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MT-MMPS as Regulators of Vessel Stability Associated with Angiogenesis.

Sounni NE, Paye A, Host L, Noël A - Front Pharmacol (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, University of Liege Liège, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: We and others have previously demonstrated that MT1-MMP overexpression in cancer cells stimulates tumor angiogenesis in vivo through VEGF upregulation (Deryugina et al., 2002; Sounni et al., 2002, 2004; Deng et al., 2009). MT1-MMP regulation of VEGF expression is dependent on Src signaling and requires the proteolytic activity of MT1-MMP (Sounni et al., 2004). Recently, Eisenach et al. (2010) have provided a complete mechanism of VEGF regulation by MT1-MMP and Src signaling. This study demonstrates that MT1-MMP regulates VEGF through a complex with VEGFR-2 and Src, activation of Akt and mTOR signaling pathway. MT1-MMP activity and signaling through cytoplasmic domain are confirmed as required for transcriptional regulation of VEGF expression in cancer cells. MT1-MMP interaction with Src has also been investigated in several in vitro models of angiogenesis and cell migration (Labrecque et al., 2004; Ouyang et al., 2010; Sabbota et al., 2010). MT1-MMP-mediated Src activation has also been described during cell migration. Recently, Sabbota et al. (2010) reported that MT1-MMP induces receptor activator of NF-κB ligand (RANKL) shedding from prostate cancer cell surface and signaling through its receptor RANK and downstream Src activation and consequently stimulates cell migration. Src activation by MT1-MMP has also been linked with ERK1/2 activation in cell migration within 3D collagen gel (Takino et al., 2010). However, MT1-MMP can form a complex with TIMP2 at the cell surface that can stimulate cancer cell migration in a non-proteolytic manner. This non-proteolytic mechanism implicates the activation of MEK1/2-ERK1/2-p90RSK signaling cascade by the MT1-MMP/TIMP-2 complex (Sounni et al., 2010b). Beside its role in ECM remodeling, MT1-MMP promotes endothelial cell migration, lumen formation, and vascular guidance tunnels in collagen matrices (Stratman et al., 2009). The observation of Lehti et al. (2005) that Mt1-mmp−/− mice present a marked reduction in mural cell density and abnormal vessel morphology in brain, suggests that membrane-associated MMP acts as a cofactor in propagating signaling through vascular smooth muscle cells (VSMC). This study, demonstrates that MT1-MMP processing of PDGFR-β is required for PDBFB/PDGFR-β signaling in VSMC and migration in vitro. Moreover, MT1-MMP induces VSMC dedifferentiation and acquisition of migratory and invasive phenotype during vascular injury through low density lipoprotein (LDL) receptor-related protein (LRP) proteolysis that promotes signaling through PDGFB/PDGFR-β axis (Lehti et al., 2009). Indeed, MT1-MMP cooperates with platelet derived S1P to induce endothelial cell migration and morphogenic differentiation (Langlois et al., 2004). Furthermore, MT1-MMP regulates signaling of the advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis in the vasculature, a target known to play a key role in diabetic vascular complications (Kamioka et al., 2011). Interestingly, expression of MT1-MMP correlates with the clinical mobilization of human CD43+ cell in patient with lymphoid malignancies (Vagima et al., 2009). Of interest, MT1-MMP expression and its association with lipid rafts facilitates G-CSF-induced hematopoietic stem/progenitor cell (HSPC) mobilization in human and murine (Shirvaikar et al., 2010). The molecular mechanisms of MT1-MMP relay on CD44 cleavage, activation of pro-MMP2 and inactivation of SDF-1 that facilitates HSPC egress from the bone marrow into circulation (Shirvaikar et al., 2011). MT1-MMP signaling in cancer cells, pericytes, and endothelial cells are schematically illustrated in Figure 2.


MT-MMPS as Regulators of Vessel Stability Associated with Angiogenesis.

Sounni NE, Paye A, Host L, Noël A - Front Pharmacol (2011)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3108474&req=5

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.
Mentions: We and others have previously demonstrated that MT1-MMP overexpression in cancer cells stimulates tumor angiogenesis in vivo through VEGF upregulation (Deryugina et al., 2002; Sounni et al., 2002, 2004; Deng et al., 2009). MT1-MMP regulation of VEGF expression is dependent on Src signaling and requires the proteolytic activity of MT1-MMP (Sounni et al., 2004). Recently, Eisenach et al. (2010) have provided a complete mechanism of VEGF regulation by MT1-MMP and Src signaling. This study demonstrates that MT1-MMP regulates VEGF through a complex with VEGFR-2 and Src, activation of Akt and mTOR signaling pathway. MT1-MMP activity and signaling through cytoplasmic domain are confirmed as required for transcriptional regulation of VEGF expression in cancer cells. MT1-MMP interaction with Src has also been investigated in several in vitro models of angiogenesis and cell migration (Labrecque et al., 2004; Ouyang et al., 2010; Sabbota et al., 2010). MT1-MMP-mediated Src activation has also been described during cell migration. Recently, Sabbota et al. (2010) reported that MT1-MMP induces receptor activator of NF-κB ligand (RANKL) shedding from prostate cancer cell surface and signaling through its receptor RANK and downstream Src activation and consequently stimulates cell migration. Src activation by MT1-MMP has also been linked with ERK1/2 activation in cell migration within 3D collagen gel (Takino et al., 2010). However, MT1-MMP can form a complex with TIMP2 at the cell surface that can stimulate cancer cell migration in a non-proteolytic manner. This non-proteolytic mechanism implicates the activation of MEK1/2-ERK1/2-p90RSK signaling cascade by the MT1-MMP/TIMP-2 complex (Sounni et al., 2010b). Beside its role in ECM remodeling, MT1-MMP promotes endothelial cell migration, lumen formation, and vascular guidance tunnels in collagen matrices (Stratman et al., 2009). The observation of Lehti et al. (2005) that Mt1-mmp−/− mice present a marked reduction in mural cell density and abnormal vessel morphology in brain, suggests that membrane-associated MMP acts as a cofactor in propagating signaling through vascular smooth muscle cells (VSMC). This study, demonstrates that MT1-MMP processing of PDGFR-β is required for PDBFB/PDGFR-β signaling in VSMC and migration in vitro. Moreover, MT1-MMP induces VSMC dedifferentiation and acquisition of migratory and invasive phenotype during vascular injury through low density lipoprotein (LDL) receptor-related protein (LRP) proteolysis that promotes signaling through PDGFB/PDGFR-β axis (Lehti et al., 2009). Indeed, MT1-MMP cooperates with platelet derived S1P to induce endothelial cell migration and morphogenic differentiation (Langlois et al., 2004). Furthermore, MT1-MMP regulates signaling of the advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis in the vasculature, a target known to play a key role in diabetic vascular complications (Kamioka et al., 2011). Interestingly, expression of MT1-MMP correlates with the clinical mobilization of human CD43+ cell in patient with lymphoid malignancies (Vagima et al., 2009). Of interest, MT1-MMP expression and its association with lipid rafts facilitates G-CSF-induced hematopoietic stem/progenitor cell (HSPC) mobilization in human and murine (Shirvaikar et al., 2010). The molecular mechanisms of MT1-MMP relay on CD44 cleavage, activation of pro-MMP2 and inactivation of SDF-1 that facilitates HSPC egress from the bone marrow into circulation (Shirvaikar et al., 2011). MT1-MMP signaling in cancer cells, pericytes, and endothelial cells are schematically illustrated in Figure 2.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, University of Liege Liège, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus