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.


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.


CONCLUSIONS
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.
Reikvam
Håkon
H
University of Bergen, Institute of Internal Medicine, Division of Haematology, Bergen, Norway.
Hatfield
Kimberley Joanne
KJ
Lassalle
Philippe
P
Kittang
Astrid Olsnes
AO
Ersvaer
Elisabeth
E
Bruserud
Øystein
Ø
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042683:Angiopoietin-1 / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000378:metabolism / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000906:Antibodies; D001897:Boronic Acids; C101134:ESM1 protein, human; D007093:Imidazoles; D016209:Interleukin-8; D009363:Neoplasm Proteins; D011509:Proteoglycans; D011719:Pyrazines; D011810:Quinoxalines; D017228:Hepatocyte Growth Factor; D000069286:Bortezomib; D042787:Receptor, TIE-2