Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.

TitleImpaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.
Publication TypeJournal Article
Year of Publication2001
AuthorsLyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S
JournalNat Med
Date Published2001 Nov
KeywordsAnimals, DNA-Binding Proteins, Endothelium, Vascular, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Inhibitor of Differentiation Protein 1, Inhibitor of Differentiation Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Mutation, Neoplasm Proteins, Neoplasms, Experimental, Neovascularization, Pathologic, Neutralization Tests, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Receptors, Growth Factor, Receptors, Vascular Endothelial Growth Factor, Repressor Proteins, Transcription Factors, Vascular Endothelial Growth Factor Receptor-1

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.

Alternate JournalNat Med
PubMed ID11689883
Grant ListCA 08748 / CA / NCI NIH HHS / United States
HL67839 / HL / NHLBI NIH HHS / United States
R01 HL61849 / HL / NHLBI NIH HHS / United States
HL66592 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Amy Chadburn, M.D.

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