MT-MMPS as Regulators of Vessel Stability Associated with Angiogenesis

Abstract

The development of vascular system depends on the coordinated activity of a number of distinct families of molecules including growth factors and their receptors, cell adhesion molecules, extracellular matrix (ECM) molecules, and proteolytic enzymes. Matrix metalloproteases (MMPs) are a family of ECM degrading enzymes required for both physiological and pathological angiogenesis. Increasing evidence, point to a direct role of membrane type-MMPs (MT-MMPs) in vascular system stabilization, maturation, and leakage. Our understanding of the nature of MT-MMP interaction with extracellular and cell surface molecules and their multiple roles in vessel walls and perivascular stroma may provide new insights into mechanisms underlying vascular cell-ECM interactions and cell fate decisions in pathological conditions. Regulation of vascular leakage by MT-MMP interactions with the ECM could also lead to novel targeting opportunities for drug delivery in tumor. This review will shed lights on the emerging roles of MT1-MMP and MT4-MMP in vascular system alterations associated with cancer progression.

Keywords: MMPs; MT-MMPs; collagen; interstitial fluid pressure; vessel permeability.

Figure 1

Structure and substrate specificity of MT1-MMP and MT4-MMP. The structure of MT1-MMP and MT4-MMP share the identical domain organization of most MMPs, including a signal sequence (SS), propeptide domain (pro), a zinc-containing catalytic domain (catalytic) with 37 identity (50% similarity), a hing region, and a hemopexin like domain (hemopexin). In addition, MT1-MMP and MT4-MMP are anchored to the cell surface through a hydrophobic a transmembrane domain (TM) and a GPI anchor, respectively. Both the transmembrane MT1-MMP and the GPI–MT4-MMP contain proprotein convertase recognition RXR/KR motif in the propeptide domain and a hydrophilic region also called stem region at the end of hemopexin like domain. Whereas MT1-MMP exhibits activity against many ECM and non-ECM components both in vitro and in vivo, MT4-MMP was found in vitro to have a minimal or no activity against ECM molecules. The substrates of MT4-MMP in vivo are not yet identified.

Figure 2

Membrane type-MMPs regulate vascular cell signaling in cancer. MT1-MMP regulates cell migration through both ECM proteolysis and non-proteolytic-dependent TIMP-2 activation of ERK1/2 pathway. MT1-MMP regulates VEGF gene expression through Src, Akt, and mTOR activation and stimulates tumor angiogenesis. In addition, it induces RANKL shedding and signaling through Src leading to cell migration. MT1-MMP cooperates with platelet derived S1P to induce signaling through G protein-coupled-receptors (GPCRs) and regulates endothelial cell migration and tubulogenesis. MT1-MMP regulates TGFβ bioavailability and its signaling through ALK5 leading to vessel maturation. Shedding of Tie-2 or degradation of decorin by MT1-MMP stimulates angiogenesis, but shedding of endoglin from endothelial cell surface inhibits angiogenesis. ProTGFβ can also be activated by MMP2 and MMP9. MT1-MMP activates PDGFRβ signaling and regulates pericyte migration and vessel maturation. MT4-MMP a metastatic MMP, is highly expressed by cancer cells and induces tumor vessel destabilization through pericyte detachment.

Figure 3

Extracellular matrix (ECM) components regulate vascular permeability in tumor. Transport of fluids and macromolecules across the vessel wall can be regulated by both (1) paracellular diffusion through the apparition of openings between vascular cells and (2) transendothelial transport through vesiculo-vacuolar organelle (VVO) across the endothelium. Inhibition of ALK5 results in increased vascular leakage and increased bio-distribution of macromolecules within tumor. Collagen and fibroblast accumulation within tumor opposes to macromolecule penetration and reduces drug delivery. Collagen metabolism by collagenases results in increased vascular leakage and accumulation of macromolecules within tumors. Short inhibition of TGFβ signaling in vascular wall and control of the ECM metabolism in perivascular stroma could enhance drug delivery in solid tumors (EC, endothelial cell; BM, basement membrane).