Engineered human tumor xenografts with functional human vascular networks

Abstract

Animal models of human tumor angiogenesis would have multiple applications. However, they are extremely difficult to standardize. In this work, we tried to generate human tumor xenografts containing a human vascular bed in immunodeficient mice by subcutaneous co-implantation of matrigel-embedded human endothelial cells (EC), human mesenchymal stem cells (MSC) as a source of mural cells and HT1080 human fibrosarcoma cells. Unfortunately, in this context human EC were rapidly substituted by their murine counterparts, and by day 16 post-implantation human CD34 positive cells were hardly detectable in intratumoral vessels. In an attempt to inhibit host EC colonization of human xenografts and promote human EC grafting, we investigated the effect of radiation prior to implantation on the vascularization and growth of tumor xenografts. Nude mice underwent either localized (implantation area) or sublethal whole-body exposure to radiation. Localized radiation inhibited both human and murine neovascularization, and even the tumor growth rate was remarkably decreased when compared to control unirradiated mice and sublethally whole-body irradiated mice. Interestingly, numerous human vessels were detectable in sublethally irradiated mice at day 30, with murine EC only overpassing human EC when spontaneous hematopoietic reconstitution has taken place. This observation strongly suggests the implication of bone marrow-derived murine endothelial precursors in tumor neovascularization. In summary, we have established a model of human tumor neovascularization that is amenable to both the study of molecular aspects in the angiogenic process and the evaluation of potential new antiangiogenic drugs.