Abstract
Tumour progression is regulated by the balance of proliferation and apoptosis in the tumour cell population. To date, the role of vascular endothelial growth factor (VEGF) in tumour growth has been attributed to the induction of angiogenesis. VEGF has been shown to be a survival factor for endothelial cells, preventing apoptosis by inducing Bcl-2 expression. In both murine (4T1) and human (MDA-MB-231) metastatic mammary carcinoma cell lines, we found that VEGF upregulated Bcl-2 expression and anti-VEGF antibodies reduced Bcl-2 expression. These alterations in Bcl-2 expression were reflected by the levels of tumour cell apoptosis. VEGF resulted in reduced tumour cell apoptosis, whereas its inhibition with anti-VEGF neutralizing antibodies induced apoptosis directly in tumour cells. Therefore, in addition to its role in angiogenesis and vessel permeability, VEGF acts as a survival factor for tumour cells, inducing Bcl-2 expression and inhibiting tumour cell apoptosis. © 2001 Cancer Research Campaign http://www.bjcancer.com
Keywords: vascular endothelial growth factor, Bcl-2, apoptosis
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- Gagnon M. L., Bielenberg D. R., Gechtman Z., Miao H. Q., Takashima S., Soker S., Klagsbrun M. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2573–2578. doi: 10.1073/pnas.040337597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gimbrone M. A., Jr, Leapman S. B., Cotran R. S., Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med. 1972 Aug 1;136(2):261–276. doi: 10.1084/jem.136.2.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gorski D. H., Beckett M. A., Jaskowiak N. T., Calvin D. P., Mauceri H. J., Salloum R. M., Seetharam S., Koons A., Hari D. M., Kufe D. W. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 1999 Jul 15;59(14):3374–3378. [PubMed] [Google Scholar]
- Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996 Aug 9;86(3):353–364. doi: 10.1016/s0092-8674(00)80108-7. [DOI] [PubMed] [Google Scholar]
- Holmgren L., O'Reilly M. S., Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995 Feb;1(2):149–153. doi: 10.1038/nm0295-149. [DOI] [PubMed] [Google Scholar]
- Jakeman L. B., Winer J., Bennett G. L., Altar C. A., Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest. 1992 Jan;89(1):244–253. doi: 10.1172/JCI115568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katoh O., Takahashi T., Oguri T., Kuramoto K., Mihara K., Kobayashi M., Hirata S., Watanabe H. Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor. Cancer Res. 1998 Dec 1;58(23):5565–5569. [PubMed] [Google Scholar]
- Kenyon B. M., Voest E. E., Chen C. C., Flynn E., Folkman J., D'Amato R. J. A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1625–1632. [PubMed] [Google Scholar]
- Krajewski S., Krajewska M., Turner B. C., Pratt C., Howard B., Zapata J. M., Frenkel V., Robertson S., Ionov Y., Yamamoto H. Prognostic significance of apoptosis regulators in breast cancer. Endocr Relat Cancer. 1999 Mar;6(1):29–40. doi: 10.1677/erc.0.0060029. [DOI] [PubMed] [Google Scholar]
- Li W. W., Grayson G., Folkman J., D'Amore P. A. Sustained-release endotoxin. A model for inducing corneal neovascularization. Invest Ophthalmol Vis Sci. 1991 Oct;32(11):2906–2911. [PubMed] [Google Scholar]
- Liu R., Page C., Beidler D. R., Wicha M. S., Núez G. Overexpression of Bcl-x(L) promotes chemotherapy resistance of mammary tumors in a syngeneic mouse model. Am J Pathol. 1999 Dec;155(6):1861–1867. doi: 10.1016/S0002-9440(10)65505-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matsushita K., Motani R., Sakuta T., Nagaoka S., Matsuyama T., Abeyama K., Maruyama I., Takada H., Torii M. Lipopolysaccharide enhances the production of vascular endothelial growth factor by human pulp cells in culture. Infect Immun. 1999 Apr;67(4):1633–1639. doi: 10.1128/iai.67.4.1633-1639.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mattsby-Baltzer I., Jakobsson A., Sörbo J., Norrby K. Endotoxin is angiogenic. Int J Exp Pathol. 1994 Jun;75(3):191–196. [PMC free article] [PubMed] [Google Scholar]
- Nör J. E., Christensen J., Mooney D. J., Polverini P. J. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol. 1999 Feb;154(2):375–384. doi: 10.1016/S0002-9440(10)65284-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
- Pidgeon G. P., Harmey J. H., Kay E., Da Costa M., Redmond H. P., Bouchier-Hayes D. J. The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br J Cancer. 1999 Dec;81(8):1311–1317. doi: 10.1038/sj.bjc.6694369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
- Shen B. Q., Lee D. Y., Gerber H. P., Keyt B. A., Ferrara N., Zioncheck T. F. Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro. J Biol Chem. 1998 Nov 6;273(45):29979–29985. doi: 10.1074/jbc.273.45.29979. [DOI] [PubMed] [Google Scholar]
- Soker S., Takashima S., Miao H. Q., Neufeld G., Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998 Mar 20;92(6):735–745. doi: 10.1016/s0092-8674(00)81402-6. [DOI] [PubMed] [Google Scholar]
- Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]