Regulation of the pathological vasculature of malignant astrocytomas by angiopoietin-1.
Malignant astrocytomas are the most common and highly vascularized of all primary adult brain tumors. The histopathological hallmarks of malignant astrocytomas are microvascular proliferation and formation of vascular entities, which are referred to as "glomeruloid bodies." The significance of glomeruloid bodies and the molecular mechanisms driving the abnormal vascular architecture in malignant astrocytomas are not understood. We have observed that overexpression of angiopoietin-1 (Ang1) in both subcutaneous and intracranial xenograft models of malignant astrocytomas reproduces many of the vascular features of these tumors, including glomeruloid bodies. To confirm that the formation of glomeruloid bodies was directly dependent on Ang1, we performed experiments where levels of Ang1 expression were regulated under tetracycline control, and we found a direct correlation between levels of Ang1 expression and the occurrence of glomeruloid bodies in xenografts. Additionally, we inhibited the action of Ang1 by blocking its cognate receptor Tie2, and we found that the formation of glomeruloid bodies was inhibited. Collectively, these results support our hypothesis that Ang1 is a key molecular regulator of pathological vascularization characteristic of malignant astrocytomas.
Zadeh
Gelareh
G
Arthur and Sonia Labatts Brain Tumor Center, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Reti
Rob
R
Koushan
Keyvan
K
Baoping
Qian
Q
Shannon
Patrick
P
Guha
Abhijit
A
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001254:Astrocytoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D011500:Protein Synthesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D042787:Receptor, TIE-2; D013752:Tetracycline