Expression of angiopoietin-1 in human glioblastomas regulates tumor-induced angiogenesis - In vivo and in vitro studies

To define a role for the angiopoietin/Tie2 system in astrocytoma angiogenes is, we examined the expression of angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) in these tumors by immunohistochemistry and in situ hybridization. F urthermore, we studied in vitro the effects elicited by glioblastoma cell-s ecreted Ang1 or by recombinant Ang1 on functions of endothelial cells (ECs) . Our observations of astrocytomas show that a stage-specific induction of angiopoietins occurs and is correlated with angiogenic phases of different intensity. Ang1 expression was found in a few astrocytes scattered in the t umor at all stages of astrocytoma progression. In blood vessels, Ang1 mRNA increased progressively in high-grade glioblastomas, in which the number of vessels was higher than in low-grade tumors. Ang2 was detected in tumor ce lls and in ECs in high-grade astrocytomas, whereas its expression was negli gible in low-grade tumors. Coculture of glioblastoma cell lines producing A ng1 with endothelium demonstrated a key role of this ligand in the control of EC network organization. We found that recombinant Ang1 in vitro induces EC spreading and reorganization of the cell monolayer into cordlike struct ures. These results suggest that Ang1 directly acts on ECs by modulating ce ll-cell and cell-matrix associations and promoting the differentiation phas e of angiogenesis.