Oosterling Steven J, van der Bij Gerben J, Bögels Marijn, ten Raa Sander, Post Jan A, Meijer Gerrit A, Beelen Robert H J, van Egmond Marjolein
Department of Surgical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Ann Surg. 2008 Jan;247(1):85-94. doi: 10.1097/SLA.0b013e3181588583.
To study the mechanisms behind surgery-induced augmentation of tumor outgrowth.
Surgery provides the best chance of cure for most primary intra-abdominal carcinomas. Effective treatment is however relatively frequent complicated by peritoneal recurrences, which often originate from free-floating intraperitoneal tumor cells that implant on peritoneal surfaces. We previously reported that surgical trauma promotes development of peritoneal metastases.
Evaluation of adhesion of CC531s rat colon carcinoma cell line intraperitoneally after laparotomy using in vivo, ex vivo, and in vitro models. Also, human ex vivo models were used to study peritoneal tumor cell adhesion.
Peritoneal imprints of operated rats showed that direct damaging of the peritoneum resulted in enhanced adhesion of rat CC531 colon carcinoma cells to submesothelial extracellular matrix (ECM) proteins in vivo, which was confirmed by electron microscopy. Additionally, the inflammatory reaction of the peritoneal cavity led to retraction of mesothelial cells, hereby also exposing ECM at peritoneal surfaces that had not been traumatized directly. Furthermore, we demonstrated that beta1 integrin subunits represented the primary mediators involved in adherence to either isolated ECM components or excised traumatized rat and human peritoneum. Importantly, incubation of CC531s cells with anti-beta1 integrin antibodies resulted in a significant decrease of tumor cell adhesion in vivo.
Surgical trauma results in exposure of ECM at directly and nondirectly damaged peritoneal surfaces, leading to increased beta1 integrin-dependent tumor cell adhesion. Perioperative therapies, which aim to block beta1 integrin subunits, might therefore serve as new clinical tools for the prevention of peritoneal recurrences.
研究手术诱导肿瘤生长增加背后的机制。
手术为大多数原发性腹内癌提供了最佳治愈机会。然而，有效治疗相对频繁地因腹膜复发而复杂化，腹膜复发通常源于种植在腹膜表面的游离腹腔内肿瘤细胞。我们之前报道过手术创伤会促进腹膜转移的发展。
使用体内、体外和离体模型评估剖腹手术后CC531s大鼠结肠癌细胞系在腹腔内的黏附情况。此外，还使用了人类离体模型来研究腹膜肿瘤细胞的黏附。
手术大鼠的腹膜印记显示，腹膜的直接损伤导致大鼠CC531结肠癌细胞在体内与间皮下细胞外基质（ECM）蛋白的黏附增强，这一点通过电子显微镜得到了证实。此外，腹腔的炎症反应导致间皮细胞回缩，从而也使未直接受创伤的腹膜表面暴露了ECM。此外，我们证明β1整合素亚基是参与黏附分离的ECM成分或切除的受创伤大鼠和人类腹膜的主要介质。重要的是，用抗β1整合素抗体孵育CC531s细胞会导致体内肿瘤细胞黏附显著减少。
手术创伤导致ECM在直接和非直接受损的腹膜表面暴露，导致β1整合素依赖性肿瘤细胞黏附增加。因此，旨在阻断β1整合素亚基的围手术期治疗可能成为预防腹膜复发的新临床工具。
