Targeting the Angiopoietin (Ang)/Tie-2 Pathway in the Crosstalk Between Acute Myeloid Leukaemia and Endothelial Cells: Studies of Tie-2 Blocking Antibodies, Exogenous Ang-2 and Inhibition of Constitutive Agonistic Ang-1 Release

Background: The Tie-2 receptor can bind its agonistic ligand Angiopoietin-1 (Ang-1) and the potential antagonist Ang-2. Tie-2 can be expressed both by primary human acute myeloid leukaemia (AML) cells and endothelial cells, and Tie-2-blocking antibodies are now being evaluated in clinical trials for cancer treatment.

Design And Methods: We investigated the effects of Tie-2-blocking antibodies, exogenous Ang-2 and pharmacological agents on AML cell proliferation and the release of angioregulatory mediators.

Results: Tie-2-blocking antibodies had a growth inhibitory effect on human AML cells co-cultured with microvascular endothelial cells, but this inhibition was not observed when leukaemic cells were co-cultured with fibroblasts or osteoblasts. AML cell viability in co-cultures was not altered by anti-Tie-2. Furthermore, anti-Tie-2 decreased hepatocyte growth factor (HGF) levels and increased CXCL8 levels in co-cultures, whereas the levels of endocan (a proteoglycan released by endothelial cells) were not altered. The only significant effects of exogenous Ang-2 were decreased levels of HGF and endocan. Constitutive AML cell release of agonistic Ang-1 was decreased by the proteasomal inhibitor bortezomib and the specific IkappaB-kinase/NFkappaB inhibitor BMS-345541.

Conclusion: We conclude that various strategies for inhibition of Tie-2-mediated signalling should be considered in AML therapy, possibly in combination with other antiangiogenic strategies.