Abstract
Angiogenesis is one of the crucial events for cancer development and growth. Two members of the vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF), which are able to heterodimerize if coexpressed in the same cell, are both required for pathologic angiogenesis. We have generated a PlGF1 variant, named PlGF1-DE in which the residues Asp72 and Glu73 were substituted with Ala, which is unable to bind and activate VEGF receptor-1 but is still able to heterodimerize with VEGF. Here, we show that overexpression in tumor cells by adenoviral delivery or stable transfection of PlGF1-DE variant significantly reduces the production of VEGF homodimer via heterodimerization, determining a strong inhibition of xenograft tumor growth and neoangiogenesis, as well as significant reduction of vessel lumen and stabilization, and monocyte-macrophage infiltration. Conversely, the overexpression of PlGF1wt, also reducing the VEGF homodimer production comparably with PlGF1-DE variant through the generation of VEGF/PlGF heterodimer, does not inhibit tumor growth and vessel density compared with controls but induces increase of vessel lumen, vessel stabilization, and monocyte-macrophage infiltration. The property of PlGF and VEGF-A to generate heterodimer 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 and is a new candidate for antiangiogenic gene therapy in cancer treatment.
Highlights
Angiogenesis is one of the major pathologic changes associated with several complex diseases, such as cancer, atherosclerosis, arthritis, diabetic retinopathy, and age-related macular degeneration [1, 2]
We have shown that the property of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) to form heterodimer when coexpressed in the same cell [8] may represent a successful strategy to reduce the production of active VEGF, inhibiting VEGF-dependent angiogenesis
This inhibition was attained using a mutant of human PlGF1 that lost the ability to bind and activate VEGFR1 but was still able to heterodimerize with VEGF
Summary
Angiogenesis is one of the major pathologic changes associated with several complex diseases, such as cancer, atherosclerosis, arthritis, diabetic retinopathy, and age-related macular degeneration [1, 2]. Among the several molecular players involved in angiogenesis, some members of vascular endothelial growth factor (VEGF) family—VEGF-A, VEGF-B, and placental growth factor (PlGF)—and the related receptors VEGFR-1 VEGF members) and VEGFR-2 ( known as Flk-1 in mice and KDR in human, recognized by VEGF-A) have a decisive role [3]. VEGFR-1 exists as soluble form generated by alternative splicing [4], representing one of the most potent antiangiogenic molecule, as confirmed for its pivotal role in cornea avascularity [5]. PlGF and VEGF-A share a strict biochemical and functional relationship because, besides having VEGFR-1 as common receptor, they can form heterodimer if coexpressed in the same cell [8]. The heterodimer may induce receptor heterodimerization, like VEGF, or bind to VEGFR-1
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