title: Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells.
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.
authors: Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avda. Pio XII 55, 31008, Pamplona, Spain.
authors: José
authors: J
authors: Medina-Echeverz
authors: Marcos
authors: M
authors: Vasquez
authors: Celia
authors: C
authors: Gomar
authors: Nuria
authors: N
authors: Ardaiz
authors: Pedro
authors: P
authors: Berraondo
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D016632:Apolipoprotein A-I; D010446:Peptide Fragments; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C504795:TGF-beta1 type III receptor (730-743), human; D016212:Transforming Growth Factor beta