Abstract
BackgroundTargeting of the renin angiotensin system (RAS) reduces tumour growth in experimental models of cancer. We aimed to establish if combined targeting of the 'classical' and 'alternative' arms of the RAS could result in synergistic inhibition of colorectal cancer (CRC) liver metastases.MethodsImmediately following induction of CRC liver metastases through intrasplenic injection of murine CRC cells, treatment with irbesartan (AT1R blocker; 50 mg/kg/day s.c.), captopril (ACE inhibitor; 750 mg/kg/day i.p.), CGP42112A (AT2R agonist; 0.6 μg/kg/hr i.p.), and/or ANG-(1-7) (24 μg/kg/hr i.p.) began and continued for 21 days. Liver to body weight ratio and/or stereology were used as a measure of tumour burden. Immunohistochemistry was used to determine AT1R and VEGF expression as well as proliferation (Ki67), apoptosis (active caspase 3) and angiogenesis (CD34).ResultsCombined RAS therapies failed to improve upon single arm therapies. However, while irbesartan previously inhibited tumour growth in this model, in the current experiments irbesartan failed to affect tumour burden. Subsequent analysis showed a cancer-cell specific upregulation of the angiotensin II type I receptor (AT1R) in irbesartan-insensitive compared to irbesartan-sensitive tumours. The upregulation of AT1R was associated with an increase in proliferation and VEGF expression by cancer cells. While animals bearing irbesartan-sensitive tumours showed a marked decrease in the number of proliferating cells in the liver and VEGF-expressing infiltrating cells in the tumour following AT1R treatment, these were unchanged by treatment in animals bearing irbesartan-insensitive (high AT1R expressing) tumours.ConclusionsAlthough the results do not support increased efficacy of combined treatment, they provide intriguing evidence of the importance of RAS expression in determining patient response and tumour growth potential and suggest that components of the RAS could be used as biomarkers to aid in patient selection.
Highlights
Targeting of the renin angiotensin system (RAS) reduces tumour growth in experimental models of cancer
We previously showed that targeting of the renin angiotensin system (RAS) with either an angiotensin (ANG) angiotensin II (II) type I receptor (AT1R) blocker or an angiotensin converting enzyme (ACE) inhibitor could inhibit tumour growth in an orthotopic syngeneic mouse model of colorectal cancer (CRC) liver metastases [2,3]
Captopril and ANG-(1-7) inhibited tumour burden while angiotensin II type 1 receptor (AT1R) blockade had no significant effect Mice were induced with CRC liver metastases and treated with irbesartan, ANG-(1-7), or captopril while control received vehicle (PBS or methyl cellulose)
Summary
Targeting of the renin angiotensin system (RAS) reduces tumour growth in experimental models of cancer. We previously showed that targeting of the renin angiotensin system (RAS) with either an angiotensin (ANG) II type I receptor (AT1R) blocker (irbesartan) or an angiotensin converting enzyme (ACE) inhibitor (captopril) could inhibit tumour growth in an orthotopic syngeneic mouse model of CRC liver metastases [2,3]. ANG-(1-7), through its specific receptor MasR, appears to counteract many of the actions induced by the classical AT1R/ANGII RAS pathway [7]. Activation of the alternative ANG II receptor, the AT2R, has been shown to inhibit tumour growth ( to lesser extent either irbesartan or captopril)[5]. Two independent Phase I clinical trials are examining ANG-(1-7) [10] and AT1R blockade [11] in the treatment of various solid tumours
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