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 Cretransgenic mice (endothelial-SCL-Cre-ER T ) using the tamoxifen-inducible Cre-ER T recombinase driven by the 5 endothelial enhancer of the stem cell leukemia (SCL) locus. These mice were intercrossed with Cre reporter strains in which ␤-galactosidase (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-Cre-ER T ;R26R mice was transplanted into irradiated recipients. When tumors were grown in recipient mice, which received tamoxifen, no tumor LacZ staining was detected. However, when tumors were grown in endothelial-SCL-Cre-ER T ;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. IntroductionThe formation of new blood vessels is required for the growth and dissemination of cancer. Endothelial cells (ECs) play a central role during this process. 1,2 Until recently, it was thought that the generation of new blood vessels in postnatal life was solely due to angiogenesis. This process is mediated by sprouting of ECs from pre-existing vasculature. 3,4 However, recent studies have suggested the process of postnatal vasculogenesis also plays a role. Vasculogenesis involves the differentiation of primitive endothelial progenitor cells (EPCs), also known as angioblasts, into mature ECs. 5,6 Accumulating evidence suggests that bone marrow (BM) is the major source of EPCs in the adult, and administration of exogenous cytokines can induce mobilization of BM cells including EPCs. [7][8][9][10] Recently, controversy has arisen about the contribution of BMderived EPCs to tumor endothelium. 11 A number of studies have observed contribution of BM cells to tumor endothelium. 8,[12][13][14][15] In contrast, De Palma and colleagues 16 did not detect any BM-derived tumor ECs. Rather, they identified a population of cells that was recruited from BM to newly developing tumor vessels. This BM population expressed CD45 and macrophage antigen-1 (Mac-1) and appeared indispensable for tumor neoangiogenesis.In this study we created a new transgenic model, which allowed temporally controlled genetic marking of ECs to trace the origin of tumor endothelium. The basic helix...

Evidence for the lineage relationship between embryonic and adult hematopoietic stem cells (HSCs) in the mouse is primarily indirect. In order to study this relationship in a direct manner, we expressed the tamoxifen-inducible Cre-ER T recombinase under the control of the stem cell leukemia (Scl ) stem-cell enhancer in transgenic mice (HSC-SCL-Cre-ER T ). To determine functionality, HSC-SCL-Cre-ER T transgenics were bred with Cre reporter mice. Flow cytometric and transplantation studies revealed tamoxifen-dependent recombination occurring in more than 90% of adult long-term HSCs, whereas the targeted proportion within mature progenitor populations was significantly lower. Moreover, the transgene was able to irreversibly tag embryonic HSCs on days 10 and 11 of gestation. These cells contributed to bone marrow hematopoiesis 5 months later.