Apelin is a potent activator of tumour neoangiogenesis

Abstract

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 hypoxiainduced upregulation of apelin gene and its overexpression in one-third of human tumours.

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…The apelinergic system has been implicated in tumour neoangiogenesis. In brain tumours, the expression of apelin and APJ is up-regulated in microvascular proliferations (Kalin et al 2007), while tumour cell lines overexpressing apelin show increased growth (Sorli et al 2007). The pathophysiological effects of apelin in angiogenesis have also been reported for the liver, where the apelinergic system is a factor in portosystemic collaterisation and splanchnic neovascularisation in portal hypotensive rats (Tiani et al 2009) as well as in neovascularisation during liver cirrhosis (Principe et al 2008).…”

“…Elevated levels of apelin have been detected in many pathological states or disease processes, such as heart disease, atherosclerosis, tumour angiogenesis and diabetes (Chen et al 2003, Sorli et al 2007, Dray et al 2010. However, in many systems, apelin has been shown to have positive effects, for example in the cardiovascular system, where it has a cardioprotective effect , Kleinz & Baxter 2008.…”

Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype

“…The significance of greater induction of apelin could be relevant to tumour growth and metastasis. Apelin is a potent activator of tumour angiogenesis and is associated with earlier onset of tumour development and increased tumour growth in vivo (Sorli et al, 2007). The consequences of decreased BNIP3 induction in CTCs may determine the metastatic potential, as the expression of BNIP3 has been associated with a less-aggressive phenotype in invasive breast carcinoma (Tan et al, 2007), and a reduction in expression of BNIP3 has been suggested to be critical for metastasis (Manka et al, 2005).…”

The apelinergic system in the developing lung: Expression and signaling

“…[39,12,26,22,4]. Recently the apelinergic system has been described to promote embryonic and tumor angiogenesis [19,9,43]. Growing evidences of apelin/APJ involvement in embryonic events currently extend beyond vascular development, into ocular [20] and heart development [42,49,14].…”