Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Cancer Biol Ther. 2013 Aug;14(8):720-7. doi: 10.4161/cbt.25092. Epub 2013 Jun 17.
Blockade of the renin angiotensin system (RAS) can inhibit tumor growth and this may be mediated via undefined immunomodulatory actions. This study investigated the effects of RAS blockade on liver macrophages (Kupffer cells; KCs) in an orthotopic murine model of colorectal cancer (CRC) liver metastases. Here we showed that pharmacological targeting of the RAS [ANG II (31.25 µg/kg/h i.p.), ANG-(1-7) (24 µg/kg/h i.p.) or the ACE inhibitor; captopril (750 mg/kg/d i.p.)] altered endogenous KC numbers in the tumor-bearing liver throughout metastatic growth. Captopril, and to a lesser extent ANG-(1-7), increased KC numbers in the liver but not tumor. KCs were found to express the key RAS components: ACE and AT1R. Treatment with captopril and ANG II increased the number of AT1R-expressing KCs, although total KC numbers were not affected by ANG II. Captopril (0.1 µM) also increased macrophage invasion in vitro. Additionally, captopril was administered with KC depletion before tumor induction (day 0) or at established metastatic growth (day 18) using gadolinium chloride (GdCl 3; 20 mg/kg). Livers were collected at day 21 and quantitative stereology used as a measure of tumor burden. Captopril reduced growth of CRC liver metastases. However, when captopril was combined with early KC depletion (day 0) tumor growth was significantly increased compared with captopril alone. In contrast, late KC depletion (day 18) failed to influence the anti-tumor effects of captopril. The result of these studies suggests that manipulation of the RAS can alter KC numbers and may subsequently influence progression of CRC liver metastases.
阻断肾素血管紧张素系统（RAS）可以抑制肿瘤生长，其可能通过未定义的免疫调节作用来实现。本研究在结直肠癌（CRC）肝转移的原位小鼠模型中，研究了 RAS 阻断对肝巨噬细胞（Kupffer 细胞；KCs）的影响。研究表明，RAS 的药理学靶向治疗[血管紧张素 II（31.25 µg/kg/h 腹腔注射）、ANG-（1-7）（24 µg/kg/h 腹腔注射）或 ACE 抑制剂；卡托普利（750 mg/kg/d 腹腔注射）]改变了整个转移性生长过程中肿瘤负荷肝中内源性 KC 的数量。卡托普利和在较小程度上 ANG-（1-7）增加了肝中的 KC 数量，但肿瘤中没有增加。发现 KCs 表达关键的 RAS 成分：ACE 和 AT1R。尽管血管紧张素 II 未影响总 KC 数量，但卡托普利和血管紧张素 II 治疗均增加了表达 AT1R 的 KC 数量。卡托普利（0.1 µM）还增加了体外巨噬细胞的侵袭。此外，在肿瘤诱导前（第 0 天）或在建立的转移性生长（第 18 天）时用氯化钆（GdCl 3；20 mg/kg）用卡托普利进行 KC 耗竭。在第 21 天收集肝脏，并使用定量立体学作为肿瘤负担的衡量标准。卡托普利可减少 CRC 肝转移的生长。然而，当卡托普利与早期 KC 耗竭（第 0 天）联合使用时，与单独使用卡托普利相比，肿瘤生长显著增加。相比之下，晚期 KC 耗竭（第 18 天）并未影响卡托普利的抗肿瘤作用。这些研究的结果表明，RAS 的操纵可以改变 KC 的数量，并可能随后影响 CRC 肝转移的进展。
