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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BMDCs promote metastasis by producing chemokines that recruit tumor cells to the lung by mechanisms that include stimulation of tumor cell extravasation.
“The BMDCs promote metastasis by producing chemokines that recruit tumor cells to the lung by mechanisms that include stimulation of tumor cell extravasation”
From Hypoxic control of metastasis (2016) · cites this paper as [94]
Cites
Angiogenesis in cancer and other diseases
Carmeliet, P., & Jain, R. K. (2000) · Nature · doi:10.1038/35025220 · Cited by 9,070 · see citing works
Isolation of Putative Progenitor Endothelial Cells for Angiogenesis
Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee, R., Li, T., Witzenbichler, B., Schatteman, G., & Isner, J. M. (1997) · Science · doi:10.1126/science.275.5302.964 · Cited by 8,725 · see citing works
Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis
Hanahan, D., & Folkman, J. (1996) · Cell · doi:10.1016/s0092-8674(00)80108-7 · Cited by 6,885 · see citing works
Vascular Endothelial Growth Factor Is a Secreted Angiogenic Mitogen
Leung, D. W., Cachianes, G., Kuang, W.-J., Goeddel, D. V., & Ferrara, N. (1989) · Science · doi:10.1126/science.2479986 · Cited by 4,988 · see citing works
Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele
Carmeliet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kieckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., et al. (1996) · Nature · doi:10.1038/380435a0 · Cited by 4,114 · see citing works
Vascular-specific growth factors and blood vessel formation
Yancopoulos, G. D., Davis, S., Gale, N. W., Rudge, J. S., Wiegand, S. J., & Holash, J. (2000) · Nature · doi:10.1038/35025215 · Cited by 3,699 · see citing works
Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene
Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O’Shea, K. S., Powell-Braxton, L., Hillan, K. J., & Moore, M. W. (1996) · Nature · doi:10.1038/380439a0 · Cited by 3,624 · see citing works
Self-citationKim, K. J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H. S., & Ferrara, N. (1993) · Nature · doi:10.1038/362841a0 · Cited by 3,605 · see citing works
Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium
Fong, G.-H., Rossant, J., Gertsenstein, M., & Breitman, M. L. (1995) · Nature · doi:10.1038/376066a0 · Cited by 2,606 · see citing works
Takahashi, T., Kalka, C., Masuda, H., Chen, D., Silver, M., Kearney, M., Magner, M., Isner, J. M., & Asahara, T. (1999) · Nature Medicine · doi:10.1038/7434 · Cited by 2,421 · see citing works
Peichev, M., Naiyer, A. J., Pereira, D., Zhu, Z., Lane, W. J., Williams, M., Oz, M., Hicklin, D. J., Witte, L., Moore, M. A. S., et al. (2000) · Blood · doi:10.1182/blood.v95.3.952.003k27_952_958 · Cited by 2,274 · see citing works
Self-citationVessel Cooption, Regression, and Growth in Tumors Mediated by Angiopoietins and VEGF
Holash, J. A., Maisonpierre, P. C., Compton, D. L., Boland, P., Alexander, C., Zagzag, D., Yancopoulos, G. D., & Wiegand, S. J. (1999) · Science · doi:10.1126/science.284.5422.1994 · Cited by 2,181 · see citing works
Induction of angiogenesis during the transition from hyperplasia to neoplasia
Folkman, J., Watson, K., Ingber, D., & Hanahan, D. (1989) · Nature · doi:10.1038/339058a0 · Cited by 1,879 · see citing works
Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization
Kalka, C., Masuda, H., Takahashi, T., Kalka-Moll, W. M., Silver, M., Kearney, M., Li, T., Isner, J. M., & Asahara, T. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3422 · Cited by 1,862 · see citing works
Evidence for Circulating Bone Marrow-Derived Endothelial Cells
Shi, Q., Rafii, S., Wu, M. H.-D., Wijelath, E. S., Yu, C., Ishida, A., Fujita, Y., Kothari, S., Möhle, R., Sauvage, L. R., et al. (1998) · Blood · doi:10.1182/blood.v92.2.362 · Cited by 1,694 · see citing works
Self-citationCarmeliet, P., Moons, L., Luttun, A., Vincenti, V., Compernolle, V., Mol, M. D., Wu, Y., Bono, F., Devy, L., Beck, H., et al. (2001) · Nature Medicine · doi:10.1038/87904 · Cited by 1,673 · see citing works
Self-citationOrigins of circulating endothelial cells and endothelial outgrowth from blood
Lin, Y., Weisdorf, D. J., Solovey, A. N., & Hebbel, R. P. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8071 · Cited by 1,531 · see citing works
MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis
Coussens, L. M., Tinkle, C. L., Hanahan, D., & Werb, Z. (2000) · Cell · doi:10.1016/s0092-8674(00)00139-2 · Cited by 1,306 · see citing works
Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts
Lyden, D. C., Young, A. Z., Zagzag, D., Yan, W. X., Gerald, W. L., O'Reilly, R., Bader, B., Hynes, R. O., Zhuang, Y., Manova, K., et al. (1999) · Nature · doi:10.1038/44334 · Cited by 912 · see citing works
Self-citationGill, M., Dias, S., Hattori, K., Rivera, M., Hicklin, D. J., Witte, L., Girardi, L. N., Yurt, R. W., Himel, H. N., & Rafii, S. (2001) · Circulation Research · doi:10.1161/01.res.88.2.167 · Cited by 797 · see citing works
Self-citationHattori, K., Dias, S., Heissig, B., Hackett, N. R., Lyden, D. C., Tateno, M., Hicklin, D. J., Zhu, Z., Witte, L., Crystal, R. G., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.9.1005 · Cited by 685 · see citing works
Self-citationPrewett, M. C., Huber, J., Li, Y., Santiago, A., O'Connor, W., King, K. D., Overholser, J. C., Hooper, A. T., Pytowski, B., Witte, L., et al. (1999) · PubMed · Cited by 660 · see citing works
Self-citationA Role for Hematopoietic Stem Cells in Promoting Angiogenesis
Takakura, N., Watanabe, T., Suenobu, S., Yamada, Y., Noda, T., Ito, Y., Satake, M., & Suda, T. (2000) · Cell · doi:10.1016/s0092-8674(00)00025-8 · Cited by 501 · see citing works
Fong, G., Zhang, L., Bryce, D. M., & Peng, J. (1999) · Development · doi:10.1242/dev.126.13.3015 · Cited by 459 · see citing works
Donovan, M. J., Lin, M. I., Wiegn, P., Ringstedt, T., Kraemer, R. T., Hahn, R. T., Wang, S., Ibáñez, C. F., Rafii, S., & Hempstead, B. L. (2000) · Development · doi:10.1242/dev.127.21.4531 · Cited by 435 · see citing works
Self-citationCirculating endothelial precursors: mystery, reality, and promise
Rafii, S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8774 · Cited by 434 · see citing works
Self-citationId helix—loop—helix proteins in cell growth and differentiation
Norton, J. D., Deed, R. W., Craggs, G., & Sablitzky, F. (1998) · Trends in Cell Biology · doi:10.1016/s0962-8924(98)80013-5 · Cited by 410 · see citing works
Jain, R. K., Safabakhsh, N., Sckell, A., Chen, Y., Jiang, P., Benjamin, L., Yuan, F., & Keshet, E. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10820 · Cited by 374 · see citing works
Tam, P., Parameswaran, M., Kinder, S. J., & Weinberger, R. P. (1997) · Development · doi:10.1242/dev.124.9.1631 · Cited by 274 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microenvironmental regulation of tumor progression and metastasis
Quail, D. F., & Joyce, J. A. (2013) · Nature Medicine · doi:10.1038/nm.3394 · Cited by 7,994 · see citing works
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Hanahan, D., & Coussens, L. M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.022 · Cited by 4,632 · see citing works
Angiogenesis in health and disease
Carmeliet, P. (2003) · Nature Medicine · doi:10.1038/nm0603-653 · Cited by 4,258 · see citing works
Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., Carey, V. J., Richardson, A. L., & Weinberg, R. A. (2005) · Cell · doi:10.1016/j.cell.2005.02.034 · Cited by 3,759 · see citing works
Vascular Endothelial Growth Factor: Basic Science and Clinical Progress
Ferrara, N. (2004) · Endocrine Reviews · doi:10.1210/er.2003-0027 · Cited by 3,707 · see citing works
Tumorigenesis and the angiogenic switch
Bergers, G., & Benjamin, L. E. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1093 · Cited by 3,559 · see citing works
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche
Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., et al. (2005) · Nature · doi:10.1038/nature04186 · Cited by 3,288 · see citing works
Self-citationVEGF receptor signalling ? in control of vascular function
Olsson, A.-K., Dimberg, A., Kreuger, J., & Claesson-Welsh, L. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1911 · Cited by 3,122 · see citing works
Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis
Hicklin, D. J., & Ellis, L. M. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2005.06.081 · Cited by 3,010 · see citing works
Self-citationAngiogenesis as a therapeutic target
Ferrara, N., & Kerbel, R. S. (2005) · Nature · doi:10.1038/nature04483 · Cited by 2,653 · see citing works
Urbich, C., & Dimmeler, S. (2004) · Circulation Research · doi:10.1161/01.res.0000137877.89448.78 · Cited by 2,364 · see citing works
Endothelial-to-mesenchymal transition contributes to cardiac fibrosis
Zeisberg, E. M., Tarnavski, O., Zeisberg, M., Dorfman, A. L., McMullen, J. R., Gustafsson, E., Chandraker, A. K., Yuan, X., Pu, W. T., Roberts, A. B., et al. (2007) · Nature Medicine · doi:10.1038/nm1613 · Cited by 2,224 · see citing works
Nanomedicine: current status and future prospects
Moghimi, S. M., Hunter, A. C., & Murray, J. C. (2005) · The FASEB Journal · doi:10.1096/fj.04-2747rev · Cited by 2,029 · see citing works
Targeting cancer stem cell pathways for cancer therapy
Yang, L., Shi, P., Zhao, G., Xu, J., Peng, W., Zhang, J., Zhang, G., Wang, X., Dong, Z., Chen, F., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0110-5 · Cited by 1,920 · see citing works
Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D. C., Moore, M. A. S., et al. (2002) · Cell · doi:10.1016/s0092-8674(02)00754-7 · Cited by 1,744 · see citing works
Self-citationTumor angiogenesis: molecular pathways and therapeutic targets
Weis, S. M., & Cheresh, D. A. (2011) · Nature Medicine · doi:10.1038/nm.2537 · Cited by 1,739 · see citing works
VEGF-targeted therapy: mechanisms of anti-tumour activity
Ellis, L. M., & Hicklin, D. J. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2403 · Cited by 1,673 · see citing works
Self-citationThe role of myeloid cells in the promotion of tumour angiogenesis
Murdoch, C., Muthana, M., Coffelt, S. B., & Lewis, C. E. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2444 · Cited by 1,642 · see citing works
Tumor Response to Radiotherapy Regulated by Endothelial Cell Apoptosis
Garcı́a-Barros, M., Paris, F., Cordon‐Cardo, C., Lyden, D. C., Rafii, S., Haimovitz‐Friedman, A., FUKS, Z. Y., & Kolesnick, R. (2003) · Science · doi:10.1126/science.1082504 · Cited by 1,591 · see citing works
Self-citationTherapeutic stem and progenitor cell transplantation for organ vascularization and regeneration
Rafii, S., & Lyden, D. C. (2003) · Nature Medicine · doi:10.1038/nm0603-702 · Cited by 1,572 · see citing works
Self-citationTumor angiogenesis and vascular normalization: alternative therapeutic targets
Viallard, C., & Larrivée, B. (2017) · Angiogenesis · doi:10.1007/s10456-017-9562-9 · Cited by 1,435 · see citing works
The anti-angiogenic basis of metronomic chemotherapy
Kerbel, R. S., & Kamen, B. A. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1369 · Cited by 1,396 · see citing works
Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340 · see citing works
De Palma, M., Venneri, M. A., Galli, R., Sergi, L. S., Politi, L. S., Sampaolesi, M., & Naldini, L. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.08.002 · Cited by 1,311 · see citing works
Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells
Aicher, A., Heeschen, C., Mildner-Rihm, C., Urbich, C., Ihling, C. H., Technau‐Ihling, K., Zeiher, A. M., & Dimmeler, S. (2003) · Nature Medicine · doi:10.1038/nm948 · Cited by 1,297 · see citing works
The metastatic niche: adapting the foreign soil
Psaila, B., & Lyden, D. C. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2621 · Cited by 1,302 · see citing works
Self-citationTumors as Organs: Complex Tissues that Interface with the Entire Organism
Egeblad, M., Nakasone, E. S., & Werb, Z. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.05.012 · Cited by 1,230 · see citing works
Folkman, J. (2006) · Annual Review of Medicine · doi:10.1146/annurev.med.57.121304.131306 · Cited by 1,209 · see citing works
Glioblastoma stem-like cells give rise to tumour endothelium
Wang, R., Chadalavada, K., Wilshire, J. A., Kowalik, U., Hovinga, K. E., Geber, A. B., Fligelman, B., Leversha, M. A., Brennan, C., & Tabar, V. S. (2010) · Nature · doi:10.1038/nature09624 · Cited by 1,203 · see citing works
Yamaguchi, J.-I., Kusano, K. F., Masuo, O., Kawamoto, A., Silver, M., Murasawa, S., Bosch‐Marcé, M., Masuda, H., Losordo, D. W., Isner, J. M., et al. (2003) · Circulation · doi:10.1161/01.cir.0000055313.77510.22 · Cited by 1,149 · see citing works
History of myeloid-derived suppressor cells
Talmadge, J. E., & Gabrilovich, D. I. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3581 · Cited by 1,148 · see citing works
Yang, L., DeBusk, L. M., Fukuda, K., Fingleton, B., Green-Jarvis, B., Shyr, Y., Matrisian, L. M., Carbone, D. P., & Lin, P. C. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.08.031 · Cited by 1,140 · see citing works
Du, R., Lu, K. V., Petritsch, C. K., Liu, P., Ganß, R., Passegue, E. A., Song, H., VandenBerg, S. R., Johnson, R. S., Werb, Z., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.01.034 · Cited by 1,131 · see citing works
VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells
Grunewald, M., Avraham, I., Dor, Y., Bachar-Lustig, E., Itin, A., Yung, S., Chimenti, S., Landsman, L., Abramovitch, R., & Keshet, E. (2006) · Cell · doi:10.1016/j.cell.2005.10.036 · Cited by 1,125 · see citing works
Luttun, A., Tjwa, M., Moons, L., Wu, Y. L., Angelillo‐Scherrer, A., Liao, F., Nagy, J. A., Hooper, A. T., Priller, J., Klerck, B. D., et al. (2002) · Nature Medicine · doi:10.1038/nm731 · Cited by 1,067 · see citing works
Self-citationSignal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis
Shibuya, M., & Claesson, L. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2005.11.012 · Cited by 1,063 · see citing works
Integrins in angiogenesis and lymphangiogenesis
Avraamides, C. J., Garmy-Susini, B., & Varner, J. A. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2353 · Cited by 1,050 · see citing works
Smyth, M. J., Dunn, G. P., & Schreiber, R. D. (2006) · Advances in immunology · doi:10.1016/s0065-2776(06)90001-7 · Cited by 872 · see citing works
VEGF-receptor signal transduction
Cross, M. J., Dixelius, J., Matsumoto, T., & Claesson, L. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00193-2 · Cited by 864 · see citing works
Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells
Shojaei, F., Wu, X., Malik, A. K., Zhong, C., Baldwin, M. E., Schanz, S., Fuh, G., Gerber, H.-P., & Ferrara, N. (2007) · Nature Biotechnology · doi:10.1038/nbt1323 · Cited by 849 · see citing works
Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization
Heeschen, C., Aicher, A., Lehmann, R., Fichtlscherer, S., Vasa‐Nicotera, M., Urbich, C., Mildner-Rihm, C., Martin, H., Zeiher, A. M., & Dimmeler, S. (2003) · Blood · doi:10.1182/blood-2003-01-0223 · Cited by 840 · see citing works
Rapid vascular regrowth in tumors after reversal of VEGF inhibition
Mancuso, M. R., Davis, R. B., Norberg, S. M., O’Brien, S., Sennino, B., Nakahara, T., Yao, V., Inai, T., Brooks, P. C., Freimark, B. D., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci24612 · Cited by 814 · see citing works
Lymphangiogenesis and lymphatic vessel remodelling in cancer
Stacker, S. A., Williams, S. P., Karnezis, T., Shayan, R., Fox, S. B., & Achen, M. G. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3677 · Cited by 812 · see citing works
Cellular abnormalities of blood vessels as targets in cancer
Bałuk, P., Hashizume, H., & McDonald, D. M. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.12.005 · Cited by 784 · see citing works
Kioi, M., Vogel, H. S., Schultz, G. M., Hoffman, R. M., Harsh, G. R., & Brown, J. M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40283 · Cited by 775 · see citing works
Targeting the tumour vasculature: insights from physiological angiogenesis
Chung, A. S., Lee, J., & Ferrara, N. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2868 · Cited by 751 · see citing works
Tumor metastasis: moving new biological insights into the clinic
Wan, L., Pantel, K., & Kang, Y. (2013) · Nature Medicine · doi:10.1038/nm.3391 · Cited by 746 · see citing works
Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions
Vasudev, N. S., & Reynolds, A. R. (2014) · Angiogenesis · doi:10.1007/s10456-014-9420-y · Cited by 735 · see citing works
Angiogenesis modulates adipogenesis and obesity
Cao, Y. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32239 · Cited by 736 · see citing works
Kolluru, G. K., Bir, S. C., & Kevil, C. G. (2012) · International Journal of Vascular Medicine · doi:10.1155/2012/918267 · Cited by 729 · see citing works
The brain tumor microenvironment
Charles, N. A., Holland, E. C., Gilbertson, R. J., Glaß, R., & Kettenmann, H. (2011) · Glia · doi:10.1002/glia.21264 · Cited by 712 · see citing works
VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism
Gerber, H., Malik, A. K., Solar, G. P., Sherman, D. A., Liang, X. H., Meng, G., Hong, K., Marsters, J. C., & Ferrara, N. (2002) · Nature · doi:10.1038/nature00821 · Cited by 706 · see citing works
The brain tumor microenvironment
Charles, N. A., Holland, E. C., Gilbertson, R., Glass, R., & Kettenmann, H. (2011) · Glia · doi:10.1002/glia.21136 · Cited by 718 · see citing works
Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?
Rafii, S., Lyden, D. C., Benezra, R., Hattori, K., & Heissig, B. (2002) · Nature reviews. Cancer · doi:10.1038/nrc925 · Cited by 678 · see citing works
Self-citationAngiogenesis-Independent Endothelial Protection of Liver: Role of VEGFR-1
LeCouter, J. E., Moritz, D. R., Li, B., Phillips, G. D. L., Liang, X. H., Gerber, H., Hillan, K. J., & Ferrara, N. (2003) · Science · doi:10.1126/science.1079562 · Cited by 677 · see citing works
Qian, B., Deng, Y., Im, J. H., Muschel, R. J., Zou, Y., Li, J., Lang, R. A., & Pollard, J. W. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006562 · Cited by 664 · see citing works
Preparing the “Soil”: The Premetastatic Niche
Kaplan, R. N., Rafii, S., & Lyden, D. C. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2407 · Cited by 665 · see citing works
Self-citationThe secreted factors responsible for pre-metastatic niche formation: Old sayings and new thoughts
Peinado, H., Lavotshkin, S., & Lyden, D. C. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.01.002 · Cited by 657 · see citing works
Self-citationReactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy
Ushio‐Fukai, M., & Nakamura, Y. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.02.044 · Cited by 651 · see citing works
Jin, D. K., Shido, K., Kopp, H., Petit, I., Shmelkov, S. V., Young, L. M., Hooper, A. T., Amano, H., Avecilla, S. T., Heissig, B., et al. (2006) · Nature Medicine · doi:10.1038/nm1400 · Cited by 645 · see citing works
Self-citationHu‐Lowe, D. D., Zou, H. Y., Grazzini, M. L., Hallin, M. E., Wickman, G., Amundson, K., Chen, J. H., Rewolinski, D. A., Yamazaki, S., Wu, X., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0652 · Cited by 640 · see citing works
Endothelial Progenitor Cells Control the Angiogenic Switch in Mouse Lung Metastasis
Gao, D., Nolan, D. J., Mellick, A. S., Bambino, K., McDonnell, K., & Mittal, V. (2008) · Science · doi:10.1126/science.1150224 · Cited by 632 · see citing works
Hattori, K., Heissig, B., Wu, Y. L., Dias, S., Tejada, R., Ferris, B., Hicklin, D. J., Zhu, Z., Böhlen, P., Witte, L., et al. (2002) · Nature Medicine · doi:10.1038/nm740 · Cited by 632 · see citing works
Self-citationGerber, H., & Ferrara, N. (2005) · Cancer Research · doi:10.1158/0008-5472.671.65.3 · Cited by 626 · see citing works
Differential Roles of Vascular Endothelial Growth Factor Receptor-1 and Receptor-2 in Angiogenesis
Shibuya, M. (2006) · BMB Reports · doi:10.5483/bmbrep.2006.39.5.469 · Cited by 623 · see citing works
Breast cancer stem cells, cytokine networks, and the tumor microenvironment
Körkaya, H., Liu, S., & Wicha, M. S. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57099 · Cited by 616 · see citing works
The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis
Petit, I., Jin, D. K., & Rafii, S. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.05.007 · Cited by 605 · see citing works
Self-citationIn vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight
Dahlman, J. E., Barnes, C., Khan, O. F., Thiriot, A., Jhunjhunwala, S., Shaw, T. E., Xing, Y., Sager, H. B., Sahay, G., Speciner, L., et al. (2014) · Nature Nanotechnology · doi:10.1038/nnano.2014.84 · Cited by 593 · see citing works
Tumour vascularization: sprouting angiogenesis and beyond
Hillen, F., & Griffioen, A. W. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9094-7 · Cited by 583 · see citing works
Therapeutic targeting of the tumor microenvironment
Joyce, J. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.024 · Cited by 580 · see citing works
Butler, J. M., Kobayashi, H., & Rafii, S. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2791 · Cited by 578 · see citing works
Self-citationId proteins in development, cell cycle and cancer
Ruzinova, M. B., & Benezra, R. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(03)00147-8 · Cited by 570 · see citing works
Self-citationThe multifaceted circulating endothelial cell in cancer: towards marker and target identification
Bertolini, F., Shaked, Y., Mancuso, P., & Kerbel, R. S. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1971 · Cited by 575 · see citing works
Vascular Endothelial Growth Factor as a Target for Anticancer Therapy
Ferrara, N. (2004) · The Oncologist · doi:10.1634/theoncologist.9-suppl_1-2 · Cited by 575 · see citing works
Comparative biology of mouse versus human cells: modelling human cancer in mice
Rangarajan, A., & Weinberg, R. A. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1235 · Cited by 567 · see citing works
FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?
Fischer, C., Mazzone, M., Jonckx, B., & Carmeliet, P. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2524 · Cited by 566 · see citing works
Therapy-Induced Acute Recruitment of Circulating Endothelial Progenitor Cells to Tumors
Shaked, Y., Ciarrocchi, A., Franco, M., Lee, C. R., Man, S., Cheung, A., Hicklin, D. J., Chaplin, D. J., Foster, F. S., Benezra, R., et al. (2006) · Science · doi:10.1126/science.1127592 · Cited by 568 · see citing works
Self-citationJabłońska, J., Leschner, S., Westphal, K., Lienenklaus, S., & Weiß, S. (2010) · Journal of Clinical Investigation · doi:10.1172/jci37223 · Cited by 563 · see citing works
Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective
Kowanetz, M., & Ferrara, N. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1520 · Cited by 564 · see citing works
Hamano, Y., Zeisberg, M., Sugimoto, H., Lively, J. C., Maeshima, Y., Yang, C., Hynes, R. O., Werb, Z., Sudhakar, A., & Kalluri, R. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00133-8 · Cited by 560 · see citing works
Matsui, J., Yamamoto, Y., Funahashi, Y., Tsuruoka, A., Watanabe, T., Wakabayashi, T., Uenaka, T., & Asada, M. (2007) · International Journal of Cancer · doi:10.1002/ijc.23131 · Cited by 548 · see citing works
Song, S., Ewald, A. J., Stallcup, W. B., Werb, Z., & Bergers, G. (2005) · Nature Cell Biology · doi:10.1038/ncb1288 · Cited by 551 · see citing works
Palma, M. D., Venneri, M. A., Roca, C., & Naldini, L. (2003) · Nature Medicine · doi:10.1038/nm871 · Cited by 549 · see citing works
Id family of helix-loop-helix proteins in cancer
Perk, J., Iavarone, A., & Benezra, R. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1673 · Cited by 535 · see citing works
Self-citationGupta, K., Kshirsagar, S. A., Chang, L., Schwartz, R. E., Law, P., Yee, D., & Hebbel, R. P. (2002) · PubMed · Cited by 527 · see citing works
Roles for Growth Factors in Cancer Progression
Witsch, E., Sela, M., & Yarden, Y. (2010) · Physiology · doi:10.1152/physiol.00045.2009 · Cited by 525 · see citing works
Endothelial progenitor cells for postnatal vasculogenesis
Asahara, T., & Kawamoto, A. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00330.2003 · Cited by 524 · see citing works
Venneri, M. A., Palma, M. D., Ponzoni, M., Pucci, F., Scielzo, C., Zonari, E., Mazzieri, R., Doglioni, C., & Naldini, L. (2007) · Blood · doi:10.1182/blood-2006-10-053504 · Cited by 504 · see citing works
Angiogenesis and chronic inflammation: cause or consequence?
Costa, C., Incio, J., & Soares, R. A. (2007) · Angiogenesis · doi:10.1007/s10456-007-9074-0 · Cited by 502 · see citing works
Self-citationEndothelial progenitor cells: identity defined?
Timmermans, F., Plum, J. R., Yöder, M. C., Ingram, D. A., Vandekerckhove, B., & Case, J. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00598.x · Cited by 494 · see citing works
Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy
Patel, S. A., Nilsson, M. B., Le, X., Cascone, T., Jain, R. K., & Heymach, J. V. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-1366 · Cited by 493 · see citing works
Contribution of bone marrow–derived endothelial cells to human tumor vasculature
Peters, B. A., Diaz, L. A., Polyák, K., Meszler, L., Romans, K., Guinan, E. C., Antin, J. H., Myerson, D., Hamilton, S. R., Vogelstein, B., et al. (2005) · Nature Medicine · doi:10.1038/nm1200 · Cited by 481 · see citing works
Mechanisms of Glioma-Associated Neovascularization
Hardee, M. E., & Zagzag, D. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.06.030 · Cited by 476 · see citing works
Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism
Malone, A. M. D., Anderson, C. T., Tummala, P., Kwon, R. Y., Johnston, T. R., Stearns, T., & Jacobs, C. R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700636104 · Cited by 477 · see citing works
Casbon, A.-J., Reynaud, D., Park, C., Khuc, E., Gan, D. D., Schepers, K., Passegue, E. A., & Werb, Z. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1424927112 · Cited by 475 · see citing works
Strategies for optimizing the response of cancer and normal tissues to radiation
Moding, E. J., Kastan, M. B., & Kirsch, D. G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4003 · Cited by 461 · see citing works
Easton, J. B., & Houghton, P. J. (2006) · Oncogene · doi:10.1038/sj.onc.1209886 · Cited by 460 · see citing works
Bertolini, F., Paul, S., Mancuso, P., Monestiroli, S., Gobbi, A., Shaked, Y., & Kerbel, R. S. (2003) · PubMed · Cited by 458 · see citing works
Tepper, O. M., Capla, J. M., Galiano, R. D., Ceradini, D. J., Callaghan, M. J., Kleinman, M. E., & Gurtner, G. C. (2004) · Blood · doi:10.1182/blood-2004-03-1051 · Cited by 446 · see citing works
Early Breast Cancer Therapy and Cardiovascular Injury
Jones, L. W., Haykowsky, M. J., Swartz, J. J., Douglas, P. S., & Mackey, J. R. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.06.037 · Cited by 446 · see citing works
- Authors
- Lyden, 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, N. R., Crystal, R. G., Moore, M. A. S., Hajjar, K. A., Manova, K., Benezra, R., & Rafii, S.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- Corresponding author
- Benezra, Robert
- Rafii, Shahin
- ORCID
- Venue
- Nature Medicine
- Published
- 2001-11
- Volume
- 7
- Issue
- 11
- Pages
- 1194-1201
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1485875137
- Cited by
- 1,860
- References
- 29
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 11 · 2023: 23 · 2022: 35 · 2021: 22 · 2020: 25 · 2019: 38 · 2018: 27 · 2017: 49 · 2016: 49 · 2015: 49 · 2014: 72 · 2013: 103 · 2012: 110
- FWCI
- 34.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01-HL-61849, HL 67839, R01HL061849, HL-66592, P01HL067839)
- National Cancer Institute (CA08748, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- tumor angiogenesis, endothelial progenitor cells, hematopoietic progenitor cells, vascular endothelial growth factor, VEGFR1, VEGFR2, tumor growth, myeloid cells, neovascularization, anti-angiogenic therapy
- MeSH terms
- Animals, DNA-Binding Proteins, Endothelium, Vascular, Hematopoietic Stem Cells, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Neoplasm Proteins, Neoplasms, Experimental, Neovascularization, Pathologic, Neutralization Tests, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Receptors, Growth Factor, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Receptor Protein-Tyrosine Kinases, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor Receptor-1, Mice, Inhibitor of Differentiation Proteins, Inhibitor of Differentiation Protein 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
