Our laboratory also observed that both adrenaline and noradrenaline could induce proliferation of colorectal cancer cells through β-adrenoceptors, preferentially the β2 receptors [26] and [38]. In contrast, there are reports showing a different action of β-adrenoceptor activation on breast cancer cells. In these studies β-adrenoceptor agonists could decrease cell proliferation in vitro and reduce tumour growth in vivo [39] and [40]. The reasons of this paradoxical nature of observations remain unknown. It might involve possible antagonistic action of some

β-adrenoceptor agonists, different molecular signals and single nucleotide polymorphisms of β-adrenoceptor in the same cancer cells [39] and [41]. It is well-known that angiogenesis is essential for tumour growth and metastasis. Physiologically, the fine equilibrium between pro- p53 inhibitor and anti-angiogenic factors governs the complex process

and angiogenic switch is off in normal tissues [42]. Cancer is the pathological condition that can tilt the balance towards more stimulatory angiogenic factors to drive the uncontrolled angiogenesis with HKI-272 mouse distinct immature vascular structures from normal blood vessels [42] and [43]. Common pro-angiogenic factors include vascular endothelial growth factors (VEGFs), placenta-derived growth factor (PlGF), platelet-derived growth factor (PDGF), transforming growth factor β(TGF-β), hypoxia-inducible factor-1 (HIF-1α), angiopoietin-2, insulin-like growth factor, and several chemokines [44]. Among these factors, VEGF is the most studied and best validated as pro-angiogenic molecule in tumour angiogenesis. PAK6 Solid evidence derived from several cancer models has proven that adrenaline and

noradrenline could upregulate the expression of VEGF and induce tumour angiogenesis and aggressive growth [24], [25], [31], [45] and [46]. Besides VEGF, several reports from different groups [24], [31], [32], [46] and [47] also identified that other angiogenic factors such as interleukin 6 (IL-6), IL-8, matrix metalloproteinase (MMP)-2 and MMP-9 could be elevated by the stimulation of adrenaline and noradrenaline in a diversity of cancer cells via β-adrenergic receptor signalling. These findings implicate that an amplification cascade might exist among these factors that synergistically strengthen angiogenesis and aggressive development of tumours. But administration of β-adrenoceptor antagonist, propranolol could completely abrogate the secretion of these factors and their mediated functions, implying that β-blockers have potential therapeutic value for the management of relevant cancers. Furthermore, Lutgendorf et al.