Abstract
The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aaltomaa S, Lipponen P, Papinaho S, Syrjanen K . 1993 J. Cancer Res. Clin Oncol. 119: 288–294
Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R . 1999a Genes Dev. 3: 295–306
Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R . 1999b Genes Dev. 13: 295–306
Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers HR, Folkman J . 1997 Proc. Natl. Acad. Sci. USA 94: 861–866
Aslakson CJ, Miller FR . 1992 Cancer Res. 52: 1399–1405
Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D . 2000 Nat. Cell Biol. 2: 737–744
Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D . 1999 Science 284: 808–812
Brantley DM, Chen CL, Muraoka RS, Bushdid PB, Bradberry JL, Kittrel F, Medina D, Matrisian LM, Kerr LD, Yull FE . 2001 Mol. Biol. Cell. 12: 1445–1455
Brantley DM, Yull FE, Muraoka RS, Hicks DJ, Cook CM, Kerr LD . 2000 Mech. Dev. 97: 149–155
Brekken RA, Huang X, King SW, Thorpe PE . 1998 Cancer Res. 58: 1952–1959
Chen J, Ruley HE . 1998 J. Biol. Chem. 273: 24670–24675
Cheng N, Brantley D, Chen J . 2002 Cytokine and Growth Factor Reviews 13: 75–85
Daniel TO, Stein E, Cerretti DP, St John PL, Robert B, Abrahamson DR . 1996 Kidney Int. Suppl 57: S73–S81
Dankort DL, Muller WJ . 1996 Transgenic models of breast cancer metastasis Kluwer Academic Publishers
Davis S, Gale NW, Aldrich TH, Maisonpierre PC, Lhotak V, Pawson T, Goldfarb M, Yancopoulos GD . 1994 Science 266: 816–819
Davy A, Gale NW, Murray EW, Klinghoffer RA, Soriano P, Feuerstein C, Robbins SM . 1999 Genes Dev. 13: 3125–3135
Davy A, Robbins SM . 2000 EMBO J. 19: 5396–5405
Easty DJ, Herlyn M, Bennett DC . 1995 Int. J. Cancer 60: 129–136
Easty DJ, Hill SP, Hsu MY, Fallowfield ME, Florenes VA, Herlyn M, Bennett DC . 1999 Int. J. Cancer 84: 494–501
Folkman J . 1990 J. Natl. Cancer Inst. 82: 4–6
Folkman J . 1994 J. Clin. Oncol. 12: 441–443
Folkman J, Watson K, Ingber D, Hanahan D . 1989 Nature 339: 58–61
Gale NW, Yancopoulos GD . 1997 Cell Tissue Res. 290: 227–241
Gale NW, Yancopoulos GD . 1999 Genes Dev. 13: 1055–1066
Gerety SS, Wang HU, Chen ZF, Anderson DJ . 1999 Molecular Cell 4: 403–414
Goede V, Fleckenstein G, Dietrich M, Osmers RG, Kuhn W, Augustin HG . 1998 Anticancer Res. 18: 2199–2202
Hanahan D . 1985 Nature 315: 115–122
Hattori M, Osterfield M, Flanagan JG . 2000 Science 289: 1360–1365
Holder N, Klein R . 1999 Development 126: 2033–2044
Holzman LB, Marks RM, Dixit VM . 1990 Mol. Cell. Biol. 10: 5830–5838
Huai J, Drescher U . 2001 J. Biol. Chem. 276: 6689–6694
Huang Q, Shan S, Braun RD, Lanzen J, Anyrhambatla G, Kong G, Borelli M, Corry P, Dewhirst MW, Li CY . 1999 Nat. Biotechnol. 17: 1033–1035
Kuehn R, Lelkes PI, Bloechle C, Niendorf A, Izbicki JR . 1999 Pancreas 18: 96–103
Laferriere J, Houle F, Taher MM, Valerie K, Huot J . 2001 J. Biol. Chem. 276: 33762–33772
Li CY, Shan S, Huang Q, Braun RD, Lanzen J, Hu K, Lin P, Dewhirst MW . 2000 J. Natl. Cancer Inst. 92: 143–147
Lin P, Buxton JA, Acheson A, Radziejewski C, Maisonpierre PC, Yancopoulos GD, Channon KM, Hale LP, Dewhirst MW, George SE, Peters KG . 1998 Proc. Natl. Acad. Sci. USA 95: 8829–8834
McBride JL, Ruiz JC . 1998 Nech. Dev. 77: 201–204
Muraoka RS, Lenferink AE, Simpson J, Brantley DM, Roebuck LR, Yakes FM, Arteaga CL . 2001 J. Cell Biol. 153: 917–932
Myers C, Charboneau A, Boudreau N . 2000 J. Cell Biol. 148: 343–351
Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL, Pasquale EB . 2000 Oncogene 19: 6043–6052
Owens RB, Smith HS, Hackett AJ . 1974 J. Natl. Cancer Inst. 53: 261–269
Pandey A, Shao H, Marks RM, Polverini PJ, Dixit VM . 1995 Science 268: 567–569
Papenfuss HD, Gross JF, Intaglietta M, Treese FA . 1979 Microvasc. Res. 18: 311–318
Passaniti A, Taylor RM, Pili R, Guo Y, Long PV, Haney JA, Pauly RR, Grant DS, Martin GR . 1992 Lab. Invest. 67: 519–528
Prewett M, Huber J, Li Y, Santiago A, O'Connor W, King K, Overholser J, Hooper A, Pytowski B, Witte L, Bohlen P, Hicklin DJ . 1999 Cancer Res. 59: 5209–5218
Preziosi R, Sarli G, Benazzi C, Marcato PS . 1995 J. Comp. Pathol. 113: 301–313
Radvanyi F, Christgau S, Baekkeskov S, Jolicoeur C, Hanahan D . 1993 Mol. Cell Biol. 13: 4223–4232
Rockwell S . 1977 Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 31: 153–160
Rockwell S . 1978 Br. J. Cancer Suppl 37: 212–215
Rockwell S . 1981 Cancer Res. 41: 527–531
Van den Broecke C, Vleminckx K, De Bruyne G, Van Hoorde L, Vakaet L, Van Roy F, Mareel M . 1996 Clin. Exp. Metastasis 14: 282–296
Walker-Daniels J, Coffman K, Azimi M, Rhim JS, Bostwick DG, Snyder P, Kerns BJ, Waters DJ, Kinch MS . 1999 The Prostate 41: 275–280
Wang HU, Chen ZF, Anderson DJ . 1998a Cell 93: 741–753
Weidner N . 1996 Angiogenesis and breast cancer Kluwer Academic Publishers
Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G . 1992 J. Natl. Cancer Inst. 84: 1875–1887
Weidner N, Semple JP, Welch WR, Folkman J . 1991 N. Engl. J. Med. 324: 1–8
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J . 2000 Nature 407: 242–248
Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R, Kinch MS . 1999 Cell Growth Differ. 10: 629–638
Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS . 2001 Cancer Res. 61: 2301–2306
Acknowledgements
We would like to thank Amanda Kizzee for excellent technical support, Nick Gale and George Yancopolous (Regeneron Inc.), Chuan-Huan Li and Mark Dewhirst (Duke University), and Doug Hanahan (UCSF) for providing EphA2-Fc construct, the 4T1-GFP subline, and RIP-Tag transgenic mice, respectively. Special thanks to Laura Debusk for assistance with cutaneous window assays, and to Rick Haselton for the transwell co-culture assay protocol and helpful discussions. We thank Ray Dubois, Brigid LM Hogan, and Lynn M Matrisian for helpful discussions, and give special thanks to Carlos L Arteaga for his ongoing support. This work was supported by National Institutes of Health grants HD36400 and DK47078, American Heart Association grant 97300889N, a JDF grant I-2001-519, and an ACS Institutional Research Grant IN-25-38 to J Chen, Vascular Biology Training Grant T32-HL-07751-06 and American Heart Association Fellowship 0120147B to D Brantley, and Cancer training grant T-32 CA09592 to N Cheng. This work was also supported by a core facilities grant 2P30CA68485 to the Vanderbilt-Ingram Cancer Center.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Brantley, D., Cheng, N., Thompson, E. et al. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21, 7011–7026 (2002). https://doi.org/10.1038/sj.onc.1205679
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205679
Keywords
This article is cited by
-
Tumor angiogenesis: causes, consequences, challenges and opportunities
Cellular and Molecular Life Sciences (2020)
-
Enabling AIEgens close assembly in tumor-overexpressed protein cluster for boosted image-guided cancer surgery
Science China Chemistry (2020)
-
Light-driven transformable optical agent with adaptive functions for boosting cancer surgery outcomes
Nature Communications (2018)
-
Dying to communicate: apoptotic functions of Eph/Ephrin proteins
Apoptosis (2018)
-
Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers
Oncogene (2017)