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Title: The renin angiotensin system regulates Kupffer cells in colorectal liver metastases.
Austin Authors: Wen, Shu Wen;Ager, Eleanor I;Neo, Jaclyn;Christophi, Christopher 
Affiliation: Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 17-Jun-2013
Publication information: Cancer Biology & Therapy 2013; 14(8): 720-7
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.
Gov't Doc #: 23792575
DOI: 10.4161/cbt.25092
Journal: Cancer biology & therapy
Type: Journal Article
Subjects: ACE inhibitor
Kupffer cell
colorectal cancer
Angiotensin I.pharmacology
Angiotensin II.pharmacology
Angiotensin-Converting Enzyme Inhibitors.pharmacology
Colorectal Neoplasms.drug therapy.metabolism.pathology
Disease Models, Animal
Kupffer Cells.drug effects.pathology
Liver Neoplasms.drug therapy.metabolism.secondary
Macrophages.drug effects.pathology
Mice, Inbred CBA
Peptide Fragments.pharmacology
Renin-Angiotensin System.drug effects.physiology
Appears in Collections:Journal articles

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