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|Autori: ||Pellicani, Rosanna|
|Supervisore afferente all'Università: ||CURCIO, FRANCESCO|
|Centro di ricerca: ||DIPARTIMENTO SCIENZE MEDICHE E BIOLOGICHE - DSMB|
|Titolo: ||MULTIMERIN2: a key regulator of tumor angiogenesis and vascular homeostasis|
|Abstract (in inglese): ||Angiogenesis, the formation of new blood vasculature from pre-existing vessels, is a hallmark of cancer. The extracellular matrix (ECM) molecule, MULTIMERIN2 (MMRN2), is specifically deposited along the vasculature in tight juxtaposition with endothelial cells (ECs). We have previously demonstrated that the glycoprotein halts ECs’ motility and impairs tumor angiogenesis through the interaction with VEGF-A165, leading to the down-regulation of VEGF-A/VEGFR2 signaling axis. In this study, we identified the region of the MMRN2 responsible for the binding, demonstrating that the interaction involves the carbohydrate chains. We have also found that MMRN2 interacts with other VEGF-A isoforms and VEGF family members suggesting that the molecule may function as a reservoir for different cytokines. Moreover, we demonstrated that the anti-migratory function of the molecule hinges on a reduced VEGFR2 phosphorylation at both Y1175 and Y1214, which leads to the down-modulation of SAPK2/p38 activation. Furthermore, we found that MMRN2 impaired VEGFR2 function by reducing its availability at the ECs’ plasma membrane.
Through in vitro and in vivo tests we demonstrated the angiostatic role of MMRN2 and its active fragment and, as a consequence, the over-expression of the molecule or its active deletion mutant by cancer cells led to a dramatic reduction of tumor growth.
Given its strategic localization, we have recently hypothesized that MMRN2 may represent a homeostatic molecule buffering the angiogenic stimuli and maintaining the endothelium quiescent. In line with this hypothesis MMRN2 is deposited over time during vessel maturation and the co-culture of ECs with pericytes boosts its secretion and organization. In addition, we have demonstrated that MMRN2 represents an adhesion substrate for pericytes and may be required for their recruitment, since pericyte coverage of the MMRN2 knockout retinal vessels is strongly impaired. We also found that the down-modulation of MMRN2 leads to an increased vascular permeability associated with an impaired expression of the tight junction-associated molecules occludin and ZO-1. Accordingly, preliminary data show that the MMRN2 knockout mice displayed an increased vascular leakage. Taken together these results pinpoint MMRN2 as a key angiostatic molecule that can be regarded as a promising novel tool for the development of new antiangiogenic drugs.|
|MIUR : ||Settore MED/04 - Patologia Generale|
|Corso di dottorato: ||Dottorato di ricerca in Scienze e tecnologie cliniche|
|Ciclo di dottorato: ||27|
|Università di conseguimento titolo: ||Università degli Studi di Udine|
|Luogo di discussione: ||Udine|
|Altre informazioni: ||Co-supervisore: Maurizio Mongiat|
|Citazione: ||Pellicani, R. MULTIMERIN2: a key regulator of tumor angiogenesis and vascular homeostasis. (Doctoral Thesis, Università degli Studi di Udine, 2016).|
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