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Angiogenesis is one of the crucial events for cancer development and growth. Two members of vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF), which are able to heterodimerize if co-expressed in the same cell, are both required for pathological angiogenesis. We generated a PlGF1 variant, named PlGF1-DE in which the residues Asp72 and Glu73 were substituted with Ala. PlGF1-DE is unable to bind and activate VEGFR-1 but can heterodimerize with VEGF (J. Biol. Chem., 279: 43929-43939, 2004). Here we demonstrate that overexpression of PlGF1-DE variant in tumor cells by adenoviral delivery or stable transfection significantly reduced the production of VEGF homodimer via heterodimerization, leading to a strong inhibition of xenograft tumor growth and neoangiogenesis, as well as significant reduction of vessel size, vessel stabilization by smooth muscle cells and monocyte-macrophage infiltration. PlGF1-DE/VEGF heterodimer, differently from wild type heterodimer able to induce VEGFR-1 dimerization as well as VEGFR-1/R-2 heterodimerization and activation, failed to induce receptors phosphorylation demonstrating that co-expression of PlGF1-DE variant in VEGF-producing cells effectively sequestered active VEGF, biasing toward the generation of a non-functional heterodimer. Conversely, overexpression of PlGF1wt, while reducing VEGF homodimer production comparably to PlGF1-DE variant through the generation of VEGF/PlGF heterodimer, did not inhibit tumor growth and vessel density compared to controls, but induced an increase of vessel size, vessel stabilization and monocyte-macrophage infiltration. The ability of PlGF and VEGF-A to heterodimerize represents a successful strategy to inhibit VEGF-dependent angiogenesis. The PlGF1-DE variant, and not PlGF1wt as previously reported, acts as a ‘dominant negative’ of VEGF molecule and is a new candidate for anti-angiogenic gene therapy in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-370.