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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

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).
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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).

Mentions: We recently investigated MT1-MMP activity in perivascular stroma and the regulation of vascular permeability in vivo (Sounni et al., 2010a). We directly assessed whether MMP inhibition in both healthy and mouse model of age-related dermal fibrosis (i.e., Col1a1r/r mice Liu et al., 1995) could impact vascular leakage in an in vivo vascular leakage assay (Miles and Miles, 1952). Surprisingly, prior treatment with broad spectrum MMP inhibitor GM6001 (Ilomastat, Galardin) significantly increases vascular leakage in both wild type and Col1a1r/r mice. This indicates that the inhibition of steady-state MMP activity renders vessels more susceptible to induced acute leakage, and implies a link between steady-state MMP activity and vascular leakage. In vivo vascular assays applied to the skin of different MMP-deficient mice such as Mmp2−/−, Mmp9−/−, Mmp8−/−, and Mmp13−/− lead to similar results except for Mt1-mmp−/− mice. Mice lacking MT1-MMP show a distinct higher steady-state vascular leakage and low levels of active TGFβ compared to their corresponding age-matched wild type littermates. Maintaining vascular homeostasis relies on molecular mechanisms coordinated by MT1-MMP activity which controls TGFβ bioavailability and signaling through ALK5 in vascular wall. In vivo inhibition of TGFβ signaling in mice treated with small amount of ALK5 inhibitor (ALK5I) for 1 week, strongly increases vascular leakage both in normal and fibrotic skin, and it also enhances macromolecules delivery in neoplastic tissues (Figure 3). The treatment of transgenic mice developing skin carcinoma (K14-HPV16 transgenic mice) and mammary adenocarcinomas (MMTV-PyMT mice) with ALK5I results in enhanced delivery and bio-distribution of macromolecules in tumors compared to mice treated with vehicle alone. Taken together, these data provide evidence for a central role for MT1-MMP-activated TGFβ in mediating vascular homeostasis and remodeling. They further indicate that TGFβ and/or MT1-MMP-selective antagonists may enhance vascular leakage and therapeutic delivery to tissues where hemodynamic limits efficient drug delivery.


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

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

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

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

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).
Mentions: We recently investigated MT1-MMP activity in perivascular stroma and the regulation of vascular permeability in vivo (Sounni et al., 2010a). We directly assessed whether MMP inhibition in both healthy and mouse model of age-related dermal fibrosis (i.e., Col1a1r/r mice Liu et al., 1995) could impact vascular leakage in an in vivo vascular leakage assay (Miles and Miles, 1952). Surprisingly, prior treatment with broad spectrum MMP inhibitor GM6001 (Ilomastat, Galardin) significantly increases vascular leakage in both wild type and Col1a1r/r mice. This indicates that the inhibition of steady-state MMP activity renders vessels more susceptible to induced acute leakage, and implies a link between steady-state MMP activity and vascular leakage. In vivo vascular assays applied to the skin of different MMP-deficient mice such as Mmp2−/−, Mmp9−/−, Mmp8−/−, and Mmp13−/− lead to similar results except for Mt1-mmp−/− mice. Mice lacking MT1-MMP show a distinct higher steady-state vascular leakage and low levels of active TGFβ compared to their corresponding age-matched wild type littermates. Maintaining vascular homeostasis relies on molecular mechanisms coordinated by MT1-MMP activity which controls TGFβ bioavailability and signaling through ALK5 in vascular wall. In vivo inhibition of TGFβ signaling in mice treated with small amount of ALK5 inhibitor (ALK5I) for 1 week, strongly increases vascular leakage both in normal and fibrotic skin, and it also enhances macromolecules delivery in neoplastic tissues (Figure 3). The treatment of transgenic mice developing skin carcinoma (K14-HPV16 transgenic mice) and mammary adenocarcinomas (MMTV-PyMT mice) with ALK5I results in enhanced delivery and bio-distribution of macromolecules in tumors compared to mice treated with vehicle alone. Taken together, these data provide evidence for a central role for MT1-MMP-activated TGFβ in mediating vascular homeostasis and remodeling. They further indicate that TGFβ and/or MT1-MMP-selective antagonists may enhance vascular leakage and therapeutic delivery to tissues where hemodynamic limits efficient drug delivery.

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