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Abstract: The discovery of new signalling pathways is always followed by the development of pharmacological agents as drugs that can be used in the treatment of diseases resulting from a dysfunction of the signalling pathway in question. Apelin signalling plays a role in the central and peripheral regulation of the cardiovascular system, in water and food intake, and possibly in immune function. Up-regulation of ligand and receptor is also associated with pathophysiological states such as cardiac dysfunction and neovascularisation. Finally, the apelin receptor is a coreceptor for the entry of several HIV-1 and SIV strains. In view of these features, the apelin receptor constitutes a very interesting target for the design of new drugs for treating the prime causes of human mortality. [Copyright &y& Elsevier]

Our laboratory has previously shown that apelin is mitogenic for endothelial cells. We have postulated that apelin represents an angiogenic factor secreted by tumour cells in order to promote the formation of new vessels necessary for tumour growth. We first demonstrate that apelin and its receptor are not expressed by the mouse TS/A mammary carcinoma cells. We therefore established clones of this tumoral cell type stably overexpressing the apelin cDNA (TS/A-apelin clones). Comparison of the in vitro proliferation rates between TS/A-mock and TS/A-apelin cells did not reveal any difference and confirmed the lack of receptor expression by tumour cells. On the other hand, apelin overexpression clearly increased the in vivo tumour growth and this increase was associated with an earlier onset of tumour development. In tumours derived from TS/A-apelin clones, the expression of the endothelial marker CD31 was increased and revealed the formation of large intratumoral vessels lined with CD31 positive cells. These data suggest that apelin behaves as a potent activator of tumour neoangiogenesis by a paracrine effect on host vessels. The pathological relevance of this finding is demonstrated by hypoxia-induced upregulation of apelin gene and its overexpression in one-third of human tumours.Oncogene (2007) 26, 7692–7699; doi:10.1038/sj.onc.1210573; published online 11 June 2007 [ABSTRACT FROM AUTHOR]