title: Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2.
abstract: BACKGROUND
  Progression of retinoblastoma is associated with increased tumor angiogenesis. However, a clear relationship between the expression of angiogenic markers in specific regions of the tumor and tumor progression has not been established. This study investigates the association between angiogenic factors in retinoblastomas with choroidal and/or optic nerve invasion (high-risk/invasive retinoblastoma) and expression of Sox2, a stem cell marker.
  
  
  OBJECTIVE
  To investigate the association between the expression of angiogenic factors and markers of tumor invasiveness, such as the stem cell marker Sox2, in retinoblastoma tissues.
  
  
  METHODS
  Immunohistochemistry was used to evaluate coexpression of the angiogenic growth factors vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR-2), and endoglin (CD105); markers of glial differentiation (vimentin and glial fibrillary acidic protein); and a neural stem cell marker (Sox2). Expression was assessed in nonneoplastic and neoplastic ocular tissues collected from enucleated eyes of patients with retinoblastoma. During qualitative data interpretation, evaluating pathologists were masked to patient grouping.
  
  
  RESULTS
  Expression of VEGF-A and VEGFR-2 in noninvasive (non-high-risk feature) retinoblastoma tumors was lower than in the invasive, or high-risk feature tumors. Moreover, our data indicate that the tumor cells, and not the surrounding stroma, secrete VEGF-A and that angiogenesis is mostly localized to the iris. Finally, our data showed that the expression of the neural stem cell marker Sox2 is associated with eyes with increased VEGF-A expression and tumor invasiveness.
  
  
  CONCLUSIONS
  Increased expression of angiogenic factors, with a concomitant increase in expression of the stem cell marker Sox2 observed in retinoblastoma tissues, may partially explain the aggressiveness of these tumors. The complex interaction of angiogenic and stem cell-related pathways in these tumors, especially in high-risk feature retinoblastoma, suggests that targeting tumor cells capable of secreting vasculogenic factors, as well as proangiogenic genes and signaling pathways, may be necessary for development of effective antimetastatic retinoblastoma drugs.
authors.affiliation: From Escuela de Biotecnología y Alimentos and Escuela de Medicina y Ciencias de la Salud, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, México, and Houston Methodist Research Institute, Houston, Texas (Mr Garcia); the Department of Ophthalmology, University of Texas, MD Anderson Cancer Center, Houston, and Retinoblastoma Center of Houston, Houston, Texas (Dr Gombos); the Department of Ophthalmology, University Medical Center, Tucson, Arizona, and Houston Methodist Research Institute, Houston, Texas (Dr Prospero); MD Program, Baylor College of Medicine, Texas, and Houston Methodist Research Institute, Houston, Texas (Mr Ganapathy); the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Ms Penland); and Pathology and Laboratory Medicine and Ophthalmology, Weill Cornell Medical College of Cornell University, New York, New York, Departments of Pathology and Genomic Medicine and Ophthalmology, Houston Methodist Hospital, Houston, Texas, Retinoblastoma Center of Houston, Houston, Texas, and Houston Methodist Research Institute, Houston, Texas (Dr Chévez-Barrios).
authors.forename: Jesús R
authors.initials: JR
authors.lastname: Garcia
authors.forename: Dan S
authors.initials: DS
authors.lastname: Gombos
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Prospero
authors.forename: Aravindh
authors.initials: A
authors.lastname: Ganapathy
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Penland
authors.forename: Patricia
authors.initials: P
authors.lastname: Chévez-Barrios
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D002829:Choroid / Q000378:metabolism / Q000473:pathology; D000071063:Endoglin; D015353:Eye Enucleation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D011956:Receptors, Cell Surface / Q000378:metabolism; D019572:Retinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D012175:Retinoblastoma / Q000378:metabolism* / Q000473:pathology; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D015703:Antigens, CD; D015415:Biomarkers; C064206:ENG protein, human; D000071063:Endoglin; D005904:Glial Fibrillary Acidic Protein; D011956:Receptors, Cell Surface; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014746:Vimentin; D040301:Vascular Endothelial Growth Factor Receptor-2