Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth.
The mechanisms by which bone marrow (BM)-derived stem cells might contribute to angiogenesis and the origin of neovascular endothelial cells (ECs) are controversial. Neovascular ECs have been proposed to originate from VEGF receptor 2-expressing (VEGFR-2+) stem cells mobilized from the BM by VEGF or tumors, and it is thought that angiogenesis and tumor growth may depend on such endothelial precursors or progenitors. We studied the mobilization of BM cells to circulation by inoculating mice with VEGF polypeptides, adenoviral vectors expressing VEGF, or tumors. We induced angiogenesis by syngeneic melanomas, APCmin adenomas, adenoviral VEGF delivery, or matrigel plugs in four different genetically tagged universal or endothelial cell-specific chimeric mouse models, and subsequently analyzed the contribution of BM-derived cells to endothelium in a wide range of time points. To study the existence of circulating ECs in a nonmyeloablative setting, pairs of genetically marked parabiotic mice with a shared anastomosed circulatory system were created. We did not observe specific mobilization of VEGFR-2+ cells to circulation by VEGF or tumors. During angiogenesis, abundant BM-derived perivascular cells were recruited close to blood vessel wall ECs but did not form part of the endothelium. No circulation-derived vascular ECs were observed in the parabiosis experiments. Our results show that no BM-derived VEGFR-2+ or other EC precursors contribute to vascular endothelium and that cancer growth does not require BM-derived endothelial progenitors. Endothelial differentiation is not a typical in vivo function of normal BM-derived stem cells in adults, and it has to be an extremely rare event if it occurs at all.
Purhonen
Susanna
S
Academy of Finland Center of Excellence in Cancer Biology and Molecular/Cancer Biology Laboratory, Molecular Cancer Biology Research Program, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
Palm
Jarmo
J
Rossi
Derrick
D
Kaskenpää
Nina
N
Rajantie
Iiro
I
Ylä-Herttuala
Seppo
S
Alitalo
Kari
K
Weissman
Irving L
IL
Salven
Petri
P
D000818:Animals; D001775:Blood Circulation / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D017930:Genes, Reporter; D007797:Laminin / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D009928:Organ Specificity / Q000187:drug effects; D010227:Parabiosis; D011509:Proteoglycans / Q000378:metabolism; D042810:Receptor, TIE-1 / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D042810:Receptor, TIE-1; D040301:Vascular Endothelial Growth Factor Receptor-2