Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases.
PLoS One
; 9(5): e96799, 2014.
Article
en En
| MEDLINE
| ID: mdl-24797128
ABSTRACT
Transforming growth factor ß (TGF-ß) 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 TGFß-inhibitory molecules. We constructed a plasmid encoding a potent TGF-ß-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-ß. 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-ß 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-ß 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-ß-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
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Factor de Crecimiento Transformador beta1
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Terapia Molecular Dirigida
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Lipoproteínas HDL
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Neoplasias Hepáticas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2014
Tipo del documento:
Article