Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.
The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.
Lyden
D
D
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Hattori
K
K
Dias
S
S
Costa
C
C
Blaikie
P
P
Butros
L
L
Chadburn
A
A
Heissig
B
B
Marks
W
W
Witte
L
L
Wu
Y
Y
Hicklin
D
D
Zhu
Z
Z
Hackett
N R
NR
Crystal
R G
RG
Moore
M A
MA
Hajjar
K A
KA
Manova
K
K
Benezra
R
R
Rafii
S
S
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D009363:Neoplasm Proteins; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics; D009500:Neutralization Tests; D011518:Proto-Oncogene Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017978:Receptors, Growth Factor / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1
D004268:DNA-Binding Proteins; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; C075640:ID3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1