RCAS/SCL-TVA animal model allows targeted delivery of polyoma middle T oncogene to vascular endothelial progenitors in vivo and results in hemangioma development.

Abstract

To recapitulate the generation of cancer stem cells in the context of an intact animal using a retroviral vector capable of in vivo delivery of oncogenes to primitive endothelial and hematopoietic stem cells. Targeting of these progenitors was achieved using transgenic mice in which the avian TVA retroviral receptor was placed under the control of the stem cell leukemia (scl/tal-1) gene promoter and SCL +19 enhancer. Injection of an avian retrovirus encoding polyoma middle T (PyMT), an oncogene that transforms endothelial cells, caused rapid lethality in all SCL-TVA mice but not in control TVA(-) littermates. The infected animals exhibited hemorrhagic foci in several organs. Histopathologic analysis confirmed the presence of hemangiomas and the endothelial origin of the PyMT-transformed cells. Surprisingly, the transformed endothelial cells contained readily detectable numbers of TVA(+) cells. By contrast, normal blood vessels had very few of these cells. The presence of TVA(+) cells in the lesions suggests that the cells originally infected by PyMT retained stem cell characteristics. Further analysis showed that the tumor cells exhibited activation of the phosphatidylinositol 3-kinase/Akt and S6/mammalian target of rapamycin pathways, suggesting a mechanism used by PyMT to transform endothelial progenitors in vivo. We conclude that this experimental system can specifically deliver oncogenes to vascular endothelial progenitors in vivo and cause a fatal neoplastic disease. This animal model should allow the generation of endothelial cancer stem cells in the natural environment of an immunocompetent animal, thereby enabling the recapitulation of genetic alterations that are responsible for the initiation and progression of human malignancies of endothelial origin.