Multimerin-2 maintains vascular stability and permeability

Pellicani, Rosanna; Poletto, Evelina; Andreuzzi, Eva; Paulitti, Alice; Doliana, Roberto; Bizzotto, Dario; Braghetta, Paola; Colladel, Roberta; Tarticchio, Giulia; Sabatelli, Patrizia; Bucciotti, Francesco; Bressan, Giorgio M.; Iozzo, Renato V.; Colombatti, Alfonso; Bonaldo, Paolo; Mongiat, Maurizio

doi:10.1016/j.matbio.2019.08.002

Cited by 39 publications

(41 citation statements)

References 58 publications

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“…Since we have recently demonstrated that EMILIN2 triggers angiogenesis by evoking IL-8 expression in endothelial cells and fibroblasts [ 52 ], we assessed if the vascularization of the gastric samples changed in relation to the expression of EMILIN2. We used an antibody specifically recognizing the cell surface glycoprotein CD31, an established endothelial cell marker.…”

Section: Resultsmentioning

confidence: 99%

“…However, despite slight survival benefits observed for instance with the use of ramucirumab, a VEGFR-2 antibody [ 45 , 46 ], anti-angiogenic therapy has provided suboptimal results. This could be due to the fact that this process is regulated by a plethora of cytokines and growth factors, receptors and also by extracellular matrix (ECM) constituents [ [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] ]. Thus, it is mandatory to better characterize the newly-formed blood vessel together with the microenvironmental structures supporting the tumor proper.…”

Section: Introductionmentioning

confidence: 99%

“…An increasing body of evidences highlights the crosstalk between angiogenesis and the immune response [ 57 , 58 ], and, in this context, the secreted glycoprotein Elastin Microfibril Interfacer 2 (EMILIN2) may play a prominent role. EMILIN2 [ 59 ] belongs to the EDEN protein family [ [60] , [61] , [62] ] and, like Multimerin-2, another member of this protein family, is involved in angiogenesis [ [49] , [50] , [51] , [52] , [63] , [64] , [65] , [66] , [67] ]. EMILIN2 modulates different signaling pathways affecting the activation of receptors on the tumor cell surface [ [68] , [69] , [70] , [71] ].…”

Section: Introductionmentioning

confidence: 99%

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Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis

Andreuzzi

Fejza

Capuano

et al. 2020

Matrix Biology Plus

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Gastric cancer is a frequent human tumor and often a lethal disease. Targeted therapy for gastric carcinomas is far behind vis-à-vis other solid tumors, primarily because of the paucity of cancer-driving mutations that could be efficiently and specifically targeted by current therapy. Thus, there is a need to discover actionable pathways/proteins and new diagnostic and prognostic biomarkers. In this study, we explored the role of the extracellular matrix glycoprotein EMILIN2, E lastin Mi crofibril In terfacer 2 , in a cohort of gastric cancer patients. We discovered that EMILIN2 expression was consistently suppressed in gastric cancer and high expression levels of this glycoprotein were linked to abnormal vascular density. Furthermore, we found that EMILIN2 had a dual effect on gastric carcinoma cells: on one hand, it decreased tumor cell proliferation by triggering apoptosis, and on the other hand, it evoked the production of a number of cytokines involved in angiogenesis and inflammation, such as IL-8. Collectively, our findings posit EMILIN2 as an important onco-regulator exerting pleiotropic effects on the gastric cancer microenvironment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis

Andreuzzi

Fejza

Capuano

et al. 2020

Matrix Biology Plus

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“… 16 , 18 , 22 , 31 These conflicting roles could be context dependent, as recently suggested by a study using the Multimerin-2 knockout model, which highlights its role in maintaining proper blood vessel homeostasis and stabilization. 17 Therefore, through the engagement of CD93, Multimerin-2 expression may be required for vessel development in specific steps of the angiogenic process. 9 , 18 Accordingly, inhibiting the CD93/Multimerin-2 interaction may disrupt vascular integrity, thus retarding angiogenesis and tumor growth.…”

Section: Discussionmentioning

confidence: 99%

The Binding of CD93 to Multimerin-2 Promotes Choroidal Neovascularization

Tosi

Neri

Barbera

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to investigate the involvement of CD93 and Multimerin-2 in three choroidal neovascularization (CNV) models and to evaluate their contribution in the neovascular progression of age-related macular degeneration (AMD). Methods Choroidal neovascular membranes collected during surgery from AMD patients were analyzed by microscopy methods. Laser-induced CNV mouse models and choroid sprouting assays (CSAs) were carried out using the CD93 knockout mouse model. An original ex vivo CSA of vascular angiogenesis, employing choroid tissues isolated from human donors, was developed. Results In contrast to healthy choroid endothelium, hyperproliferative choroidal endothelial cells (ECs) of AMD patients expressed high levels of CD93, and Multimerin-2 was abundantly deposited along the choroidal neovasculature. CD93 knockout mice showed a significant reduced neovascularization after laser photocoagulation, and their choroidal ECs displayed a decreased ability to produce sprouts in ex vivo angiogenesis assays. Moreover, the presence of an antibody able to hamper the CD93/Multimerin-2 interaction reduced vascular sprouting in the human CSA. Conclusions Our results demonstrate that CD93 and its interaction with Multimerin-2 play an important role in pathological vascularization of the choroid, disclosing new possibilities for therapeutic intervention to neovascular AMD.

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“…Importantly, multimerin-2 controls EC function and it is important for the maintenance of vascular stability. In fact, the downregulation of multimerin-2 in ECs causes the dismantlement of cell-cell junctions, leading to increased vessel permeability and leakage [123]. Thus, it is plausible to speculate that the loss of multimerin-2 could be associated with a worse drug delivery and poor prognosis for CRC and GC patients.…”

Section: Int J Mol Sci 2020 21 X For Peer Review 3 Of 34mentioning

confidence: 99%

Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

Andreuzzi

Capuano

Poletto

et al. 2020

IJMS

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Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients’ outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies.

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Multimerin-2 maintains vascular stability and permeability

Cited by 39 publications

References 58 publications

Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis

Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis

The Binding of CD93 to Multimerin-2 Promotes Choroidal Neovascularization

Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

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