Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases

In vitro, mouse CRC cell (MoCR) proliferation was inhibited by treatment with CGP42112A in a dose dependent manner while apoptosis was increased. Immunofluorescent staining for key signalling and secondary messengers, PLA2 and iNOS, were also increased by CGP42112A treatment in vitro. Immunohistochemical staining for proliferation (PCNA) and the apoptosis (active caspase 3) markers confirmed a CGP42112A-associated inhibition of proliferation and induction of apoptosis of mouse CRC cells (MoCR) in vivo. However, angiogenesis and vascular endothelial growth factor (VEGF) appeared to be increased by CGP42112A treatment in vivo. This increase in VEGF secretion by MoCRs was confirmed in vitro. Despite this apparent pro-angiogenic effect, a syngenic orthotopic mouse model of CRC liver metastases showed a reduction in liver to body weight ratio, an indication of tumour burden, following CGP42112A treatment compared to untreated controls.These results suggest that AT2R activation might provide a novel target to inhibit tumour growth. Its potential to stimulate angiogenesis could be compensated by combination with anti-angiogenic agents.Metastasis to the liver is the leading cause of death in patients with colorectal cancer (CRC)[1]. For the majority of these patients the only treatment option is palliative chemotherapy [2,3]. The renin angiotensin system (RAS) is expressed in several cancers and regulates proliferation and angiogenesis in several pathological conditions [4,5]. Experimental animal models show a stimulatory effect of the key RAS peptide angiotensin (ANG) II through the ANG II type 1 receptor (AT1R) on tumour growth, while blockade this pathway inhibits tumour growth[6,7], including in a mouse model of CRC liver metastases [8]. However, the effects of the RAS can also be mediated through an alterative receptor, the angiotensin II type 2 receptor (AT2R), as well as an alternative peptide ANG-(1-7) and its receptor (the MasR). The AT2R generally exerts actions a