Upregulation of endoglin (CD105) expression during childhood brain tumor-related angiogenesis. Anti-angiogenic therapy.
During postnatal development, the formation of new blood vessels is possible only through angiogenesis. The initial growth of solid neoplasms, including childhood brain tumors, during the genetically determined stages of carcinogenesis, even at clinically undetectable sizes (a few mm3), depends upon the continuous formation of new blood capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a malignant, invasive cellular immunophenotype (CIP) and distant metastases are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during brain tumor related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded (3-5 microns thick), as well as frozen tissue sections (6 microns thick) of 62 childhood brain tumors [34 medulloblastomas (MEDs) and 28 astrocytomas (ASTRs)], were employed for the assessment of EDG expression. Both an indirect, four-step, alkaline phosphatase (AP) conjugated, biotin-streptavidin based (or a diamino-benzidine [DAB]) conjugated immunoperoxidase antigen detection technique were employed, utilizing the SN6h anti-EDG monoclonal antibody (DAKO Corp.). Another antigen detection method, based on the Histogold (Zymed) reaction was also employed using the same antibody on formalin fixed, paraffin-wax embedded tissues. Strong expression (A; +3 to +4) of EDG on endothelial cells and demonstrated in all 62 childhood brain tumor cases. The most striking feature of the newly formed tumor-related capillaries was the presence of a markedly enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. A close apposition between the capillaries and the adjacent parenchyma was also observed. Brain tumors, especially glioblastoma, are among the most vascularized human neoplasms, and thus are candidates for antiangiogenic therapy. VEGF/PF-R1 (flt-1) and VEGF/PF-R2 (flk-1) are formed de novo in a glioma progression-dependent manner. Further studies should substantiate the importance of EDG in the earliest possible detection, diagnosis and NRA inhibition-based treatment of mammalian solid neoplasms, especially childhood brain tumors.
Department of Pathology, School of Medicine, University of Southern California, Los Angeles, USA.
B
B
Bodey
B
B
Bodey
S E
SE
Siegel
H E
HE
Kaiser
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001254:Astrocytoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D002648:Child; D019281:Dimerization; D000071063:Endoglin; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008527:Medulloblastoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D018242:Neuroectodermal Tumors, Primitive / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1