| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of 1 Cancer Biology, 2 Medicine, Division of Rheumatology, 4 Division of Nephrology, and 6 Cell Biology, Vanderbilt University School of Medicine, Nashville, TN;
3 Immunex Corporation, Seattle, WA; and
5 Regeneron Inc., Tarrytown, NY
Requests for reprints: Jin Chen, Vanderbilt University School of Medicine, A-4323 MCN, 1161 21st Avenue South, Nashville, TN 37232. Phone: (615) 343-3819; Fax: (615) 343-7392. E-mail: Jin.Chen{at}mcmail.vanderbilt.edu
Angiogenesis is a multistep process involving a diverse array of molecular signals. Ligands for receptor tyrosine kinases (RTKs) have emerged as critical mediators of angiogenesis. Three families of ligands, vascular endothelial cell growth factors (VEGFs), angiopoietins, and ephrins, act via RTKs expressed in endothelial cells. Recent evidence indicates that VEGF cooperates with angiopoietins to regulate vascular remodeling and angiogenesis in both embryogenesis and tumor neovascularization. However, the relationship between VEGF and ephrins remains unclear. Here we show that interaction between EphA RTKs and ephrinA ligands is necessary for induction of maximal neovascularization by VEGF. EphA2 RTK is activated by VEGF through induction of ephrinA1 ligand. A soluble EphA2-Fc receptor inhibits VEGF-, but not basic fibroblast growth factor-induced endothelial cell survival, migration, sprouting, and corneal angiogenesis. As an independent, but complementary approach, EphA2 antisense oligonucleotides inhibited endothelial expression of EphA2 receptor and suppressed ephrinA1- and VEGF-induced cell migration. Taken together, these data indicate an essential role for EphA receptor activation in VEGF-dependent angiogenesis and suggest a potential new target for therapeutic intervention in pathogenic angiogenesis.
Key Words: Angiogenesis • Eph receptor tyrosine kinase • Ephrin ligand • VEGF
This article has been cited by other articles:
|
|
 |
|
  T. Yamashita, K. Ohneda, M. Nagano, C. Miyoshi, N. Kaneko, Y. Miwa, M. Yamamoto, O. Ohneda, and Y. Fujii-Kuriyama Hypoxia-inducible Transcription Factor-2{alpha} in Endothelial Cells Regulates Tumor Neovascularization through Activation of Ephrin A1 J. Biol. Chem., July 4, 2008; 283(27): 18926 - 18936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. B. Fang, D. M. Brantley-Sieders, Y. Hwang, A.-J. L. Ham, and J. Chen Identification and Functional Analysis of Phosphorylated Tyrosine Residues within EphA2 Receptor Tyrosine Kinase J. Biol. Chem., June 6, 2008; 283(23): 16017 - 16026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Niu, A. Azfer, O. Zhelyabovska, S. Fatma, and P. E. Kolattukudy Monocyte Chemotactic Protein (MCP)-1 Promotes Angiogenesis via a Novel Transcription Factor, MCP-1-induced Protein (MCPIP) J. Biol. Chem., May 23, 2008; 283(21): 14542 - 14551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Masuda, R. Usui, and Y. Maru Fibronectin Type I Repeat Is a Nonactivating Ligand for EphA1 and Inhibits ATF3-dependent Angiogenesis J. Biol. Chem., May 9, 2008; 283(19): 13148 - 13155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Larsen, M. W. Pedersen, M.-T. Stockhausen, M. V. Grandal, B. v. Deurs, and H. S. Poulsen Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor-Induced Cancer Cell Motility Mol. Cancer Res., March 1, 2007; 5(3): 283 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Alam, J Fujimoto, I Jahan, E Sato, and T Tamaya Overexpression of ephrinB2 and EphB4 in tumor advancement of uterine endometrial cancers Ann. Onc., March 1, 2007; 18(3): 485 - 490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kojima, J.-H. Chang, and D. T. Azar Proangiogenic Role of ephrinB1/EphB1 in Basic Fibroblast Growth Factor-Induced Corneal Angiogenesis Am. J. Pathol., February 1, 2007; 170(2): 764 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. N. Landen Jr., C. Lu, L. Y. Han, K. T. Coffman, E. Bruckheimer, J. Halder, L. S. Mangala, W. M. Merritt, Y. G. Lin, C. Gao, et al. Efficacy and Antivascular Effects of EphA2 Reduction With an Agonistic Antibody in Ovarian Cancer. J Natl Cancer Inst, November 1, 2006; 98(21): 1558 - 1570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Brantley-Sieders, W. B. Fang, Y. Hwang, D. Hicks, and J. Chen Ephrin-A1 Facilitates Mammary Tumor Metastasis through an Angiogenesis-Dependent Mechanism Mediated by EphA Receptor and Vascular Endothelial Growth Factor in Mice Cancer Res., November 1, 2006; 66(21): 10315 - 10324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ojima, H. Takagi, K. Suzuma, H. Oh, I. Suzuma, H. Ohashi, D. Watanabe, E. Suganami, T. Murakami, M. Kurimoto, et al. EphrinA1 Inhibits Vascular Endothelial Growth Factor-Induced Intracellular Signaling and Suppresses Retinal Neovascularization and Blood-Retinal Barrier Breakdown Am. J. Pathol., January 1, 2006; 168(1): 331 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. He, Y. Ding, J. Zhou, V. Krasnoperov, S. Zozulya, S. R. Kumar, S. J. Ryan, P. S. Gill, and D. R. Hinton Soluble EphB4 Regulates Choroidal Endothelial Cell Function and Inhibits Laser-Induced Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4772 - 4779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wykosky, D. M. Gibo, C. Stanton, and W. Debinski EphA2 as a Novel Molecular Marker and Target in Glioblastoma Multiforme Mol. Cancer Res., October 1, 2005; 3(10): 541 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Brantley-Sieders, J. Caughron, D. Hicks, A. Pozzi, J. C. Ruiz, and J. Chen EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation J. Cell Sci., April 15, 2004; 117(10): 2037 - 2049. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Noren, M. Lu, A. L. Freeman, M. Koolpe, and E. B. Pasquale Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth PNAS, April 13, 2004; 101(15): 5583 - 5588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bruhl, C. Urbich, D. Aicher, A. Acker-Palmer, A. M. Zeiher, and S. Dimmeler Homeobox A9 Transcriptionally Regulates the EphB4 Receptor to Modulate Endothelial Cell Migration and Tube Formation Circ. Res., April 2, 2004; 94(6): 743 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Hafner, G. Schmitz, S. Meyer, F. Bataille, P. Hau, T. Langmann, W. Dietmaier, M. Landthaler, and T. Vogt Differential Gene Expression of Eph Receptors and Ephrins in Benign Human Tissues and Cancers Clin. Chem., March 1, 2004; 50(3): 490 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. S. Alves, O. Faure, S. Graff-Dubois, D.-A. Gross, S. Cornet, S. Chouaib, I. Miconnet, F. A. Lemonnier, and K. Kosmatopoulos EphA2 as Target of Anticancer Immunotherapy: Identification of HLA-A*0201-Restricted Epitopes Cancer Res., December 1, 2003; 63(23): 8476 - 8480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Pratt and M. S. Kinch Ligand Binding Up-Regulates EphA2 Messenger RNA Through the Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Pathway Mol. Cancer Res., December 1, 2003; 1(14): 1070 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. El-Mousawi, L. Tchistiakova, L. Yurchenko, G. Pietrzynski, M. Moreno, D. Stanimirovic, D. Ahmad, and V. Alakhov A Vascular Endothelial Growth Factor High Affinity Receptor 1-specific Peptide with Antiangiogenic Activity Identified Using a Phage Display Peptide Library J. Biol. Chem., November 21, 2003; 278(47): 46681 - 46691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Palmer and R. Klein Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function Genes & Dev., June 15, 2003; 17(12): 1429 - 1450. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
