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 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 beta-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.
Göthert
Joachim R
JR
Division of Cancer Biology, Telethon Institute for Child Health Research, Centre for Child Health Research and Western Australian Institute for Medical Research, University of Western Australia, West Perth, Australia. joachim.goethert@uni-essen.de
Gustin
Sonja E
SE
van Eekelen
J Anke M
JA
Schmidt
Uli
U
Hall
Mark A
MA
Jane
Stephen M
SM
Green
Anthony R
AR
Göttgens
Berthold
B
Izon
David J
DJ
Begley
C Glenn
CG
D000375:Aging / Q000502:physiology; D000483:Alleles; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000473:pathology; D002454:Cell Differentiation; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D004727:Endothelium / Q000098:blood supply / Q000196:embryology / Q000378:metabolism* / Q000473:pathology*; D005434:Flow Cytometry; D017930:Genes, Reporter / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D011995:Recombination, Genetic / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology
D013629:Tamoxifen