Matrix Metalloproteinase-14 (MT1-MMP)–Mediated Endoglin Shedding Inhibits Tumor Angiogenesis

Hawinkels, Lukas J.A.C.; Kuiper, Patricia; Wiercinska, Eliza; Verspaget, Hein W.; Liu, Zhen; Pardali, Evangelia; Sier, Cornelis F.M.; Dijke, Peter ten

doi:10.1158/0008-5472.can-09-4466

Cited by 242 publications

(248 citation statements)

References 48 publications

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“…7). Experimental support for this hypothesis has been recently reported, demonstrating that MT1-MMP is in fact a major endoglin-shedding protease (75). This is compatible with the fact that ␤-glycan, another TGF-␤ coreceptor with a partial sequence homology to endoglin, can be shed by MT1-MMP (171).…”

Section: Role Of Other Endoglin Forms In Vascular Physiopathologysupporting

confidence: 59%

The physiological role of endoglin in the cardiovascular system

López‐Novoa

Bernabeu

2010

American Journal of Physiology-Heart and Circulatory Physiology

187

200

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Endoglin (CD105) is an integral membrane glycoprotein that serves as a coreceptor for members of the transforming growth factor-β superfamily of proteins. A major role for endoglin in regulating transforming growth factor-β-dependent vascular remodeling and angiogenesis has been postulated based on the following: 1) endoglin is the gene mutated in hereditary hemorrhagic telangiectasia type 1, a disease characterized by vascular malformations; 2) endoglin knockout mice die at midgestation because of defective angiogenesis; 3) endoglin is overexpressed in neoangiogenic vessels, during inflammation, and in solid tumors; and 4) endoglin regulates the expression and activity of endothelial nitric oxide synthase, which is involved in angiogenesis and vascular tone. Besides the predominant form of the endoglin receptor (long endoglin isoform), two additional forms of endoglin have been recently reported to play a role in the vascular pathology and homeostasis: the alternatively spliced short endoglin isoform and a soluble endoglin form that is proteolytically cleaved from membrane-bound endoglin. The purpose of this review is to underline the role that the different forms of endoglin play in regulating angiogenesis, vascular remodeling, and vascular tone, as well as to analyze the molecular and cellular mechanisms supporting these effects.

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Section: Role Of Other Endoglin Forms In Vascular Physiopathologysupporting

confidence: 59%

The physiological role of endoglin in the cardiovascular system

López‐Novoa

Bernabeu

2010

American Journal of Physiology-Heart and Circulatory Physiology

187

200

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“…Hawinkels et al have shown that endoglin shedding was mediated by matrix metalloproteinase (MMP)-14 and resulted in vitro in reduced spontaneous and VEGF-induced endothelial sprouting. 20 The clinical and correlative data in our phase II study suggest that TRC105 therapy will not be effective as a single agent in the present schedule in HCC. Only one patient achieved an objective response and was progression free at four months.…”

Section: Discussionmentioning

confidence: 84%

A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib

et al. 2015

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Background: Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors. Objective: The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib. Methods: Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105. Results: A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N ¼ 3) and epistaxis (G1; N ¼ 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study. Conclusions: TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.

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“…Despite the fact that 129/Ola and C57BL/6 inbred endoglin haploinsufficient mice strains are available as a model of hereditary hemorrhagic telangiectasia, they do not develop atherosclerosis 48) . Inhibition of endoglin activity by antibodies has been proposed in targeted inhibition of angiogenesis during tumor development 16,49) ; however, no data about atherosclerosis and endoglin antibodies are available.…”

Section: Discussionmentioning

confidence: 99%

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

Vecerova¹,

Strasky²,

Rathouska³

et al. 2012

JAT

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Aim: Transforming growth factor-beta (TGF-) plays important role in atherogenesis via TGF-receptors and Smad proteins, which determine its signaling activity. In this study, we hypothesized, whether non-lipid related effects of atorvastatin, affect both endoglin/ALK-5/Smad2/eNOS and/or endoglin/ALK-1/Smad1/VEGF previously proposed pathways in ApoE/LDLR double knockout mice. Methods: ApoE/LDLR double knockout mice were divided into two groups. The chow group (CHOW) (n 8) was fed with chow diet, while in the atorvastatin group (ATV) (n 8) atorvastatin was added to the chow diet at dose 50 mg/kg/day. Biochemical analyses of lipid profile, lesion area measurement, immunohistochemistry and Western blot analysis of endoglin, ALK-1, 5, phosphorylated and non-phosphorylated forms Smad-1, 2, VEGF and eNOS proteins in mice aorta were performed. Results: Biochemical analysis of blood serum and morphometric analysis of aortic lesion size showed that atorvastatin treatment resulted in a significant increase of cholesterol levels and simultaneously in reduced lesion size in aortic sinus when compared to CHOW mice. Western blot analysis revealed that atorvastatin treatment significantly increase the expressions of endoglin by 102%, ALK-1 by 113%, ALK-5 by 296%, pSmad-1 by 202%, pSmad-2 by 34%, VEGF by 68% and eNOS by 687% as compared with CHOW mice. Immunofluorescence staining revealed endoglin coexpression with all studied markers that were increased by atorvastatin treatment mainly in endothelial cells covering atherosclerotic plaques. Conclusion: This study shows that atorvastatin treatment increases the expression of endoglin, ALK-1, ALK-5, phosphorylated forms of Smad1 and Smad2, VEGF and eNOS and reduces atherosclerotic lesion size beyond its lipid lowering effects. Therefore, we propose that endoglin related receptors and signal transducers might play protective role in atherogenesis.

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Matrix Metalloproteinase-14 (MT1-MMP)–Mediated Endoglin Shedding Inhibits Tumor Angiogenesis

Cited by 242 publications

References 48 publications

The physiological role of endoglin in the cardiovascular system

The physiological role of endoglin in the cardiovascular system

A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

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