Background and Aims:
Over 50% of colorectal cancer (CRC) patients develop liver metastases. Surgical resection is the only potentially curative treatment for these patients, but 40-80% of them develop disease recurrence (1,2). Liver regeneration, following metastatic resection, induces upregulation of growth factors/cytokines that impact on micrometastases present in the remnant liver leading to tumour recurrence. Macrophages are a major part of the tumour microenvironment and depending on local stimuli macrophages can adopt different phenotypes (M1/M2) influencing tumour progression. Inhibition of the Renin Angiotensin System (RAS) has shown to inhibit tumour growth. This study aims to determine how macrophages are effected by Captopril (RAS inhibitor) treatment on tumour development.
Methods:
Changes in macrophage receptors and secreted factors are investigated in murine CRC liver metastases, following RAS inhibition. Mice were treated with Captopril (250mg/kg) or with saline. Livers were harvested on days 16 or 21 after tumour induction and archived as formalin fixed paraffin embedded (FFPE). Double immunohistochemistry was performed for F4/80 (macrophage marker) and activation markers (Arginase, IL-10, VEGF) to determine macrophage phenotype.
Macrophage cell lines (J774 and P388D1) and a mouse CRC cell line (MoCR) were cultured with Captopril. Cytokines/growth factors released in response to treatment were evaluated with ELISA.
Results
Captopril reduced tumour infiltrating macrophages and particularly VEGF expressing macrophages in vivo. Captopril reduced the secretion of TNF-α, a pro-inflammatory cytokine, by macrophages in in vitro cultures.
Conclusion
Captopril treatment during and following liver resection inhibits infiltration of macrophages including VEGF-secreting macrophages and in vitro alters macrophages towards an anti-inflammatory phenotype.