The renin–angiotensin system and cancer: old dog, new tricks

Abstract

For cancers to develop, sustain and spread, the appropriation of key homeostatic physiological systems that influence cell growth, migration and death, as well as inflammation and the expansion of vascular networks are required. There is accumulating molecular and in vivo evidence to indicate that the expression and actions of the renin-angiotensin system (RAS) influence malignancy and also predict that RAS inhibitors, which are currently used to treat hypertension and cardiovascular disease, might augment cancer therapies. To appreciate this potential hegemony of the RAS in cancer, an expanded comprehension of the cellular actions of this system is needed, as well as a greater focus on translational and in vivo research.

The renin-angiotensin system meets the hallmarks of cancer

“…5 It is likely that dysregulation of the normal physiological actions of the RAS in inflammation and angiogenesis might function to synergistically promote growth during malignancy. 8 Some reports using an AT1R antagonist and AT1R genedeficient (AT1a-/-) mice have shown that blocking AT1R signalling inhibited the growth of the following cells type: vascular endothelial, 19 prostate, 20 renal cell carcinoma 21 and pancreas. 22 In 2007, Imai and colleagues determined that AT1R-induced vascular endothelial growth factor a (VEGFa) signalling, in both host and tumour tissues, is one of the key regulators of tumour growth and tumour-associated angiogenesis.…”

“…8 A hypoxic tumour environment, coupled with excessive accumulation of ROS, leads to oxidative stress, followed by increased protein modifications, cellular damage and death or increased growth factor signalling. 28 AngII induces the expression of p47phox and the production of the O2-radical through the activation of the AT1R in prostate cancer cells.…”

“…8 Signaling through the AT2R is linked to the promotion of apoptosis. In prostate cancer cells, AT2R overexpression induced apoptosis independently of AngII but was dependent on p38 mitogen-activated protein kinase (MAPK), caspase 8 and caspase 3 and was mediated through an extrinsic cell death-signalling pathway that was partially dependent on TP53, but not P21, activation.…”

“…8 The most studied components of the RAS, in the process of cell proliferation, are AngII and its receptors, which induce hyperplasia or hypertrophy in cultured vascular smooth muscle cells derived from the aorta. Interestingly, AngII has antagonist functions.…”

A network-based gene-weighting approach for pathway analysis

“…Taking p53 gene for example, the computed gene weights suggest that it acts as a core gene in pathways such as the p53 hypoxia signaling pathway ( Figure 1B) and p53 signaling pathway (with a high weight ranking top 1), and it participates but not dominates in pathways such as Huntington's disease pathway and cell cycle checkpoint pathway (ranking 72 and 102, respectively; Supplementary information, Table S1). Another example is the EGFR gene, which is suggested to be a more central gene in some pathways (such as AT1R pathway [27] and EGF pathway [28]) than others (such as calcium signaling pathway [29] and cytokine-cytokine receptor interaction [30]) (Supplementary information, Table S2). We have tested another functional association network named FunCoup [31], which produced similar gene weights in the pathways, with p53 hypoxia signaling pathway again taken as an example ( Figure 1C).…”