The Renin-Angiotensin System and Cancer

Abstract

The renin-angiotensin system (RAS), classically known for its role in cardiovascular homeostasis, is increasingly recognized to be dysregulated in cancer. Epidemiological studies have largely demonstrated a cancer-protective role of RAS inhibitors (RASi), which is further supported by in vitro and xenograft models of cancer. The hierarchical model of cancer proposes the presence of cancer stem cells (CSCs), a small population of highly tumorigenic cancer cells sitting atop of a cellular hierarchy being responsible for sustaining tumor growth, intratumoral heterogeneity, loco-regional recurrence, distant metastasis, disease progression and treatment failure. CSCs have been identified in numerous cancer types, and the expression of components of the RAS by CSCs suggests CSCs may be a novel therapeutic target by modulation of the RAS. The classical view of the RAS centers around angiotensin II (ATII) as the main active peptide, which promote angiogenesis, fibrosis, inflammation, cellular proliferation, migration and invasion, and inhibition of apoptosis by activating angiotensin II receptor 1 (AT1R), and its interaction with angiotensin II receptor 2 (AT2R) antagonizes these effects. ATII signaling via AT1R is thought to drive mitogenic processes in cancer and contribute to other pathological conditions including fibro-proliferative conditions and vascular anomalies. Blockade of the classical RAS by traditional RASi, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and β-blockers, can be circumvented by enzymes such as cathepsins B, D and G which provide alternative pathways of ATII biosynthesis. The presence of these “bypass loops” that provide in-built redundancies, and converging signaling pathways, including the upstream Wnt/β-catenin pathway and the downstream NOX-ROS-NF-κB-COX signaling cascades, enables the RAS to continue functioning despite blockade by traditional RASi. This suggests that effective inhibition of the RAS may require a multi-step blockade. Further complexities to this model include the intimate interaction of CSCs with their surrounding dynamic tumor microenvironment (TME). The TME facilitates intercellular communication between CSCs and the surrounding niche to foster an environment favorable for sustaining tumorigenesis through cytokine networks, RAS signaling, and disruption of stem cell signaling pathways. Thus, effective modulation of CSCs requires additional consideration of the role of the surrounding TME. Instead of the long-standing pursuit of a ‘silver-bullet’, single point intervention in the treatment of cancer, future treatments will involve a combination of medications. This may be achieved by re-purposing existing, commonly used, low-cost, and safe medications that modulate the RAS, its “bypass loops” and convergent signaling pathways. There is currently a paucity of clinical trials assessing the effectiveness of this treatment approach for cancer.