , 2001, Journal of cell science.