Grewal Simran, Korthouwer Rianne, Bögels Marijn, Braster Rens, Heemskerk Niels, Budding Andries E, Pouw Stephan M, van Horssen Jack, Ankersmit Marjolein, Meijerink Jeroen, van den Tol Petrousjka, Oosterling Steven, Bonjer Jaap, Gül Nuray, van Egmond Marjolein
Department of Molecular Cell Biology and Immunology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
Department of Surgery, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands.
Oncoimmunology. 2018 Jul 26;7(9):e1461302. doi: 10.1080/2162402X.2018.1461302. eCollection 2018.
Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal carcinoma (CRC). However, bacterial translocation during intestinal surgery has been correlated with poor long-term oncological outcome. Therefore, we investigated the influence of bacterial contamination during colon surgery on CRC liver metastases development. Blood and liver samples of patients undergoing resection of primary CRC or liver metastases were collected. Cell numbers, activation markers and inflammatory mediators were determined. Tumor cell adhesion and outgrowth after sham- or colectomy operations were determined in a rat model, in which tumor cells had been injected into the portal vein. White blood cells and granulocytes were increased in per- and post-operative patient blood samples. IL-6 was also increased post-operatively compared to the preoperative level. Expression of NOX-2, NOX-4 and polymorphonuclear cells (PMNs) numbers were elevated in post-operative human liver samples. stimulation of macrophages with plasma of rats after colectomy resulted in production of reactive oxygen species (ROS). Colectomy in rats increased D-lactate levels in plasma, supporting bacterial translocation. Decreased expression of tight junction molecules and increased tumor cell adhesion and outgrowth was observed. Treatment with a selective decontamination of the digestive tract (SDD) cocktail decreased tumor cell adherence after colectomy. In conclusion, postoperative bacterial translocation may activate liver macrophages and PMNs, resulting in ROS production. As we previously showed that ROS release led to liver vasculature damage, circulating tumor cells may adhere to exposed extracellular matrix and grow out into liver metastases. This knowledge is pivotal for development of therapeutic strategies to prevent surgery-induced liver metastases development.
手术切除原发性肿瘤为结直肠癌（CRC）患者提供了最佳的治愈机会。然而，肠道手术期间的细菌易位与长期肿瘤学不良预后相关。因此，我们研究了结肠手术期间细菌污染对CRC肝转移发生的影响。收集了接受原发性CRC或肝转移瘤切除手术患者的血液和肝脏样本。测定了细胞数量、激活标志物和炎症介质。在将肿瘤细胞注入门静脉的大鼠模型中，测定了假手术或结肠切除术后肿瘤细胞的黏附和生长情况。患者术前和术后血液样本中的白细胞和粒细胞增加。与术前水平相比，术后IL-6也增加。术后人类肝脏样本中NOX-2、NOX-4的表达和多形核细胞（PMN）数量升高。用结肠切除术后大鼠的血浆刺激巨噬细胞会产生活性氧（ROS）。大鼠结肠切除术会使血浆中D-乳酸水平升高，支持细菌易位。观察到紧密连接分子表达降低，肿瘤细胞黏附和生长增加。用消化道选择性去污（SDD）鸡尾酒治疗可降低结肠切除术后肿瘤细胞的黏附。总之，术后细菌易位可能激活肝脏巨噬细胞和PMN，导致ROS产生。正如我们之前所表明的，ROS释放会导致肝血管损伤，循环肿瘤细胞可能黏附于暴露的细胞外基质并生长形成肝转移瘤。这一知识对于开发预防手术诱导的肝转移瘤发生的治疗策略至关重要。
