The Endogenous Anti-angiogenic VEGF Isoform, VEGF165b Inhibits Human Tumour Growth in Mice

Overview

Journal Br J Cancer

Specialty Oncology

Date 2008 Mar 20

PMID 18349828

Citations 81

Authors

Es Rennel

E Waine

H Guan

Y Schuler

W Leenders

J Woolard

M Sugiono

D Gillatt

Es Kleinerman

Do Bates

Sj Harper

Affiliations

Soon will be listed here.

Abstract

Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGFxxx, and the anti-angiogenic family formed by distal splice site selection in the terminal exon, termed VEGFxxxb, where xxx is the amino acid number. The most studied isoforms, VEGF165 and VEGF165b have been shown to be present in tumour and normal tissues respectively. VEGF165b has been shown to inhibit VEGF- and hypoxia-induced angiogenesis, and VEGF-induced cell migration and proliferation in vitro. Here we show that overexpression of VEGF165b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF165b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF165b can inhibit growth of multiple tumour types in vivo indicating that VEGF165b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF165b expression by regulation of splicing, overexpression of VEGF165b, or therapeutic delivery of VEGF165b to tumours.

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References

Barry Delongchamps N, Peyromaure M, Dinh-Xuan A . Role of vascular endothelial growth factor in prostate cancer. Urology. 2006; 68(2):244-8. DOI: 10.1016/j.urology.2006.03.010. View

Ferrara N . Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 2003; 29(6 Suppl 16):10-4. DOI: 10.1053/sonc.2002.37264. View

Schumacher V, Jeruschke S, Eitner F, Becker J, Pitschke G, Ince Y . Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome. J Am Soc Nephrol. 2007; 18(3):719-29. DOI: 10.1681/ASN.2006020124. View

Bates D, Cui T, Doughty J, Winkler M, Sugiono M, Shields J . VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res. 2002; 62(14):4123-31. View

Woolard J, Wang W, Bevan H, Qiu Y, Morbidelli L, Pritchard-Jones R . VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 2004; 64(21):7822-35. DOI: 10.1158/0008-5472.CAN-04-0934. View

Venables J . Aberrant and alternative splicing in cancer. Cancer Res. 2004; 64(21):7647-54. DOI: 10.1158/0008-5472.CAN-04-1910. View

Miller-Kasprzak E, Jagodzinski P . 5-Aza-2'-deoxycytidine increases the expression of anti-angiogenic vascular endothelial growth factor 189b variant in human lung microvascular endothelial cells. Biomed Pharmacother. 2007; 62(3):158-63. DOI: 10.1016/j.biopha.2007.07.015. View

Pritchard-Jones R, Dunn D, Qiu Y, Varey A, Orlando A, Rigby H . Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer. 2007; 97(2):223-30. PMC: 2360298. DOI: 10.1038/sj.bjc.6603839. View

Ferrer F, Miller L, Andrawis R, Kurtzman S, Albertsen P, Laudone V . Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. J Urol. 1997; 157(6):2329-33. View

10.

Westphal J, Vant Hullenaar R, Peek R, Willems R, Crickard K, Crickard U . Angiogenic balance in human melanoma: expression of VEGF, bFGF, IL-8, PDGF and angiostatin in relation to vascular density of xenografts in vivo. Int J Cancer. 2000; 86(6):768-76. DOI: 10.1002/(sici)1097-0215(20000615)86:6<768::aid-ijc3>3.0.co;2-e. View

11.

Mezquita P, Parghi S, Brandvold K, Ruddell A . Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation. Oncogene. 2004; 24(5):889-901. DOI: 10.1038/sj.onc.1208251. View

12.

Kusters B, Kats G, Roodink I, Verrijp K, Wesseling P, Ruiter D . Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis. Oncogene. 2007; 26(39):5808-15. DOI: 10.1038/sj.onc.1210360. View

13.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350(23):2335-42. DOI: 10.1056/NEJMoa032691. View

14.

Cebe Suarez S, Pieren M, Cariolato L, Arn S, Hoffmann U, Bogucki A . A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci. 2006; 63(17):2067-77. PMC: 11136335. DOI: 10.1007/s00018-006-6254-9. View

15.

Ladomery M, Harper S, Bates D . Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm. Cancer Lett. 2006; 249(2):133-42. DOI: 10.1016/j.canlet.2006.08.015. View

16.

Perrin R, Konopatskaya O, Qiu Y, Harper S, Bates D, Churchill A . Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia. 2005; 48(11):2422-7. DOI: 10.1007/s00125-005-1951-8. View

17.

Jackson M, Bentel J, Tilley W . Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia. J Urol. 1997; 157(6):2323-8. View

18.

Ferrara N . Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004; 25(4):581-611. DOI: 10.1210/er.2003-0027. View

19.

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

20.

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