Genetically tagging endothelial cells in vivo:: bone marrow-derived cells do not contribute to tumor endothelium

Tumor growth is dependent in part on neoangiogenesis. Functional involvement of bone marrow (BM)-derived cells in this process has been demonstrated. However, it remains controversial as to whether tumor endothelium itself is BM derived. Here we sought to address this issue with an endothelial-specific, inducible transgenic model. We generated Cre-transgenic mice (endothelial-SCL-Cre-ERT) using the tamoxifen-inducible Cre-ERT recombinase driven by the 5' endothelial enhancer of the stem cell leukemia (SCL) locus. These mice were intercrossed with Cre reporter strains in which beta-galactosi-dase (LacZ) or enhanced yellow fluorescent protein (EYFP) are expressed upon Cre-mediated recombination. After tamoxifen administration, endothelial LacZ staining was observed in embryonic and adult tissues. Cre-mediated recombination was also observed in newly generated tumor endothelium. In adult BM cells we could only detect trace amounts of recombination by flow cytometry. Subsequently, BM from endothelial-SCL-CreER(T);R26R mice was transplanted into irradiated recipients. When tumors were grown in recipient mice, which received tamoxifen, no tumor LacZ staining was etected. However, when tumors were grown in endothelial-SCL-Cre-ERT;R26R mice 3 weeks after the cessation of tamoxifen treatment, there was widespread endothelial LacZ staining present. Thus, this genetic model strongly suggests that BM cells do not contribute to tumor endothelium and demonstrates the lineage relation between pre-existing endothelium and newly generated tumor endothelial cells. (C) 2004 by The American Society of Hematology.