Therapeutic Targeting of Cancer Stem Cells via Modulation of the Renin-Angiotensin System

Abstract

Cancer stem cells (CSCs) are proposed to be the cells that initiate tumorigenesis and maintain tumor development due to their self-renewal and multipotency properties. CSCs have been identified in many cancer types and are thought to be responsible for treatment resistance, metastasis, and recurrence. As such, targeting CSCs specifically should result in durable cancer treatment. One potential option for targeting CSCs is by manipulation of the renin-angiotensin system (RAS) and pathways that converge on the RAS with numerous inexpensive medications currently in common clinical use. In addition to its crucial role in cardiovascular and body fluid homeostasis, the RAS is vital for stem cell maintenance and differentiation and plays a role in tumorigenesis and cancer prevention, suggesting that these roles may converge and result in modulation of CSC function by the RAS. In support of this, components of the RAS have been shown to be expressed in many cancer types and have been more recently localized to the CSCs in some tumors. Given these roles of the RAS in tumor development, clinical trials using RAS inhibitors either singly or in combination with other therapies are underway in different cancer types. This review outlines the roles of the RAS, with respect to CSCs, and suggests that the presence of components of the RAS in CSCs could offer an avenue for therapeutic targeting using RAS modulators. Due to the nature of the RAS and its crosstalk with numerous other signaling pathways, a systems approach using traditional RAS inhibitors in combination with inhibitors of bypass loops of the RAS and other signaling pathways that converge on the RAS may offer a novel therapeutic approach to cancer treatment.

Keywords: bypass loops; cancer stem cells; renin-angiotensin system; stem cell differentiation; tumorigenesis.

Figure 1

Overview of the renin-angiotensin system with its bypass loops and convergent signaling pathways. The renin-angiotensin system (black) regulates blood pressure, stem cell differentiation, and tumor development. Bypass loops of the RAS involving enzymes such as chymase and cathepsins B, D, and G (green) provide redundancy, while convergent inflammatory and developmental signaling pathways (blue) have multiple roles and effects. Angiotensinogen (AGN) is physiologically synthesized and released by the liver and is cleaved by renin to form angiotensin I (ATI). Renin is formed following binding of pro-renin to the pro-renin receptor. ATI is converted to angiotensin II (ATII) by angiotensin converting enzyme (ACE). ATII interacts with the G-protein coupled receptors ATII receptor 1 (ATIIR1) and ATII receptor 2 (ATIIR2) to restore homeostasis, via vasoconstriction and vasodilation, respectively. ATII can also give rise to angiotensin III via the action of aminopeptidase A, and Angiotensin 1–7 which binds and activates the G-protein coupled receptor MAS. Cathepsins B and D are also renin-activating enzymes that convert pro-renin to renin. Cathepsin D converts AGN to ATI, and cathepsin G converts ATI to ATII or AGN directly to ATII. Chymase converts ATI to ATII. Pro-renin also induces Wnt/β-catenin signaling in a feedback loop. ATIIR1 can also result in inflammatory signaling via the NOX-ROS-NFκB-COX2 signaling axis. ROS, reactive oxygen species.

Figure 2

The renin-angiotensin system and its bypass loops and converging signaling pathways can be targeted at different points. The renin-angiotensin system (black) regulates blood pressure, stem cell differentiation, and tumor development. Bypass loops in the system involving cathepsins and chymase (green) provide redundancy, while convergent inflammatory and development signaling pathways (blue) have multiple roles and effects. Multiple points of the pathway can be targeted by specific inhibitors (red). ACE, angiotensin converting enzyme; ARBs, ATIIR1 blockers; ROS, reactive oxygen species; NSAIDS, non-steroidal anti-inflammatory drugs.