Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF

Abstract

Our analyses in several different tumor settings challenge the prevailing view that malignancies and metastases generally initiate as avascular masses that only belatedly induce vascular support. Instead, we find that malignant cells rapidly coopt existing host vessels to form an initially well-vascularized tumor mass. Paradoxically, the coopted vasculature does not undergo angiogenesis to support the growing tumor, but instead regresses (perhaps as part of a normal host defense mechanism) via a process that involves disruption of endothelial cell/smooth muscle cell interactions and endothelial cell apoptosis. This vessel regression in turn results in necrosis within the central part of the tumor. However, robust angiogenesis is initiated at the tumor margin, rescuing the surviving tumor and supporting further growth. The expression patterns of Angiopoietin-2 (the natural antagonist for the angiogenic Tie2 receptor) and vascular endothelial growth factor (VEGF) strongly implicate these factors in the above processes. Angiopoietin-2 is highly induced in co-opted vessels, prior to VEGF induction in the adjacent tumor cells, providing perhaps the earliest marker of tumor vasculature and apparently marking the coopted vessels for regression. Subsequently, VEGF upregulation coincident with Angiopoietin-2 expression at the tumor periphery is associated with robust angiogenesis. Thus, in tumors, Angiopoietin-2 and VEGF seem to reprise the roles they play during vascular remodeling in normal tissues, acting to regulate the previously underappreciated balance between vascular regression and growth.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Asano M, Yukita A, Matsumoto T, Kondo S and Suzuki H. . 1995 Cancer Res. 55: 5296–5301.

  • Benjamin LE, Golijanin D, Itin A, Pode D and Keshet E. . 1999 J. Clinical Invest. 103: 159–165.

  • Benjamin LE, Hemo I and Keshet E. . 1998 Dev. 125: 1591–1598.

  • Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W and Nagy A. . 1996 Nature 380: 435–439.

  • Davis S, Aldrich TH, Jones PF, Acheson A, Compton D, Vivek J, Ryan T, Bruno J, Radjiewski C, Maisonpierre PC and Yancopoulos GD. . 1996 Cell 87: 1161–1169.

  • Dumont DJ, Gradwohl G, Fong G-H, Puri MC, Gerstenstein M, Auerbach A and Breitman ML. . 1994 Genes Dev. 8: 1897–1909.

  • Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U and Alitalo K. . 1997 Oncogene 14: 2475–2483.

  • Ferrara N. . 1999 Curr. Top. Microbiol. Immunol. 237: 1–30.

  • Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hillan KJ and Moore MW. . 1996 Nature 380: 439–442.

  • Folkman J. . 1971 N. Engl. J. Med. 285: 1182–1186.

  • Folkman J. . 1990 J. Natl. Cancer Instit. 82: 4–6.

  • Folkman J and D'Amore PA. . 1996 Cell 87: 1153–1155.

  • Goldman CK, Kendall RL, Cabrera G, Soroceanu L, Heike Y, Gillespie GY, Siegal GP, Mao X, Bett AJ, Huckle WR, Thomas KA and Curiel DT. . 1998 Proc. Natl. Acad. Sci. USA. 95: 8795–8800.

  • Hanahan D and Folkman J. . 1996 Cell 86: 353–364.

  • Holash J, Maisonpierre PC, Compton C, Boland P, Alexander CR, Zagzag D, Yancopoulos GD and Wiegand SJ. . 1999 Science 284: 1994–1998.

  • Holmgren L, O'Reilly MS and Folkman J. . 1995 Nature Medi. 1: 149–153.

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS and Ferrara N. . 1993 Nature 362: 841–844.

  • Kwak HJ, So JN, Lee SJ, Kim I and Koh GY. . 1999 FEBS Lett 448: 249–253.

  • Lin P, Buxton JA, Acheson A, Radziejewski C, Maisonpierre PC, Yancopoulos GD, Channon KM, Hale LP, Dewhirst MW, George SE and Peters KG. . 1998 Proc. Natl. Acad. Sci. USA. 95: 8829–8834.

  • Lin P, Polverini P, Dewhirst M, Shan S, Rao PS and Peters K. . 1997 J. Clin. Invest. 100: 2072–2078.

  • Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN and Yancopoulos GD. . 1997 Science 277: 55–60.

  • Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A and Strawn LM. . 1996 Cancer Res. 56: 1615–1620.

  • Millauer B, Shawver LK, Plate KH, Risau W and Ullrich A. . 1994 Nature 367: 576–579.

  • Nagano N, Sasaki H, Aoyagi M and Hirakawa K. . 1993 Acta Neuropathol. 86: 117–125.

  • Papapetropoulos A, Carcia-Cardena G, Dengler TJ, Maisonpierre PC, Yancopoulos GD and Sessa WC. . 1999 Lab. Invest. 79: 213–221.

  • Pezzella F, Pastorino U, Tagliabue E, Andreola S, Sozzi G, Gasparini G, Menard S, Gatter KC, Harris AL, Fox S, Buyse M, Pilotti S, Pierotti M and Rilke F. . 1997 Am. J. Pathol. 151: 1417–1423.

  • Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W and Qin Y. . 1995 Nature 376: 70–74.

  • Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML and Schuh AC. . 1995 Nature 376: 62–66.

  • Shweiki D, Neeman M, Itin A and Keshet E. . 1995 Proc. Natl. Acad. Sci USA. 92: 768–772.

  • Stratmann A, Risau W and Plate KH. . 1998 Am. J. Pathol. 153: 1459–1466.

  • Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN and Yancopoulos GD. . 1996 Cell 87: 1171–1180.

  • Suri C, McLain J, Thurston G, McDonald DM, Oldmixon EH, Sato TN and Yancopoulos GD. . 1998 Science 282: 468–471.

  • Warren RS, Yuan H, Matli MR, Gillett NA and Ferrara N. . 1995 J. Clin. Invest. 95: 1789–1797.

  • Wesseling P, van der Laak JA, de Leeuw H, Ruiter DJ and Burger PC. . 1994 J. Neurosurg. 81: 902–909.

  • Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS and Peters KG. . 1997 Circ. Res. 81: 567–574.

  • Zagzag D, Hooper A, Friedlander DR, Chan W, Holash J, Wiegand SJ, Yancopoulos GD and Grumet M. . 1999 Exper. Neurol. In press.

Download references

Acknowledgements

We thank Dr D Zagzag and the various members of the Regeneron community for their input and discussions. We are especially grateful to Claudia Murphy and Evan Burrows for their excellent assistance with graphics.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holash, J., Wiegand, S. & Yancopoulos, G. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18, 5356–5362 (1999). https://doi.org/10.1038/sj.onc.1203035

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203035

Keywords

This article is cited by

Search

Quick links