RT Journal Article SR Electronic T1 Regression of Human Breast Carcinoma in Nude Mice After Adsflt Gene Therapy is Mediated by Tumor Vascular Endothelial Cell Apoptosis JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.07.19.210856 DO 10.1101/2020.07.19.210856 A1 Angelina Felici A1 Donald P. Bottaro A1 Antonella Mangoni A1 Petra Reusch A1 Dieter Marmé A1 Imre Kovesdi A1 Dinuka M. De Silva A1 Young H. Lee A1 Maurizio C. Capogrossi A1 Judith Mühlhauser YR 2020 UL http://biorxiv.org/content/early/2020/07/19/2020.07.19.210856.abstract AB Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks tumors were injected either with Adsflt, or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Adsflt-infected group (33 ± 22 mm3) was decreased by 91% relative to that of the negative control group (388 ± 94 mm3; P<0.05). Moreover, 10 of 15 Adsflt-infected tumors exhibited complete regression. The vascular density in Adsflt-infected tumors was reduced by 50% relative to that of negative controls (P<0.05), consistent with sFLT-1-mediated tumor regression through an anti-angiogenic mechanism. Moreover, cell necrosis and fibrosis associated with long-term regression of Adsflt–infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Adsflt intratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects.Competing Interest StatementD Bottaro is an inventor on US Government held patents for inventions related to MET and VEGFR pathway inhibition, methods to detect and diagnose cancer, and methods to inhibit cell motility and tumor metastasis.AdadenovirusCMVcytomegalovirus;sFLT-1soluble FLT-1;VEGFvascular endothelial growth factor