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Tumour angiogenesis is essential for cancer growth and metastasis. Many new pathways have been recognised in the last few years, including genes involved in embryonic development of the vasculature, e.g. the notch/delta, ephrin/eph and the HOX genes. Furthermore, vascular mimicry, intussusception and recruitment of circulating endothelial cells may contribute to tumour vessels, as well as endothelial proliferation. A close link has emerged between hypoxia and the regulation of angiogenesis, with many angiogenic factors involved in hypoxia in endothelial cells and cancer cells. Examples include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), adrenomedullin, oxygen-regulated protein 150, tumour necrosis factor (TNF) alpha, endothelins. Conversely, anti-angiogenic molecules such as thrombospondin are downregulated. The main pathway regulating these responses seems to be via the hypoxia inducible factor I alpha and its modulation by proline hydroxylases. Many oncogenes amplify the effects of the hypoxia pathway, e.g. PTEN mutations. Thus, a plethora of targets is now available for therapy. Most tumours express many different pathways, but some key ones are emerging. VEGF seems to be a core factor for endothelial growth, and blockade of hypoxia signalling also inhibits angiogenesis. One of the difficulties in assessing response to therapy, if only new vessels are inhibited, is that only small amounts of regression may occur. However, clinical trials are now incorporating pharmacodynamic measurements such as vascular permeability and responses have been reported for a wide range of anti-angiogenic agents, in particular the VEGF pathway inhibitors. Marked synergy with conventional treatment modalities has been shown in preclinical models and this paradigm is being followed in clinical trial development. Second generation drugs are now entering phase III trials and are likely to enter routine practice. © 2003 Elsevier Ltd. All rights reserved.

Original publication

DOI

10.1016/S1359-6349(03)00007-7

Type

Journal article

Journal

European Journal of Cancer, Supplement

Publication Date

01/01/2003

Volume

1

Pages

1 - 12