A novel soluble isoform of the human TGF-β type 2 receptor exerts strong antitumor activity in colorectal cancer-derived cell lines

Abstract

TGF-beta signaling pathway is a key regulator of cancer progression, par ticularly incolorectal cancer where 90% of microsatellite instable (MSI) tumors exhibitmutations in the TGF-beta receptor type 2 (TGFBR2) gene. Here, we show thatlentiviral mediated overexpression of TGFBR2-SE, a recently discovered solubleisoform of the human TGF-beta type 2 receptor, fused to the human IgG1 Fc fragment(TGFBR2-SE/Fc) reduces in vitro cell proliferation and migration while induces cellcycle arrest and apoptosis in the primary human colorectal cancer derived cell lineHCT116. Moreover, TGFBR2-SE/Fc impairs tumorigenicity of BALB/c nudeathymic mice xenografts, increasing the survival rate of the animals. Tumorsoverexpressing TGFBR2-SE/Fc were considerable smaller or even unable to beestablished as only 3 out of 6 mice developed tumors in the TGFBR2-SE/Fc group.Mechanistically, TGFBR2-SE/Fc downregulates TGF-beta canonical pathway andleads to the activation of tumor suppressor genes such as p21, p57 and p53 aswell as to the inactivation of cell cycle progression elements such as cyclin B1 a ndId1. These findings suggest a strong antitumor activity of TGFBR2-SE/Fc based onblocking TGF-beta signaling pathway and Smad2/3 independent changes in geneexpression supporting the further exploration and development of TGFBR2-SE/Fcas a new biopharmace utical for the treatment of solid tumors.