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.
Highlights
Reviewed by: Aamir Ahmad, Mitchell Cancer Institute, United States Masahiro Hitomi, Cleveland Clinic, Lerner Research Institute, United States
Due to the nature of the renin-angiotensin system (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
Given the importance of the RAS for maintaining blood pressure, numerous modulators that inhibit the RAS at different points in the pathway have been developed (Figure 2). These groups of RAS inhibitors are commonly used in the clinic for the treatment of hypertension and include β-blockers, angiotensin converting enzyme (ACE) inhibitors (ACEI), and ATIIR1 blockers (ARBs) as well as newer agents targeting other points in the pathway, inhibitors targeting bypass loops in the RAS pathway, and inhibitors used in other canonical signaling pathways that converge on the RAS (e.g., Wnt/β-catenin inhibitors, metformin, and non-steroidal antiinflammatory drugs) (Figure 2)
Summary
Tumors consist of diverse cell populations. The cellular heterogeneity observed in tumors has led to the suggestion that cancer may be sustained by cancer stem cells (CSCs), which, like normal embryonic stem cells (ESCs), are able to selfrenew and undergo differentiation into multiple cell types. Heterogeneity within CSCs extends beyond tumorigenic potential and encompasses genetic and epigenetic changes as well as local environmental determinants and temporal and spatial differences [8] These differences have implications for effective therapies, as some cancer cells have been shown to resist chemotherapy and radiotherapy, and it has been suggested that they could be targeted for differentiation as a therapeutic approach [8]. The number of CSCs and their ability to form mammospheres in culture is increased following chemotherapy of breast cancer patients [15] and Trastuzumab treatment of a breast cancer cell line [16] Given their ability to generate a diverse cell population within a tumor and their ability to resist conventional cancer treatments, CSCs are proposed to be the cause of loco-regional recurrence and distant metastasis, and treatment failure. Given that CSCs express a unique set of markers, another approach toward identifying and eliminating these cells is to characterize other common features of CSCs and exploit these features for therapeutic targeting using drugs in common use, such as via modulation of signaling pathways such as the reninangiotensin system (RAS)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
