Isoforms of Vascular Endothelial Growth Factor Act in a Coordinate Fashion To Recruit and Expand Tumor Vasculature

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2000 Sep 13

PMID 10982845

Citations 73

Authors

J Grunstein

J J Masbad

R Hickey

F Giordano

R S Johnson

Affiliations

Soon will be listed here.

Abstract

Vascular endothelial growth factor (VEGF) is an essential regulator of vascularization. It is expressed as several splice variants; the major forms contain 120 amino acids, 164 amino acids, and 188 amino acids. We utilized transformed cells nullizygous for VEGF to specifically express each of these isoforms in isolation, in order to determine the role of each in tumorigenic neo-vascularization. We found that only the intermediate isoform, VEGF164, could fully rescue tumor growth; VEGF120 partially rescued tumor growth, and VEGF188 failed completely to rescue tumor expansion. Surprisingly, the vascular density of VEGF188 isoform-expressing tumors is significantly greater than that of wild-type VEGF cells and the other isoform-specific tumors. The failure of the hypervascular VEGF188-expressing tumors to grow may be due to inadequate perfusion of the massive number of microvessels in these tumors; three-dimensional imaging of the tumorigenic vasculature indicated little or no recruitment of the peripheral vasculature. This demonstrates that the VEGF isoforms perform unique functions which together enable tumorigenic vascularization.

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References

Banga J . [Therapeutic angiogenesis through intramuscular injection of the gene for vascular endothelial growth factor (VEGF)]. Ned Tijdschr Geneeskd. 2000; 144(3):113-6. View

Okamoto K, Oshika Y, Fukushima Y, Ohnishi Y, Tokunaga T, Tomii Y . Xenografts of human solid tumors frequently express cellular-associated isoform of vascular endothelial growth factor (VEGF) 189. Oncol Rep. 1999; 6(6):1201-4. DOI: 10.3892/or.6.6.1201. View

Senger D, Galli S, Dvorak A, Perruzzi C, Harvey V, Dvorak H . Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983; 219(4587):983-5. DOI: 10.1126/science.6823562. View

Lin G, BOIJSEN E, Hagerstrand I, Lunderquist A . Microvasculature architecture of small liver metastases in man. A correlation between microfil vascular preparations and histologic sections. Invest Radiol. 1984; 19(4):296-302. DOI: 10.1097/00004424-198407000-00011. View

Keck P, Hauser S, Krivi G, Sanzo K, Warren T, Feder J . Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989; 246(4935):1309-12. DOI: 10.1126/science.2479987. View

Ferrara N, Houck K, Jakeman L, Winer J, Leung D . The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991; 47(3):211-8. DOI: 10.1002/jcb.240470305. View

Mombaerts P, Iacomini J, Johnson R, Herrup K, Tonegawa S, Papaioannou V . RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992; 68(5):869-77. DOI: 10.1016/0092-8674(92)90030-g. View

Shweiki D, Itin A, Soffer D, Keshet E . Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992; 359(6398):843-5. DOI: 10.1038/359843a0. View

Houck K, Leung D, Rowland A, Winer J, Ferrara N . Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem. 1992; 267(36):26031-7. View

10.

Park J, Keller G, Ferrara N . The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell. 1993; 4(12):1317-26. PMC: 275767. DOI: 10.1091/mbc.4.12.1317. View

11.

Levy A, Levy N, Wegner S, Goldberg M . Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem. 1995; 270(22):13333-40. DOI: 10.1074/jbc.270.22.13333. View

12.

Liu Y, Cox S, Morita T, Kourembanas S . Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5' enhancer. Circ Res. 1995; 77(3):638-43. DOI: 10.1161/01.res.77.3.638. View

13.

Ikeda E, Achen M, Breier G, Risau W . Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem. 1995; 270(34):19761-6. DOI: 10.1074/jbc.270.34.19761. View

14.

Shima D, Deutsch U, DAmore P . Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS Lett. 1995; 370(3):203-8. DOI: 10.1016/0014-5793(95)00831-s. View

15.

Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T . Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 1995; 55(20):4575-80. View

16.

Bacic M, Edwards N, Merrill M . Differential expression of vascular endothelial growth factor (vascular permeability factor) forms in rat tissues. Growth Factors. 1995; 12(1):11-5. DOI: 10.3109/08977199509003209. View

17.

Kolch W, Martiny-Baron G, Kieser A, Marme D . Regulation of the expression of the VEGF/VPS and its receptors: role in tumor angiogenesis. Breast Cancer Res Treat. 1995; 36(2):139-55. DOI: 10.1007/BF00666036. View

18.

Aiello L, Pierce E, Foley E, Takagi H, Chen H, Riddle L . Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A. 1995; 92(23):10457-61. PMC: 40630. DOI: 10.1073/pnas.92.23.10457. View

19.

Levy A, Levy N, Goldberg M . Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem. 1996; 271(5):2746-53. DOI: 10.1074/jbc.271.5.2746. View

20.

Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M . Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996; 380(6573):435-9. DOI: 10.1038/380435a0. View