Koh Shir Lin, Ager E I, Costa P L N, Malcontenti-Wilson C, Muralidharan V, Christophi C
Department of Surgery, Austin Health, The University of Melbourne, Burgundy Street, Heidelberg, VIC, 3084, Australia.
Clin Exp Metastasis. 2014 Apr;31(4):395-405. doi: 10.1007/s10585-014-9635-8. Epub 2014 Jan 18.
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.
部分肝切除术（PH）是部分患有结直肠癌肝转移（CRCLM）患者的首选治疗方法，但其肿瘤复发率为40%-80%。肾素-血管紧张素系统（RAS）阻断可抑制肿瘤生长，并被认为可促进肝再生。我们在小鼠模型中记录了RAS阻断对肿瘤生长和肝再生的影响。对78只CBA小鼠进行CRCLM诱导，随后进行70%的PH。通过肝脏（和肿瘤）重量、CRCLM负担百分比和肿瘤结节计数（第16、21天）来测量肝再生（第2、6天）和CRCLM肿瘤负荷。对RAS成分的mRNA表达进行了表征。使用两独立样本T检验或曼-惠特尼检验（SPSS）进行统计分析。卡托普利不损害肝再生。到第21天，卡托普利降低了肿瘤负担（肝脏中CRCLM的百分比）（对照组为48.7±4.7%，卡托普利组为24.4±6.2%；p=0.008）、肿瘤体积（1046.2±200.2mm³，388.3±150.4；p=0.02）、每个图像视野的肿瘤结节计数（181.1±28.5，68±17.6；p=0.005）和肿瘤血管生成（71.8±6.4个血管/mm²，43.1±7.6；p=0.015）。卡托普利增强了肿瘤凋亡（1±0.2%，2.5±0.7；p=0.028）。肝再生和肿瘤发展增加了肝脏ACE水平。在再生肝脏内肿瘤发展的晚期，RAS阻断通过抗血管生成和促肿瘤凋亡有效地延缓了CRCLM肿瘤生长，且不影响PH后的肝再生。卡托普利可能对接受PH治疗CRCLM的患者具有治疗益处。
