Role of renin-angiotensin system in gastric oncogenesis

Abstract

The renin-angiotensin system (RAS) plays an important role not only in homeostasis but also in carcinogenesis. Recent epidemiological studies suggest that hypertensive patients with upregulated systemic RAS functions are at a significantly increased risk for the subsequent development of cancers with poor outcomes, and moreover that RAS inhibitors reduce tumor development, progression, and metastasis. Notably, Helicobacter pylori infection, one of the major predictors of gastric carcinogenesis, generally leads to RAS component overexpression, as exemplified by that of angiotensin I, angiotensin II, angiotensin I converting enzyme and angiotensin II receptor. Gastric mucosal RAS expression gradually increases with time after H. pylori infection with respect to the severity of inflammatory cell infiltration. Gastric carcinogenic potential is therefore considered to relate to RAS component expression levels and activities. This hypothesis is supported by findings that RAS genotypic variation can lead to high component expression levels (e.g. angiotensin I converting enzyme, chymase and angiotensinogen), and thereby increase the risk of development of gastric cancer. Thus, the RAS may be potently associated with the pathogenesis of H. pylori-related gastric carcinogenesis, and RAS inhibitors may provide tools for specifically preventing this disease.

Figure 1

The renin-angiotensin system (RAS) pathways. There are two RAS types, circulatory and local. ACE, angiotensin converting enzyme.

Figure 2

Association with renin-angiotensin system (RAS) activity and time course after Helicobacter pylori infection into gastric mucosa. EGF, epidermal growth factor; IL, interleukin; VEGF, vascular endothelial growth factor.

Figure 3

(a) Angiotensin II type 1 receptor (AT1R) mRNA levels and mononuclear cell (MNC) infiltration scores in the antrum and body. AT1R mRNA levels correlated significantly with the MNC infiltration score. (b) Correlation between AT1R mRNA and interleukin (IL)-17 mRNA levels. AT1R mRNA levels strongly correlated with IL-17 mRNA levels. □, Antrum; , Body.

Figure 4

Gastric antrum mucosal angiotensin II type 1 receptor (AT1R) mRNA levels in Mongolian gerbils infected with Helicobacter pylori wild type, babA-KO and oipA-KO strains over 12 months. Maximum levels of AT1R mRNA were observed 12 months after inoculation in both the antrum and body. Levels of AT1R mRNA in babA-KO and oipA-KO strains were lower than that in wild type strain. *P 0.05 compared with the antrum. □, 0 months; , 1 month; , 3 months; , 6 months; ■, 12 months.

Figure 5

Gastric mucosal angiotensin II type 1 receptor (AT1R) levels in Mongolian gerbil ulcer (GU+) and non-ulcer groups (GU−) in Helico-bacter pylori wild type, babA-KO and oipA-KO strains. *P 0.05 (vs ulcer-free group). □, Gastritis alone; , GU.