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Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy

BACKGROUND: 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 i...

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Autores principales: 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, Joao N., Pastorino, Fabio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170797/
https://www.ncbi.nlm.nih.gov/pubmed/34078433
http://dx.doi.org/10.1186/s13046-021-01993-9
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author 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, Joao N.
Pastorino, Fabio
author_facet 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, Joao N.
Pastorino, Fabio
author_sort Brignole, Chiara
collection PubMed
description BACKGROUND: 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 anti-tumor 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01993-9.
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spelling pubmed-81707972021-06-02 Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy 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, Joao N. Pastorino, Fabio J Exp Clin Cancer Res Research BACKGROUND: 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 anti-tumor 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01993-9. BioMed Central 2021-06-02 /pmc/articles/PMC8170797/ /pubmed/34078433 http://dx.doi.org/10.1186/s13046-021-01993-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
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, Joao N.
Pastorino, Fabio
Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy
title Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy
title_full Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy
title_fullStr Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy
title_full_unstemmed Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy
title_short Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy
title_sort cell surface nucleolin represents a novel cellular target for neuroblastoma therapy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170797/
https://www.ncbi.nlm.nih.gov/pubmed/34078433
http://dx.doi.org/10.1186/s13046-021-01993-9
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