The renin angiotensin system regulates Kupffer cells in colorectal liver metastases

Abstract

Blockade of the renin angiotensin system (RAS) can inhibit tumor growth and this may be mediated via undefined immunomodulatory actions. This study investigated the effects of RAS blockade on liver macrophages (Kupffer cells; KCs) in an orthotopic murine model of colorectal cancer (CRC) liver metastases. Here we showed that pharmacological targeting of the RAS [ANG II (31.25 µg/kg/h i.p.), ANG-(1–7) (24 µg/kg/h i.p.) or the ACE inhibitor; captopril (750 mg/kg/d i.p.)] altered endogenous KC numbers in the tumor-bearing liver throughout metastatic growth. Captopril, and to a lesser extent ANG-(1–7), increased KC numbers in the liver but not tumor. KCs were found to express the key RAS components: ACE and AT1R. Treatment with captopril and ANG II increased the number of AT1R-expressing KCs, although total KC numbers were not affected by ANG II. Captopril (0.1 µM) also increased macrophage invasion in vitro. Additionally, captopril was administered with KC depletion before tumor induction (day 0) or at established metastatic growth (day 18) using gadolinium chloride (GdCl_3; 20 mg/kg). Livers were collected at day 21 and quantitative stereology used as a measure of tumor burden. Captopril reduced growth of CRC liver metastases. However, when captopril was combined with early KC depletion (day 0) tumor growth was significantly increased compared with captopril alone. In contrast, late KC depletion (day 18) failed to influence the anti-tumor effects of captopril. The result of these studies suggests that manipulation of the RAS can alter KC numbers and may subsequently influence progression of CRC liver metastases.

Keywords: :

• macrophage
• captopril
• ACE inhibitor
• Kupffer cell
• colorectal cancer

Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.

Acknowledgments

This work was supported by Cancer Australia's Priority-driven Collaborative Cancer Research Scheme (co-funded by Cancer Australia and Cure Cancer Australia Foundation) and by the Cancer Council of Victoria. EIA was supported by an NHMRC Post-doctoral Training Award. SWW and JN were supported by an Australian Rotary Health Research Fund PhD Scholarship. TF aided in editing the manuscript. SWW performed experimental and statistical analysis and drafted the manuscript. EIA and SWW contributed equally to experimental design and protocol optimization. JN contributed to the RAS treatment and tissue collection. EIA and CC reviewed the manuscript and aided in the development of the concepts tested.