The impact of renin-angiotensin system inhibitors on colorectal neoplasm development

Abstract

Background: Renin-angiotensin system (RAS) inhibitors have shown potential chemopreventive effects against colorectal cancer (CRC). However, little is known about the impact of RAS inhibitors on the risk of colorectal precancerous lesions.

Methods: Preclinically, we established mouse models of colitis-associated colon cancer and xenografts: vehicle, 1 mg/kg, 5 mg/kg enalapril groups. Body weight, colon length, and colorectal tumor size were evaluated on the euthanization day. Clinically, we retrospectively recruited 8,388 asymptomatic adults undergoing their first-ever colonoscopy for health check-ups (index cohort). From the index cohort, we selected individuals undergoing follow-up colonoscopy (follow-up cohort). The study outcome was incidental and recurrent colorectal neoplasms, including CRC. We evaluated the prevalence and risk of colorectal neoplasms associated with RAS inhibitor use of ≥ 1 year.

Results: In the experimental study, enalapril administration significantly attenuated weight loss and colon shortening, reduced tumor numbers in colitis-associated colon cancer models, and decreased tumor volume in the xenografts. In the index cohort, while the initial analysis showed a positive association with the RAS inhibitor use (unadjusted odds ratio [OR], 1.22), this shifted toward an inverse trend after adjusting for confounders (adjusted OR, 0.91). During follow-up (median, 41.0 months), incidental and recurrent colorectal neoplasms were less common in the RAS inhibitor group (32.6%) than in the other anti-hypertensives group (39.1%) (P < 0.001), despite similar intervals between the index and follow-up endoscopies. In the follow-up cohort, hypertension itself was a risk factor for colorectal neoplasm development (adjusted hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.00-2.53; P = 0.049), whereas RAS inhibitor use was significantly associated with a 27% lower risk (adjusted HR, 0.73; 95% CI, 0.59-0.95; P = 0.035).

Conclusions: Long-term, regular use of RAS inhibitors independently reduces the risk of colorectal neoplasms, irrespective of dosage or drug type. Given their potential chemopreventive effects on colorectal neoplasms, RAS inhibitors may serve as a preventive strategy starting from the precancerous stage.

Keywords: Chemoprevention; Colorectal cancer; RAS inhibitor; Translational research.

Fig. 1. Flowchart for the study participants in the index and follow-up cohorts.

RAS, renin-angiotensin system. ^aOnly subjects who met the criteria for adequate bowel preparation (Aronchick scale < 4 or a Boston Bowel Preparation score ≥ 6) were included in the analysis. ^bControls matched 1:1 with anti-hypertensive users based on age and sex. ^cOur institution’s recommendations for follow-up colonoscopy were based on the American Gastroenterological Association guidelines.

Fig. 2. Effect of enalapril on azoxymethane/dextran sulfate sodium-induced colitis-associated colon cancer model. (A) Gross appearance of colon specimen showed that oral administration of astragalin improved colon shortening and reduced tumor number. (B) Oral administration of enalapril significantly reduced the degree of body weight loss compared with that of vehicle-treated mice. (C) Mice in enalapril group showed longer colon length than those in vehicle group. (D) Administration of enalapril significantly reduced tumor number.

Fig. 3. Effect of enalapril on colon cancer xenograft model. (A) The representative appearances of gross tumor were presented. (B) The administration of oral enalapril inhibited tumor growth significantly. There was no significant difference between enalapril 1 mg/kg and 5 mg/kg groups.

Fig. 4. Schematic figure for the chemopreventive effect of renin-angiotensin system inhibitors on colorectal cancer.

ACE, angiotensin converting enzyme; ATR, angiotensin receptor; PD-1, programmed cell death protein-1; ARB, angiotensin receptor blocker; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor-beta; PDGF, platelet-derived growth factor; bFGF, basic fibroblast growth factor.