The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies

Abstract

The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1-7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies.Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment.

Keywords: ACE inhibitors; ARBs, sex hormone-dependent cancer, GI cancer; Cancer biology; Renin-angiotensin-aldosterone system.

Fig. 1

RAAS peptides, receptors and enzymes Angiotensinogen is the precursor of all angiotensin derivatives. Angiotensinogen can be cleaved by renin to produce Ang (I) Ang I cleaves into Ang II by ACE or chymase. Some peptidases, like TOP, NEP, and PEP, can convert Ang I into Ang 1–7. ACE2 can hydrolyze Ang II to create Ang 1–7 as well. In addition, Ang I can be cleaved by ACE2 to create Ang 1–9, which can be cleaved by ACE or NEP to generate Ang 1–7. Ang III (Ang 2–8) can be driven from Ang II by APA. As Ang III is further cleaved, it produces Ang IV (Ang 3–8). Through the decarboxylation of Asp1, Ang A is produced from Ang (II) Ang A could be converted to alamandine by ACE2. Alamandine can also be produced by decarboxylation of the aspartate residue in Ang 1–7

Fig. 2

Angiotensin derivatives and their associated receptors The downstream pathways affecting proliferation, apoptosis, angiogenesis, and cancer as well as an overview of the receptors and effectors affecting the RAAS pathway is displayed and the dual effect of this pathway on cancer is depicted. The interactions between Ang II/AT1R and Ang I/AT2R and Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can have a significant impact on the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Activation or inhibition of the PI3K/AKT/mTOR pathway and the RAS/RAF/ERK1/2 pathway, which are downstream of the RASS pathway, are the most effective pathways in cancer development or cancer prevention