Blockade of the renin-angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver.
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 mm(3), 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/mm(2), 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.
Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia. shir_lin@hotmail.com.
Shir Lin
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Koh
Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia.
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Ager
Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia.
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Costa
Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia.
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Malcontenti-Wilson
Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia.
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Muralidharan
Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia.
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Christophi
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012084:Renin-Angiotensin System / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D002216:Captopril
Colorectal cancer liver metastases; Liver regeneration; Mouse model; Partial hepatectomy; Tumor growth and stimulation