Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: release profile and pharmacological modulation.
OBJECTIVE
Angiogenesis seems important for both leukemogenesis and chemosensitivity in acute myelogenous leukemia (AML). Angiogenesis is regulated by the balance between pro- and antiangiogenic cytokines, which also indicates an important role of matrix metalloproteases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteases (TIMPs). We investigated the constitutive release of MMPs and TIMPs for a large group of consecutive AML patients.


METHODS
AML cells were cultured in vitro either alone or together with microvascular endothelial cells, and levels of MMPs and TIMPs were determined in culture supernatants.


RESULTS
AML cells showed constitutive release of several MMPs and TIMPs. For all patients, detectable MMP-10 release was observed, and most patients showed detectable release of at least one additional MMP, usually MMP-9 or MMP-2. A significant correlation was found between MMP-9 and TIMP-1 release and the release of several CCL and CXCL chemokines. MMP-9 release was higher for AML cells with monocytic differentiation corresponding to the FAB-subtype M4/M5 AML; it was mainly released in its inactive form, but endogenously active MMP-9 could be detected even in the presence of the constitutively released TIMP-1/2. Endothelial cells released relatively high levels of MMP-10, and these levels were further increased by coculture with AML cells. Patients achieving complete hematological remission after only one induction cycle showed relatively low constitutive MMP-2 release.


CONCLUSIONS
We conclude that primary human AML cells show constitutive release of both MMPs and TIMPs, and this release may be important for leukemogenesis and possibly also for chemosensitivity.
Reikvam
Håkon
H
Institute of Internal Medicine, Division for Hematology, University of Bergen, Bergen, Norway.
Hatfield
Kimberley J
KJ
Oyan
Anne M
AM
Kalland
Karl H
KH
Kittang
Astrid O
AO
Bruserud
Oystein
O
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000494:pharmacology; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002478:Cells, Cultured / Q000166:cytology; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003561:Cytarabine / Q000008:administration & dosage; D004224:Diterpenes / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000378:metabolism
C486592:3-ingenyl angelate; C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D042702:Angiopoietin-2; D018943:Anthracyclines; D001897:Boronic Acids; D018925:Chemokines; D016895:Culture Media, Serum-Free; D004224:Diterpenes; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D011810:Quinoxalines; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D003561:Cytarabine; D000069286:Bortezomib; D042787:Receptor, TIE-2; D020782:Matrix Metalloproteinases