Cardiooncology. 2026 May 1. doi: 10.1186/s40959-026-00495-x. Online ahead of print.
ABSTRACT
BACKGROUND: The higher incidence of cancer in patients with cardiovascular disease (CVD) has historically been explained by shared risk factors. Recent studies suggest, however, a causal relationship. Nevertheless, the mechanisms of CVD-induced cancer are incompletely understood. Here, we hypothesize that angiotensin II (ANGII) links CVD and increased cancer growth.
OBJECTIVE: We investigated the impact of ANGII-induced CVD on cancer growth in vivo, differentiating between a direct effect of ANGII on tumor cells or indirect effects secondary to CVD.
METHODS: The effect of ANGII on cancer growth was studied in C57BL/6J mice with cancer. Cancer was either induced by subcutaneous injection of Lewis lung carcinoma (LLC) cells, MC38 colon cancer cells, or by genetic susceptibility (APCmin mice). To differentiate between direct and indirect effects of ANGII on cancer growth three strategies were implemented: (i) Evaluating a protocol with and without overlap between ANGII treatment and the injection of tumor cells, (ii) comparing the effect of a high (2000 ng.kg- 1.min- 1) and low (400 ng.kg- 1.min- 1) dose of ANGII on intestinal polyp growth in APCmin mice and (iii) comparing the impact of ANGII on tumor growth in high (LLC) and low (MC38) angiotensin II receptor type I (AT1) expressing tumor cells.
RESULTS: High dose ANGII-treatment induced left ventricle (LV) hypertrophy and cardiac fibrosis, and enhanced growth of injected tumor cells, but only when LCC tumor cells with high expression of AT1 were used, and when these cells were injected during ANGII treatment. ANGII did not increase cancer growth when LCC cells were injected after halting ANGII treatment, or when MC38 tumor cells with low AT1 levels were used. ANGII also increased the number of intestinal polyps in APCmin mice, even at a low dose that did not induce LV hypertrophy or cardiac fibrosis. Lastly, an analysis of publicly available cancer databases showed that AT1 gene copy number variation is increased in most human cancer lines and tumors.
CONCLUSION: This study indicates that ANGII has direct effects on cancer growth, warranting further research into the role of an activated renin-angiotensin-aldosterone-system (RAAS) as a mechanistic link between CVD and cancer growth in AT1-positive tumors.
PMID:42067907 | DOI:10.1186/s40959-026-00495-x