It has been shown that tumour associated macrophages (TAM) and MMP9 released by TAM play an essential role in angiogenesis through presenting VEGF access to relevant receptors on endothelial cells and degrading extracellular matrix to release other pro-angiogenic factors [49] and [50]. Additionally, a recent study by Park et al. [51] unravelled that noradrenaline induced VEGF expression in several cancer cell lines from prostate, breast and liver via a HIF-1α-dependent manner. Further investigation disclosed that

a β-blocker propranolol could completely abolish VEGF production and reduce HIF-1α expression EX 527 purchase initiated by noradrenaline in cancer cells [51]. Tumour metastasis as a main 3-deazaneplanocin A concentration cause of cancer-related death

is a multistep in cellular/biological process involving the invasion-metastasis cascade. A sequence of molecular events are used to delineate the process including cancer cell local invasion, intravasation, transportation, inoculation, extravasation, micrometastasis formation and colonization (metastatic macroscopic tumour formation) [1], [52] and [53]. Activation of β-adrenergic system seems to involve in each step of the cancer invasion-metastasis cascade. Preclinical investigations have indicated that administration of β-blockers in perioperative and postoperative periods can improve immune status and inhibit cancer metastasis in several cancer models [54], [55] and [56]. Substantial evidence has demonstrated that stress hormones adrenaline and

noradrenaline can induce the release of MMP-2, MMP-7 and MMP-9 in a couple of cancer cell lines and models which are highly associated with metastasis through degradation of extracellular matrix to facilitate cancer cell invasion and migration [24], [31] and [57]. But β-blockers, especially nearly β2-antagonists, can suppress the secretion of MMPs and reverse the effects related to MMPs such as invasion and migration [58], [59], [60] and [61]. Strell and colleagues [62] further found that noradrenaline promoted the adhesion of breast cancer cell MDA-MB-231 to human pulmonary microvascular endothelial cells (HMVEC) through the release of growth-regulated oncogene alpha (GROα) and β1-integrin pathway. The process analogizes the extravasation of cancer cells into secondary metastatic loci. Accordingly, β-blockers could abrogate the effects initiated by noradrenaline. Sloan et al. [63] illustrated in an orthotopic mouse model of breast cancer in which stress stimulation or pharmacological activation of β-adrenergic system by isoproterenol induced a 30-fold increase in metastasis to distant organs, which might be mediated by the infiltration of macrophages into primary tumour parenchyma. Stress-induced macrophages can produce the expression of many pro-metastatic genes and exhibit the intendancy towards M2-like differentiation related to aggressive tumour development.