Alternative splicing in angiogenesis: The vascular endothelial growth factor paradigm

doi:10.1016/j.canlet.2006.08.015

Cancer Letters

Volume 249, Issue 2, 8 May 2007, Pages 133-142

https://doi.org/10.1016/j.canlet.2006.08.015 Get rights and content

Abstract

Alternative splicing, first discovered in the 1970s, has emerged as one of the key generators of proteomic diversity. Not surprisingly, alternative splicing is increasingly linked to the etiology of cancer. This is illustrated by vascular endothelial growth factor (VEGF), the dominant angiogenic factor. Recently, an antiangiogenic family of VEGF isoforms was discovered, and termed VEGF_xxxb. VEGF_xxxb isoforms arise from an alternative 3′ splice site in exon 8, and differ by a mere six amino acids at the C-terminus. These alternative six amino acids radically change the functional properties of VEGF. VEGF_xxxb isoform expression is regulated in human tissues and development, and disregulated in many pathological states including cancer. Understanding what regulates VEGF_xxxb alternative splicing, and therefore the balance of pro- and antiangiogenic isoforms is of great importance and will be explored in detail over the next few years.

Section snippets

The discovery of splicing

One of the most surprising outcomes of the human genome sequencing project is the fact that there are only about 30,000 human genes. Yet the number of proteins in the human proteome exceeds this number by at least an order of magnitude. How could such a relatively limited number of genes express perhaps in excess of a million proteins, even taking into account post-translational modifications? We now know that to a large extent, the answer lies in a ground-breaking discovery reported in 1977 by

Angiogenesis in cancer

The growth and metastasis of tumors require six classical steps, described by Hanahan as the hallmarks of cancer. Limitless replicative potential is obviously a requirement for tumor growth, and this is usually accompanied by growth factor self-sufficiency, insensitivity to growth inhibitors, invasive ability, and an ability to evade apoptosis. The final hallmark is the ability to develop a vascular supply, as growth requires oxygen and nutrients, supplied by the vasculature. The progression of

Regulation of VEGF splice form expression

A proximal C-terminal splicing switch appears to occur in a number of diseases associated with angiogenesis, including cancer. This results in an increase in the ratio of pro- to antiangiogenic VEGF isoforms. This is most clearly demonstrated in the human vitreous. In non-diabetic human vitreous VEGF_xxxb comprises 63% of the VEGF. In diabetics with proliferative retinopathy, this proportion drops to 16% – a pro-angiogenic phenotype therefore predominates [41]. In pre-eclampsia, the link between

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Mini-reviewAlternative splicing in angiogenesis: The vascular endothelial growth factor paradigm

Abstract

Section snippets

The discovery of splicing

Angiogenesis in cancer

Regulation of VEGF splice form expression

Cell

Biochim. Biophys. Acta

Adv. Cancer Res.

Biochem. Biophys. Res. Commun.

Blood

Mol. Ther.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Exp. Mol. Pathol.

Genomics

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Chest

Mol. Cell

Spliced segments at the 5′ terminus of adenovirus 2 late mRNA

Proc. Natl. Acad. Sci.

Initial sequencing and analysis of the human genome

Nature

A genomic view of alternative splicing

Nat. Genet.

Pre-mRNA splicing and human disease

Genes Dev.

Aberrant and alternative splicing in cancer

Cancer Res.

Unbalanced alternative splicing and its significance in cancer

BioEssays

Understanding alternative splicing: towards a cellular code

Nat. Rev. Mol. Cell. Biol.

Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome

Hum. Mol. Gen.

Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion

Mol. Cell. Biol.

VEGF gene therapy: stimulating angiogenesis or angioma-genesis?

Nat. Med.

Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

Nature

Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells

Cancer Res.

Mini-review
Alternative splicing in angiogenesis: The vascular endothelial growth factor paradigm