Authors: J. Hatfield, K.; Reikvam, H.; Bruserud, O.

Source: Current Medicinal Chemistry, Volume 17, Number 36, December 2010 , pp. 4448-4461(14)

Publisher: Bentham Science Publishers

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-κB (NF-κB) 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: Acute myelogenous leukemia; angiogenesis; bone marrow microenvironment; chemokines; chemosensitivity; matrix metalloproteases; tissue inhibitors of matrix metalloproteases; Matrix metalloproteinases (MMPs); extracellular matrix (ECM); acute myeloid leukemia (AML); nuclear factor-B (NF-B); angiogenesis; leukemogenesis; tissue inhibitor of MMPs; extracellular matrix (ECM); collagenases; gelatinases; stromelysins; matrilysins; mitogen activated protein kinases (MAPK); transmembrane glycoprotein; cysteine-zinc interaction; hyaluronan receptor; 2-macroglobulin; Thrombospondin-1; lipoprotein; chemotactic cytokines; hematopoietic development; mesenchymal cells; all-trans retinoic acid; tumor necrosis factor(TNF); hematologic malignancies; vascular endothelial growth factor (VEGF); fibroblast growth factor (bFGF); autocrine manner; hematopoietic stem cells; bone marrow microenvironment; myeloid cells; leukemogenesis; antiapoptotic signaling; plasminogen; hemorrhages; hematopoiesis; cytotoxic agents; anthracyclines

Document Type: Research article

DOI: http://dx.doi.org/10.2174/092986710794183033

Publication date: 2010-12-01

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• Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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