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Blockade of the renin–angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver

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Abstract

Partial hepatectomy (PH), the preferred option for selected patients with colorectal cancer liver metastases (CRCLM), is associated with 40–80 % tumor recurrence rates. Renin–angiotensin system (RAS) blockade inhibits tumor growth and has been suggested to improve liver regeneration. We documented the effect of RAS blockade on tumor growth and liver regeneration in a murine model. CRCLM induction followed by 70 % PH was performed on 78 CBA mice. Liver regeneration (days 2, 6) and CRCLM tumor load were measured by liver (and tumor) weights, percentage of CRCLM burden and tumor nodule count (days 16, 21). mRNA expression of the RAS components was characterised. Statistical analysis was performed using 2-independent sample T test or Mann–Whitney test (SPSS). Captopril did not impair liver regeneration. By day 21, Captopril decreased tumor burden (percentage of CRCLM in the liver) (48.7 ± 4.7 % control, 24.4 ± 6.2 Captopril; p = 0.008), tumor volume (1046.2 ± 200.2 mm3, 388.3 ± 150.4; p = 0.02), tumor nodule count per image field (181.1 ± 28.5, 68 ± 17.6; p = 0.005) and tumor angiogenesis (71.8 ± 6.4 vessels/mm2, 43.1 ± 7.6; p = 0.015) compared to controls. Captopril enhanced tumor apoptosis (1 ± 0.2 %, 2.5 ± 0.7; p = 0.028). Liver regeneration and tumor development increased liver ACE levels. Blockade of the RAS effectively retarded CRCLM tumor growth at the late stage of tumor development within the regenerating liver without impeding liver regeneration following PH, via anti-angiogenesis and pro-tumor apoptosis. Captopril may be of therapeutic benefit in patients undergoing PH for CRCLM.

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Acknowledgments

This work has been supported by Austin Health Medical Research Foundation, The University of Melbourne, Australian Rotary Health, Priority-driven Collaborative Cancer Research Scheme and the Cancer Council of Victoria. Dr. Ager was supported by an NHMRC post-doctoral training fellowship.

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Authors and Affiliations

  1. Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia

    Shir Lin Koh, E. I. Ager, P. L. N. Costa, C. Malcontenti-Wilson, V. Muralidharan & C. Christophi

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  1. Shir Lin Koh
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  2. E. I. Ager
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Correspondence to Shir Lin Koh.

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This work was supported by Austin Health Medical Research Foundation, The University of Melbourne, Australian Rotary Health, Priority-driven Collaborative Cancer Research Scheme and the Cancer Council of Victoria. Dr. Ager was supported by an NHMRC post-doctoral training fellowship. There are no financial disclosures from any authors.

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Koh, S.L., Ager, E.I., Costa, P.L.N. et al. Blockade of the renin–angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver. Clin Exp Metastasis 31, 395–405 (2014). https://doi.org/10.1007/s10585-014-9635-8

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