Umansky, V. (Viktor)

Filtering

20141

Settings

Author search.filters.isAuthorOfPublication.ca6cec58-97da-4d79-84fd-9590c81238c2

Search Results

Now showing 1 - 1 of 1
  • Thumbnail Image
    Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases
    (Public Library of Science, 2014-05) Dotor, J. (Javier); Berraondo, P. (Pedro); Gomar, C. (Celia); Diaz-Valdes, N. (Nancy); Frank, K. (Kathrin); Umansky, V. (Viktor); Aranda, F. (Fernando); Ardaiz, N. (Nuria); Prieto, J. (Jesús); Medina-Echeverz, J. (José); Fioravanti, J. (Jessica)
    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.