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Sci. Signal., 24 February 2009
Vol. 2, Issue 59, p. re1
[DOI: 10.1126/scisignal.259re1]


Positive and Negative Modulation of Angiogenesis by VEGFR1 Ligands

Yihai Cao*

Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.

Gloss: In order to grow beyond a mass that can be supported by diffusion to and from the vasculature of surrounding normal tissue, tumors must acquire their own blood supply. Abnormal vascularization also contributes to a range of nonmalignant diseases. The vascular endothelial growth factor (VEGF) family of five growth factors and three associated transmembrane receptor tyrosine kinases (VEGFR1, 2, and 3) are key modulators of normal and pathogenic angiogenic and vasculogenic processes. VEGF-A, when signaling through VEGFR2, is a potent mitogen for vascular endothelial cells. Targeting VEGF-A–mediated signaling is one treatment for several common cancers, although the benefits are currently modest. This Review, which contains four figures and 132 references, discusses the effect of placental growth factor (PlGF) and VEGF-B, two VEGF family members that bind exclusively to VEGFR1, on angiogenic processes and examines the possibility that concurrent targeting of VEGF-A and PlGF might improve the clinical effectiveness of antiangiogenic therapy in the treatment of malignant and nonmalignant diseases.

* Corresponding author. E-mail, yihai.cao{at}

Citation: Y. Cao, Positive and Negative Modulation of Angiogenesis by VEGFR1 Ligands. Sci. Signal. 2, re1 (2009).

Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth.
X. Yang, Y. Zhang, Y. Yang, S. Lim, Z. Cao, J. Rak, and Y. Cao (2013)
PNAS 110, 13932-13937
   Abstract »    Full Text »    PDF »
Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues.
Y. Yang, Y. Zhang, Z. Cao, H. Ji, X. Yang, H. Iwamoto, E. Wahlberg, T. Lanne, B. Sun, and Y. Cao (2013)
PNAS 110, 12018-12023
   Abstract »    Full Text »    PDF »
The Basis for the Distinct Biological Activities of Vascular Endothelial Growth Factor Receptor-1 Ligands.
A. Anisimov, V.-M. Leppanen, D. Tvorogov, G. Zarkada, M. Jeltsch, T. Holopainen, S. Kaijalainen, and K. Alitalo (2013)
Science Signaling 6, ra52
   Abstract »    Full Text »    PDF »
VEGFR1 and NRP1 Endothelial Expressions Predict Distant Relapse after Radical Prostatectomy in Clinically Localized Prostate Cancer.
Anticancer Res 33, 2065-2075
   Abstract »    Full Text »    PDF »
Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs.
E.-M. E. Hedlund, X. Yang, Y. Zhang, Y. Yang, M. Shibuya, W. Zhong, B. Sun, Y. Liu, K. Hosaka, and Y. Cao (2013)
PNAS 110, 654-659
   Abstract »    Full Text »    PDF »
Endothelial Differentiation of SHED Requires MEK1/ERK Signaling.
L. W. Bento, Z. Zhang, A. Imai, F. Nor, Z. Dong, S. Shi, F. B. Araujo, and J. E. Nor (2013)
Journal of Dental Research 92, 51-57
   Abstract »    Full Text »    PDF »
Overcoming Resistance to Antiangiogenic Therapies.
S. Tejpar, H. Prenen, and M. Mazzone (2012)
Oncologist 17, 1039-1050
   Abstract »    Full Text »    PDF »
Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes.
F. Guilloton, G. Caron, C. Menard, C. Pangault, P. Ame-Thomas, J. Dulong, J. De Vos, D. Rossille, C. Henry, T. Lamy, et al. (2012)
Blood 119, 2556-2567
   Abstract »    Full Text »    PDF »
{beta}-Hairpin Peptide That Targets Vascular Endothelial Growth Factor (VEGF) Receptors: DESIGN, NMR CHARACTERIZATION, AND BIOLOGICAL ACTIVITY.
D. Diana, A. Basile, L. De Rosa, R. Di Stasi, S. Auriemma, C. Arra, C. Pedone, M. C. Turco, R. Fattorusso, and L. D. D'Andrea (2011)
J. Biol. Chem. 286, 41680-41691
   Abstract »    Full Text »    PDF »
Bevacizumab Treatment for Advanced Breast Cancer.
R. H. Alvarez, V. Guarneri, F. Icli, S. Johnston, D. Khayat, S. Loibl, M. Martin, C. Zielinski, P. Conte, and G. N. Hortobagyi (2011)
Oncologist 16, 1684-1697
   Abstract »    Full Text »    PDF »
Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy.
J. Yao, X. Wu, G. Zhuang, I. M. Kasman, T. Vogt, V. Phan, M. Shibuya, N. Ferrara, and C. Bais (2011)
PNAS 108, 11590-11595
   Abstract »    Full Text »    PDF »
The Biflavonoid Amentoflavone Inhibits Neovascularization Preventing the Activity of Proangiogenic Vascular Endothelial Growth Factors.
V. Tarallo, L. Lepore, M. Marcellini, F. Dal Piaz, L. Tudisco, S. Ponticelli, F. W. Lund, P. Roepstorff, A. Orlandi, C. Pisano, et al. (2011)
J. Biol. Chem. 286, 19641-19651
   Abstract »    Full Text »    PDF »
Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding.
S. Xu, J. Wu, B. Sun, C. Zhong, and J. Ding (2011)
Nucleic Acids Res. 39, 4438-4449
   Abstract »    Full Text »    PDF »
Computational discrete models of tissue growth and regeneration.
F. Azuaje (2011)
Brief Bioinform 12, 64-77
   Abstract »    Full Text »    PDF »
VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer.
M. J. Waldner, S. Wirtz, A. Jefremow, M. Warntjen, C. Neufert, R. Atreya, C. Becker, B. Weigmann, M. Vieth, S. Rose-John, et al. (2010)
J. Exp. Med. 207, 2855-2868
   Abstract »    Full Text »    PDF »
Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis.
H. F. Langer, K.-J. Chung, V. V. Orlova, E. Y. Choi, S. Kaul, M. J. Kruhlak, M. Alatsatianos, R. A. DeAngelis, P. A. Roche, P. Magotti, et al. (2010)
Blood 116, 4395-4403
   Abstract »    Full Text »    PDF »
Do Anti-angiogenic or Angiogenic Factors Contribute to the Protection of Birth Weight at High Altitude Afforded by Andean Ancestry?.
R. D. Davila, C. G. Julian, M. J. Wilson, V. A. Browne, C. Rodriguez, A. W. Bigham, M. D. Shriver, E. Vargas, and L. G. Moore (2010)
Reproductive Sciences 17, 861-870
   Abstract »    PDF »
Wake-up call for endothelial cells.
Y. Cao (2010)
Blood 115, 2336-2337
   Full Text »    PDF »
A Placental Growth Factor Variant Unable to Recognize Vascular Endothelial Growth Factor (VEGF) Receptor-1 Inhibits VEGF-Dependent Tumor Angiogenesis via Heterodimerization.
V. Tarallo, L. Vesci, O. Capasso, M. T. Esposito, T. Riccioni, L. Pastore, A. Orlandi, C. Pisano, and S. De Falco (2010)
Cancer Res. 70, 1804-1813
   Abstract »    Full Text »    PDF »
VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy.
R. Cao, Y. Xue, E.-M. Hedlund, Z. Zhong, K. Tritsaris, B. Tondelli, F. Lucchini, Z. Zhu, S. Dissing, and Y. Cao (2010)
PNAS 107, 856-861
   Abstract »    Full Text »    PDF »
Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature.
E.-M. Hedlund, K. Hosaka, Z. Zhong, R. Cao, and Y. Cao (2009)
PNAS 106, 17505-17510
   Abstract »    Full Text »    PDF »

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