title: MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth.
abstract: Angiogenesis is a key process occurring under both physiological and pathological conditions and is a hallmark of cancer. We have recently demonstrated that the extracellular matrix (ECM) molecule MULTIMERIN2 exerts an angiostatic function through the binding to VEGF-A. In this study we identify the region of the molecule responsible for the binding and demonstrate that the interaction involves the carbohydrate chains. MULTIMERIN2 interacts with other VEGF-A isoforms and VEGF family members such as VEGF-B, -C, -D and PlGF-1 suggesting that the molecule may function as a reservoir for different cytokines. In response to VEGF-A165, we show that MULTIMERIN2 impairs the phosphorylation of VEGFR2 at both Y1175 and Y1214 residues, halts SAPK2/p38 activation and negatively affects endothelial cell motility. In addition, MULTIMERIN2 and its active deletion mutant decrease the availability of the VEGFR2 receptor at the EC plasma membrane. The ectopic expression of MULTIMERIN2 or its active deletion mutant led to a striking reduction of tumor-associated angiogenesis and tumor growth. In conclusion, these data pinpoint MULTIMERIN2 as a key angiostatic molecule and disclose the possibility to develop new prognostic tools and improve the management of cancer patients.
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Colladel
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pellicani
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Andreuzzi
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Paulitti
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Tarticchio
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Todaro
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.affiliation: Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mongiat
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis; D002241:Carbohydrates / Q000737:chemistry*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D002241:Carbohydrates; C089826:EMILIN3 protein, human; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: angiogenesis; endothelial cell sprouting; extracellular matrix (ECM); tumor microenvironment; vascular endothelial growth factor (VEGF)