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Title: Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy
Authors: Brignole, Chiara
Bensa, Veronica
Fonseca, Nuno A. 
Del Zotto, Genny
Bruno, Silvia
Cruz, Ana F. 
Malaguti, Fabiana
Carlini, Barbara
Morandi, Fabio
Calarco, Enzo
Perri, Patrizia
Moura, Vera 
Emionite, Laura
Cilli, Michele
De Leonardis, Francesco
Tondo, Annalisa
Amoroso, Loredana
Conte, Massimo
Garaventa, Alberto
Sementa, Angela R.
Corrias, Maria V.
Ponzoni, Mirco
Moreira, João N. 
Pastorino, Fabio
Keywords: Neuroblastoma; Cell surface protein; Nucleolin; Targeted therapy; Nanotechnology
Issue Date: 2-Jun-2021
Publisher: Springer Nature
Project: Italian ministry of Health under the frame of EuroNanoMed II-2015 (ER-2015- 2360441-Eranet to F.P.) and Associazione Italiana per la Ricerca sul Cancro, Investigator Grant n. 18474 to M.P. and n. 24397 to F.P 
POCI-01-0145-FEDER- 016390 
Euronanomed (FCT reference ENMed/0005/2015) 
CENT RO-01-0145-FEDER-000012-HealthyAging2020 
Italian Foundation for Neuroblastoma research and Associazione Oncologia Pediatrica E Neuroblastoma (OPEN) ONLUS 
Serial title, monograph or event: Journal of Experimental and Clinical Cancer Research
Volume: 40
Issue: 1
Abstract: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Nucleolin (NCL) is a protein overexpressed and partially localized on the cell surface of tumor cells of adult cancers. Little is known about NCL and pediatric tumors and nothing is reported about cell surface NCL and NB. Methods: NB cell lines, Schwannian stroma-poor NB tumors and bone marrow (BM)-infiltrating NB cells were evaluated for the expression of cell surface NCL by Flow Cytometry, Imaging Flow Cytometry and Immunohistochemistry analyses. The cytotoxic activity of doxorubicin (DXR)-loaded nanocarriers decorated with the NCL-recognizing F3 peptide (T-DXR) was evaluated in terms of inhibition of NB cell proliferation and induction of cell death in vitro, whereas metastatic and orthotopic animal models of NB were used to examine their in vivo antitumor potential. Results: NB cell lines, NB tumor cells (including patient-derived and Patient-Derived Xenografts-PDX) and 70% of BM-infiltrating NB cells show cell surface NCL expression. NCL staining was evident on both tumor and endothelial tumor cells in NB xenografts. F3 peptide-targeted nanoparticles, co-localizing with cell surface NCL, strongly associates with NB cells showing selective tumor cell internalization. T-DXR result significantly more effective, in terms of inhibition of cell proliferation and reduction of cell viability in vitro, and in terms of delay of tumor growth in all NB animal model tested, when compared to both control mice and those treated with the untargeted formulation. Conclusions: Our findings demonstrate that NCL could represent an innovative therapeutic cellular target for NB.
ISSN: 1756-9966
DOI: 10.1186/s13046-021-01993-9
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
I&D CIBB - Artigos em Revistas Internacionais
FFUC- Artigos em Revistas Internacionais

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