Abstract
Tumor growth and progression depend on angiogenesis, a process of new blood vessels formation from a preexisting vascular endothelium. Tumors promote angiogenesis by secreting or activating angiogenic factors that stimulate endothelial proliferation and migration and capillary morphogenesis. The newly formed blood vessels provide nutrients and oxygen to the tumor, increasing its growth. Thus, angiogenesis plays a key role in cancer progression and development of metastases. An important growth factor that promotes angiogenesis and participates in a variety of physiological and pathological processes is the vascular endothelial growth factor (VEGF-A or VEGF). Overexpression of VEGF results in increased angiogenesis in normal and pathological conditions. The existence of an alternative site of splicing at the 3′ untranslated region of the mRNA results in the expression of isoforms with a C-terminal region which are downregulated in tumors and may have differential inhibitory effects. This suggests that control of splicing can be an important regulatory mechanism of angiogenesis in cancer.
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Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487
Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD et al (2002) VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 62:4123–4131
Bates DO, MacMillan PP, Manjaly JG, Qiu Y, Hudson SJ, Bevan HS et al (2006) The endogenous anti-angiogenic family of splice variants of VEGF, VEGFxxxb, are down-regulated in pre-eclamptic placentae at term. Clin Sci 110:575–585
Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410
Bourgeois CF, Lejeune F, Stevenin J (2004) Broad specificity of SR (serine/arginine) proteins in the regulation of alternative splicing of pre-messenger RNA. Prog Nucleic Acid Res Mol Biol 78:37–88
Caceres JF, Kornblihtt AR (2002) Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet 18:186–193
Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nature Med 6:389–395
Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660
Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257
Cebe Suarez S, Pieren M, Cariolato L, Arn S, Hoffmann U, Bogucki A et al (2006) A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci 63:2067–2077
Cooper JC, Sharkey AM, Charnock-Jones DS, Palmer CR, Smith SK (1996) VEGF mRNA levels in placentae from pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol 103:1191–1196
Couffinhal T, Kearney M, Witzenbichler B, Chen D, Murohara T, Losordo DW et al (1997) Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries. Am J Pathol 150:1673–1685
Duh E, Aiello LP (1999) Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 48:1899–1906
Fava RA, Olsen NJ, Spencer-Green G, Yeo KT, Yeo TK, Berse B et al (1994) Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180:341–346
Ferrara N (2002) Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 29:10–14
Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611
Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25
Ferroni P, Spila A, Martini F, D’Alessandro R, Mariotti S, Del Monte G et al (2006) Prognostic value of vascular endothelial growth factor tumor tissue content of colorectal cancer. Oncology 69:145–153
Fraser HM, Dickson SE, Lunn SF, Wulff C, Morris KD, Carroll VA et al (2000) Suppression of luteal angiogenesis in the primate after neutralization of vascular endothelial growth factor. Endocrinology 141:995–1000
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Harper SJ, Bates DO (2008) VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer 8:880–887
Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342
Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E et al (2005) Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502–3508
Inoue K, Ozeki Y, Suganuma T, Sugiura Y, Tanaka S (1997) Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Association with angiogenesis and tumor progression. Cancer 79:206–213
Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M et al (1998) Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 78:1379–1384
Jingjing L, Xue Y, Agarwal N, Roque RS (1999) Human Muller cells express VEGF183, a novel spliced variant of vascular endothelial growth factor. Investig Ophthalmol Vis Sci 40:752–759
Kawamura H, Li X, Harper SJ, Bates DO, Claesson-Welsh L (2008) Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res 68:4683–4692
Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M et al (2000) Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res 6:572–577
Kerbel RS (2008) Molecular origins of cancer: tumor angiogenesis. N Engl J Med 358:2039–2049
Kuroyanagi N, Onogi H, Wakabayashi T, Hagiwara M (1998) Novel SR-protein-specific kinase, SRPK2, disassembles nuclear speckles. Biochem Biophys Res Commun 242:357–364
Ladomery MR, Harper SJ, Bates DO (2007) Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm. Cancer Lett 249:133–142
Lai MC, Lin RI, Tarn WY (2003) Differential effects of hyperphosphorylation on splicing factor SRp55. Biochem J 371:937–945
Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M et al (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77:858–863
Maeda T, Matsumura S, Hiranuma H, Jikko A, Furukawa S, Ishida T et al (1998) Expression of vascular endothelial growth factor in human oral squamous cell carcinoma: its association with tumor progression and p53 gene status. J Clin Pathol 51:771–775
Manley JL, Tacke R (1996) SR proteins and splicing control. Genes Dev 10:1569–1579
Misteli T, Caceres JF, Spector DL (1997) The dynamics of a pre-mRNA splicing factor in living cells. Nature 387:523–527
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22
Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ et al (2008) Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and grwoth factors. J Cell Sci 121:3487–3495
Olsson A-K, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling-in control of vascular function. Nature Rev Mol Cell Biol 7:359–371
Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME (2008) Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 27:331–371
Perrin RM, Konopatskaya O, Qiu Y, Harper S, Bates DO, Churchill AJ (2005) Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia 48:2422–2427
Peters KG, De Vries C, Williams LT (1993) Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci USA 90:8915–8919
Poltorak Z, Cohen T, Sivan R, Kandelis Y, Spira G, Vlodavsky I et al (1997) VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 272:7151–7158
Poon RT, Fan ST, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–1225
Prasad J, Colwill K, Pawson T, Manley JL (1999) The protein kinase Clk/Sty directly modulates SR protein activity: both hyper- and hypophosphorylation inhibit splicing. Mol Cell Biol 19:6991–7000
Pritchard-Jones RO, Dunn DB, Qiu Y, Varey AH, Orlando A, Rigby H et al (2007) Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 97:223–230
Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684
Qiu Y, Bevan H, Weeraperuma S, Wratting D, Murphy D, Neal CR et al (2008) Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF165b. Faseb J 22:1104–1112
Qiu Y, Hoareau-Aveilla C, Oltean S, Harper SJ, Bates DO (2009) The anti-angiogenic isoforms of VEGF in health and disease. Biochem Soc Trans 37:1207–1213
Rennel E, Waine E, Guan H, Schuler Y, Leenders W, Woolard J et al (2008) The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice. Br J Cancer 98:1250–1257
Rennel ES, Harper SJ, Bates DO (2009) Therapeutic potential of manipulating VEGF splice isoforms in oncology. Future Oncol 5:703–712
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431
Schneider BP, Miller KD (2005) Angiogenesis of breast cancer. J Clin Oncol 23:1782–1790
Schumacher VA, Jeruschke S, Eitner F, Becker JU, Pitschke G, Ince Y et al (2007) Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome. J Am Soc Nephrol 18:719–729
Uehara M, Sano K, Ikeda H, Sekine J, Irie A, Yokota T et al (2004) Expression of vascular endothelial growth factor and prognosis of oral squamous cell carcinoma. Oral Oncol 40:321–325
Varey AH, Rennel ES, Qiu Y, Bevan HS, Perrin RM, Raffy S et al (2008) VEGF165b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer 98:1366–1379
Wang HY, Lin W, Dyck JA, Yeakley JM, Songyang Z, Cantley LC et al (1998) SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells. J Cell Biol 140:737–750
Whittle C, Gillespie K, Harrison R, Mathieson PW, Harper SJ (1999) Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant. Clin Sci 97:303–312
Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO et al (2004) VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 64:7822–7835
Yun CY, Velazquez-Dones AL, Lyman SK, Fu XD (2003) Phosphorylation-dependent and -independent nuclear import of RS domain-containing splicing factors and regulators. J Biol Chem 278:18050–18055
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Biselli-Chicote, P.M., Oliveira, A.R.C.P., Pavarino, E.C. et al. VEGF gene alternative splicing: pro- and anti-angiogenic isoforms in cancer. J Cancer Res Clin Oncol 138, 363–370 (2012). https://doi.org/10.1007/s00432-011-1073-2
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DOI: https://doi.org/10.1007/s00432-011-1073-2