| First Author | Medina-Echeverz J | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 5 | Pages | e96799 |
| PubMed ID | 24797128 | Mgi Jnum | J:217368 |
| Mgi Id | MGI:5613799 | Doi | 10.1371/journal.pone.0096799 |
| Citation | Medina-Echeverz J, et al. (2014) Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases. PLoS One 9(5):e96799 |
| abstractText | Transforming growth factor beta (TGF-beta) 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 TGFbeta-inhibitory molecules. We constructed a plasmid encoding a potent TGF-beta-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-beta. 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-beta signaling in the liver and to enhance IL-12 -mediated IFN-gamma production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-gamma and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2-/-IL2rgamma-/- immunodeficient mice. This effect was associated with downregulation of TGF-beta 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-beta-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms. |
