Review Article | Published:

VEGF targets the tumour cell

Nature Reviews Cancer volume 13, pages 871882 (2013) | Download Citation

Abstract

The function of vascular endothelial growth factor (VEGF) in cancer is not limited to angiogenesis and vascular permeability. VEGF-mediated signalling occurs in tumour cells, and this signalling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumour initiation. In addition to VEGF receptor tyrosine kinases, the neuropilins are crucial for mediating the effects of VEGF on tumour cells, primarily because of their ability to regulate the function and the trafficking of growth factor receptors and integrins. This has important implications for our understanding of tumour biology and for the development of more effective therapeutic approaches.

Key points

  • Tumour cells express vascular endothelial growth factor (VEGF) receptors and respond to autocrine and paracrine VEGF signals.

  • VEGF signalling in tumour cells affects tumour functions independently of angiogenesis.

  • VEGF signalling in tumour cells is mediated by VEGF receptor tyrosine kinases (RTKs) and neuropilins (NRPs).

  • NRPs may be at the centre of VEGF signalling because they regulate the function of RTKs and integrins that are crucial for tumour cell function.

  • Autocrine VEGF signalling may be essential for tumour initiation because it regulates the size of the cancer stem cell pool and the self-renewal of cancer stem cells.

  • Therapeutic approaches that aim to target NRPs and VEGF RTKs on tumour cells could be useful to promote tumour regression and to diminish the probability of tumour recurrence, especially when used in combination with VEGF-specific antibodies and other modes of therapy.

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Acknowledgements

Work in the authors' laboratory is supported by US National Institutes of Health (NIH) grants CA168464 and CA159856, and by a US Department of Defense prostate cancer grant W81XWH-12-1-0308.

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  1. Department of Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.

    • Hira Lal Goel
    •  & Arthur M. Mercurio

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Competing interests

The authors declare no competing financial interests.

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Correspondence to Arthur M. Mercurio.

Glossary

Integrins

A family of more than 20 heterodimeric cell surface extracellular matrix (ECM) receptors. Integrins connect the ECM to the cytoskeleton and can transmit signalling information bidirectionally.

Plexins

A large family of transmembrane proteins that share homology in their extracellular domains with the MET receptor and semaphorins.

Epithelial–mesenchymal transition

(EMT). A conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Hypoxia-inducible factor

(HIF). A dimeric transcription factor that is formed of α- and β-subunits and that is involved in the hypoxia-sensitive regulation of numerous genes, including glycolytic enzymes, glucose transporters and angiogenic factors.

Focal adhesions

Dynamic, macromolecular protein complexes that link the extracellular matrix to the actin cytoskeleton through integrins.

PDZ-binding domain

(PSD95, DLG and ZO1-binding domain). A structural, protein–protein interaction domain, which is 80–90 amino acids in length, that often functions as a scaffold for signalling complexes and/or as a cytoskeletal anchor for transmembrane proteins.

Immunoreceptor tyrosine-based activation motif

(ITAM). A motif (YXXL or YXXI) that can be phosphorylated in response to receptor ligation and that functions as a docking site for other proteins involved in signal transduction.

Autophagy

A cellular response in which the cell metabolizes its own contents and organelles to maintain energy production. Although such a process can eventually result in cell death, it can also be used to maintain cell survival in conditions of limiting nutrients.

CD133

A cell-surface glycoprotein, which is also known as Prominin 1, that can be used as a marker for some cancer stem cells.

Polycomb group

Proteins that were first described in Drosophila melanogaster and that are required for normal development. They work in multiprotein complexes that are called Polycomb repressive complexes, which establish regions of chromatin in which gene expression is repressed.

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https://doi.org/10.1038/nrc3627

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