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sFlt-1 Gene Therapy of Follicular Thyroid Carcinoma

Department of Vascular Surgery (C.Y., C.F., S.W., Y.L.), The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; and University of Pittsburgh Cancer Institute and Department of Pathology (C.Y., C.F., K.Z.Q.W., N.H., X.L., M.L.), University of Pittsburgh School Medicine, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Mengfeng Li, 5117 Centre Avenue, Suite G12.g, Hillman Cancer Center Research Pavilion, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213. E-mail: Mengfeng{at}pitt.edu.

Tumor progression largely depends on blood supply and neovessel formation, and angiogenesis is emerging as a promising target for cancer therapy. Vascular endothelial growth factor (VEGF), a major proangiogenic molecule, stimulates angiogenesis via promoting endothelial proliferation, survival and migration. VEGF has been found to be up-regulated in various types of tumors and to be associated with tumor progression and poor prognosis. Inhibition of VEGF or its signaling pathway has been shown to suppress tumor angiogenesis and tumor growth. In the present study, we tested the antiangiogenic and antitumor effects of soluble VEGF receptor-1 [soluble Flt (sFlt)-1] on the growth of follicular thyroid carcinoma (FTC). We constructed a 293 embryonic kidney cell line (293-Flt1–3d) that expresses sFlt-1, which is composed of the first three extracellular domains of Flt-1. The 293-Flt1–3d cells inhibited the in vitro growth of human umbilical vein endothelial cells in a paracrine manner. The in vivo antitumor and antiangiogenic activities of the 293-Flt1–3d cells were tested. When 293-Flt1–3d cells were inoculated at a site remote to the FTC-133 tumor transplant, the growth of FTC-133 tumors were inhibited by 70.37%, as compared with the control treatment with 293 cells expressing control gene LacZ. Immunohistochemical analysis of microvessel densities in treated tumors demonstrated that 293-Flt1–3d cells robustly suppressed intratumoral angiogenesis. Our data suggest that a mammalian cell-mediated approach could effectively deliver sFlt-1 gene therapy and inhibit tumor angiogenesis and tumor growth.

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