title: Angiogenesis and angiogenic tyrosine kinase receptor expression in pediatric brain tumors.
abstract: Tumor angiogenesis and receptor tyrosine kinases (RTK) are major novel targets in anticancer molecular therapy. Accordingly, we characterized the vascular network and the expression pattern of angiogenic RTK in the most frequent pediatric brain tumors. In a retrospective collection of 44 cases (14 astrocytoma, 16 ependymoma and 14 medulloblastoma), immunohistochemistry for VEGFR1, VEGFR2, PDGFRα, PDGFRβ, and c-Kit as well as microvessel labeling with CD34 and SMA were conducted on surgical specimens. We found a significantly higher vascular density in ependymoma. Glomeruloid formations were abundant in medulloblastoma but rare or almost absent in astrocytoma and ependymoma, respectively. C-Kit and VEGFR2 labeled blood vessels were more abundant in ependymoma than in the other two types of tumors. In contrast, medulloblastoma contained higher number of PDGFRα expressing vessels. In tumor cells, we found no VEGFR2 but VEGFR1 expression in all three tumor types. PDGFRα was strongly expressed on the tumor cells in all three malignancies, while PDGFRβ tumor cell expression was present in the majority of medulloblastoma cases. Interestingly, small populations of c-Kit expressing cancer cells were found in a number of medulloblastoma and ependymoma cases. Our study suggests that different angiogenic mechanisms are present in ependymoma and medulloblastoma. Furthermore ependymoma patients may benefit from anti-angiogenic therapies based on the high vascularization as well as the endothelial expression of c-kit and VEGFR2. The expression pattern of the receptors on tumor cells also suggests the targeting of specific angiogenic tyrosine kinase receptors may have direct antitumor activity. Further preclinical and biomarker driven clinical investigations are needed to establish the application of tyrosine kinase inhibitors in the treatment of pediatric brain tumors.
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Virág
authors.forename: István
authors.initials: I
authors.lastname: Kenessey
authors.forename: Christine
authors.initials: C
authors.lastname: Haberler
authors.forename: Violetta
authors.initials: V
authors.lastname: Piurkó
authors.forename: Katalin
authors.initials: K
authors.lastname: Bálint
authors.forename: Balázs
authors.initials: B
authors.lastname: Döme
authors.forename: József
authors.initials: J
authors.lastname: Tímár
authors.forename: Miklós
authors.initials: M
authors.lastname: Garami
authors.forename: Balázs
authors.initials: B
authors.lastname: Hegedűs
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007223:Infant; D008297:Male; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D012189:Retrospective Studies; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000588866:KDR protein, human; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2