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Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells

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Abstract

Transforming growth factor beta (TGF-β) promotes tumor growth, invasion and metastasis in established tumors. In this study, we analyzed the effect of overexpressing an anti-TGF-β peptide fused to apolipoprotein A-I (ApoA-I) as a scaffold molecule. We generated and characterized stable MC38 colon carcinoma clones expressing ApoA-I fused to the anti-TGF-β peptide P144 and ApoA-I as control cells. We evaluated in vitro the gene expression profile, cell cycle and anchorage-independent growth. The in vivo tumorigenic potential and immunogenicity were analyzed inoculating the MC38 clones into C57BL/6 mice, recombination-activating gene 1 knockout mice or mice deficient in NK cells either subcutaneously or intrasplenically to generate hepatic metastases. While overexpression of ApoA-I had no effect on the parameters analyzed, ApoA-I fused to P144 markedly diminished the tumorigenic capacity and metastatic potential of MC38 in vitro and in vivo, thus generating a highly immunogenic cell line. MC38 cells transfected with ApoA-I fused to P144 triggered memory T cell responses able to eliminate the parental cell line upon re-challenge. In summary, expression of ApoA-I fused to P144 is a novel strategy to modulate TGF-β in tumor cells. These results highlight the potential of TGF-β as a target in the development of new antitumor treatments.

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Abbreviations

ApoA-I:

Apolipoprotein A-I

ApoLinkerP144:

Fusion protein of apolipoprotein A-I and P144

Cox2 :

Cyclooxygenase 2

FC:

Fold change

Foxo3a :

Forkhead box O3

HDL:

High-density lipoproteins

H3f3a :

Histone H3.3

MC38 Apo:

MC38 stable clones overexpressing apolipoprotein A-I

MC38 ApoLinkerP144:

MC38 stable clones overexpressing the fusion protein of apolipoprotein A-I and P144

Mmp2 :

Matrix metallopeptidase 2

Mmp9 :

Matrix metallopeptidase 9

Rag-1 :

Recombination-activating gene 1

SR-B1:

Scavenger receptor class B type I

Tlr4 :

Toll-like receptor 4

TGF-β:

Transforming growth factor beta

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Acknowledgments

We are grateful to Dr. Paul Miller for English editing. This work was supported by the grant PI13/00207 from Instituto de Salud Carlos III, financed by the FEDER program of the European Union. Pedro Berraondo was supported by a Miguel Servet contract from Instituto de Salud Carlos III.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avda. Pio XII 55, 31008, Pamplona, Spain

    José Medina-Echeverz, Marcos Vasquez, Celia Gomar, Nuria Ardaiz & Pedro Berraondo

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  1. José Medina-Echeverz
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  2. Marcos Vasquez
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  3. Celia Gomar
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  4. Nuria Ardaiz
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  5. Pedro Berraondo
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Correspondence to Pedro Berraondo.

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Medina-Echeverz, J., Vasquez, M., Gomar, C. et al. Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells. Cancer Immunol Immunother 64, 717–725 (2015). https://doi.org/10.1007/s00262-015-1681-9

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  • DOI: https://doi.org/10.1007/s00262-015-1681-9

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