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

Abstract

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.

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Figure 1: Transplantation of wild-type (WT) BM rescues tumor growth in Id-mutant mice.
Figure 2: Transplantation of WT BM restores vascular channel formation.
Figure 3: BM-derived cells reconstitute the angiogenic defect in Id1+/−Id3−/− mutant mice.
Figure 4: Contribution of VEGFR1+ hematopoietic cells in early vascularization.
Figure 5: Loss of the Id genes and neutralizing antibody against VEGFR2 impairs mobilization of CEPs.
Figure 6: Neutralizing antibody against both VEGFR1 and VEGFR2 is essential to completely block tumor angiogenesis and growth.

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Acknowledgements

We thank S. Kerns, S. Gonzalez, M. Besada, J. Knowles and J. Osoria and the Molecular Core facility (MSKCC) for technical assistance; H. Felsenfeld, S. Felsenfeld, O. Medina and J. Otero for discussions and critical reading; J. Doody and F. Liao for VE-Cadherin antibodies and discussions. This study was supported by the NCI CA 08748 (R.B.) NHLBI, R01 HL61849, HL66592 (S.R.), HL67839 (S.R., K.A.H. and D.L.), American Cancer Society-101396 (S.R.), The Leukemia and Lymphoma Society (S.R.), Portuguese Science and Technology Foundation (S.D. and C.C.) and partially by the Doris Duke foundation (D.L.), the Children's Brain Tumor Foundation (D.L.) and Angiogenex (R.B.).

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Correspondence to Robert Benezra or Shahin Rafii.

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Lyden, D., Hattori, K., Dias, S. et al. Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7, 1194–1201 (2001). https://doi.org/10.1038/nm1101-1194

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