The Crosstalk Between the Matrix Metalloprotease System and the Chemokine Network in Acute Myeloid Leukemia
Abstract:Matrix metalloproteinases (MMPs) comprise a large family of zinc-dependent endopeptidases, which are best known for their ability to degrade essentially all components of the extracellular matrix (ECM). By breaking down ECM, MMPs may remove physical barriers, thus allowing cells to migrate and potentially invade other tissues. Recent evidence, however, shows that the proteolytic activities of MMPs also affect several fundamental physiological processes. Primary human acute myeloid leukemia (AML) cells often show constitutive release of several MMPs and chemokines, and there seems to be a crosstalk between the MMP system and the chemokine network. Firstly, the nuclear factor-B (NF-B) system represents a common regulator at the transcriptional level both for MMPs (e.g. MMP-1 and MMP-9) and for the constitutive release of several chemokines (CCL2-4/CXCL1/8) by primary human AML cells. Secondly, the crosstalk at the molecular level probably includes MMP-mediated structural alteration and activation of constitutively released chemokines involved in AML cell migration (e.g. CXCL12) and stimulation of bone marrow angiogenesis (e.g. CXCL8). Thirdly, at a functional level the two systems interact because the chemokine network plays a role in similar physiological processes as the MMPs, including AML cell proliferation and migration and local regulation of angiogenesis. Both the chemokine system and MMPs are currently being evaluated as targets in anti-angiogenesis/cancer therapy and may also have potential therapeutic implications in AML. This review introduces the different members of the MMP family and describes their interactions with the chemokine network and the possible involvement of MMPs together with chemokines in leukemogenesis and chemosensitivity in AML.
Keywords: 2-macroglobulin; Acute myelogenous leukemia; Matrix metalloproteinases (MMPs); Thrombospondin-1; acute myeloid leukemia (AML); all-trans retinoic acid; angiogenesis; anthracyclines; antiapoptotic signaling; autocrine manner; bone marrow microenvironment; chemokines; chemosensitivity; chemotactic cytokines; collagenases; cysteine-zinc interaction; cytotoxic agents; extracellular matrix (ECM); fibroblast growth factor (bFGF); gelatinases; hematologic malignancies; hematopoiesis; hematopoietic development; hematopoietic stem cells; hemorrhages; hyaluronan receptor; leukemogenesis; lipoprotein; matrilysins; matrix metalloproteases; mesenchymal cells; mitogen activated protein kinases (MAPK); myeloid cells; nuclear factor-B (NF-B); plasminogen; stromelysins; tissue inhibitor of MMPs; tissue inhibitors of matrix metalloproteases; transmembrane glycoprotein; tumor necrosis factor(TNF); vascular endothelial growth factor (VEGF)
Document Type: Research Article
Publication date: December 1, 2010
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