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Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases

Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We const...

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Autores principales: Medina-Echeverz, José, Fioravanti, Jessica, Díaz-Valdés, Nancy, Frank, Kathrin, Aranda, Fernando, Gomar, Celia, Ardaiz, Nuria, Dotor, Javier, Umansky, Viktor, Prieto, Jesús, Berraondo, Pedro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010484/
https://www.ncbi.nlm.nih.gov/pubmed/24797128
http://dx.doi.org/10.1371/journal.pone.0096799
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author Medina-Echeverz, José
Fioravanti, Jessica
Díaz-Valdés, Nancy
Frank, Kathrin
Aranda, Fernando
Gomar, Celia
Ardaiz, Nuria
Dotor, Javier
Umansky, Viktor
Prieto, Jesús
Berraondo, Pedro
author_facet Medina-Echeverz, José
Fioravanti, Jessica
Díaz-Valdés, Nancy
Frank, Kathrin
Aranda, Fernando
Gomar, Celia
Ardaiz, Nuria
Dotor, Javier
Umansky, Viktor
Prieto, Jesús
Berraondo, Pedro
author_sort Medina-Echeverz, José
collection PubMed
description Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2(−/−)IL2rγ(−/−) immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8(+) T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms.
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spelling pubmed-40104842014-05-09 Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases Medina-Echeverz, José Fioravanti, Jessica Díaz-Valdés, Nancy Frank, Kathrin Aranda, Fernando Gomar, Celia Ardaiz, Nuria Dotor, Javier Umansky, Viktor Prieto, Jesús Berraondo, Pedro PLoS One Research Article Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2(−/−)IL2rγ(−/−) immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8(+) T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms. Public Library of Science 2014-05-05 /pmc/articles/PMC4010484/ /pubmed/24797128 http://dx.doi.org/10.1371/journal.pone.0096799 Text en © 2014 Medina-Echeverz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Medina-Echeverz, José
Fioravanti, Jessica
Díaz-Valdés, Nancy
Frank, Kathrin
Aranda, Fernando
Gomar, Celia
Ardaiz, Nuria
Dotor, Javier
Umansky, Viktor
Prieto, Jesús
Berraondo, Pedro
Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases
title Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases
title_full Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases
title_fullStr Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases
title_full_unstemmed Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases
title_short Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases
title_sort harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010484/
https://www.ncbi.nlm.nih.gov/pubmed/24797128
http://dx.doi.org/10.1371/journal.pone.0096799
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