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Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma
Published on: September 3, 2021
The renin angiotensin system regulates Kupffer cells in colorectal liver metastases
Shu Wen Wen1, Eleanor I Ager, Jaclyn Neo
1Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. ShuWen.Wen@qimr.edu.au
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.
Insights
Targeting the renin-angiotensin system (RAS) with captopril impacts liver macrophages (Kupffer cells) and influences colorectal cancer liver metastasis growth. Early depletion of Kupffer cells negates captopril
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Blockade of the renin-angiotensin system (RAS) shows potential in inhibiting tumor growth, possibly through immunomodulatory mechanisms.
- The role of liver macrophages (Kupffer cells; KCs) in colorectal cancer (CRC) liver metastases and their interaction with the RAS remains incompletely understood.
Purpose of the Study:
- To investigate the effects of RAS blockade on Kupffer cells in an orthotopic murine model of CRC liver metastases.
- To determine if modulating KCs influences the anti-tumor effects of RAS inhibition.
Main Methods:
- Pharmacological targeting of the RAS using ANG II, ANG-(1-7), and captopril in a murine CRC liver metastasis model.
- Assessment of KC numbers and expression of RAS components (ACE, AT1R) in the liver and tumor.
- In vitro assessment of macrophage invasion.
- KC depletion using gadolinium chloride at different time points relative to tumor induction and captopril treatment.
Main Results:
- Captopril and ANG-(1-7) increased KC numbers in the tumor-bearing liver, while ANG II did not affect total KC numbers but increased AT1R expression.
- Captopril demonstrated anti-tumor effects, reducing CRC liver metastases growth.
- Early KC depletion (before tumor induction) combined with captopril significantly increased tumor growth, whereas late depletion (at established metastasis) did not alter captopril's anti-tumor effect.
Conclusions:
- Manipulation of the RAS can alter Kupffer cell populations in the liver.
- Kupffer cells play a crucial role in mediating the anti-tumor effects of captopril against CRC liver metastases, particularly when treatment is initiated early.
- These findings suggest that targeting the RAS, in conjunction with understanding KC dynamics, could be a therapeutic strategy for CRC liver metastases.
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