Minimal contribution of marrow-derived endothelial precursors to tumor vasculature.
During embryogenesis, vascular and hemopoietic cells originate from a common precursor, the hemangioblast. Recent evidence suggests the existence of endothelial precursors in adult bone marrow cells, but it is unclear whether those precursors have a role in tumor neovascularization. In this report, we demonstrate that murine bone marrow contains endothelial progenitors, which arise from a cell with self-renewing capacity, and can integrate into tumor microvasculature, albeit at a very low frequency. A transgenic double-reporter strategy allowed us to demonstrate definitively that tumor bone marrow-derived endothelial cells arise by transdifferentiation of marrow progenitors rather than by cell fusion. Single cell transplants showed that a common precursor contributes to both the hemopoietic and endothelial lineages, thus demonstrating the presence of an adult hemangioblast. Furthermore, we demonstrate that increased vascular endothelial growth factor (VEGF)-A secretion by tumor cells, as well as activation of VEGF receptor-2 in bone marrow cells does not alter the mobilization and incorporation of marrow-derived endothelial progenitors into tumor vasculature. Finally, in human umbilical cord blood cells, we show that endothelial precursors make up only approximately 1 in 10(7) mononuclear cells but are highly enriched in the CD133+ cell population. By ruling out cell fusion, we clearly demonstrate the existence of an adult hemangioblast, but the differentiation of marrow stem cells toward the endothelial lineage is an extremely rare event. Furthermore, we show that VEGF-A stimulation of hemopoietic cells does not significantly alter this process.
Larrivée
Bruno
B
Department of Medicine, University of British Columbia, Canada.
Niessen
Kyle
K
Pollet
Ingrid
I
Corbel
Stéphane Y
SY
Long
Michael
M
Rossi
Fabio M
FM
Olive
Peggy L
PL
Karsan
Aly
A
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D019070:Cell Lineage; D042783:Endothelial Cells / Q000166:cytology*; D005312:Fetal Blood / Q000166:cytology; D006023:Glycoproteins / Q000032:analysis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000098:blood supply*; D010455:Peptides / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2