Section of Surgery, Department of Clinical Sciences, Malmö, Skåne University Hospital, Lund University, 20502, Malmö, Sweden.
Clin Exp Metastasis. 2021 Aug;38(4):401-410. doi: 10.1007/s10585-021-10103-0. Epub 2021 Jun 11.
Peritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, β1 and β3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.
腹膜转移是结直肠癌的一个隐匿方面。本研究旨在确定调节结肠癌细胞粘附和腹腔手术后腹膜伤口扩散的机制。将 CT-26 结肠癌细胞腹腔内注射到小鼠中，并在使用 CXCR2 拮抗剂或整合素-αV-抗体治疗后定量检测腹腔内的转移性结节。CT-26 细胞表达细胞表面趋化因子受体 CXCR2、CXCR3、CXCR4 和 CXCR5。CXCR2 配体 CXCL2 的刺激剂量依赖性地增加 CT-26 细胞的体外增殖和迁移。CXCR2 拮抗剂 SB225002 剂量依赖性地降低 CXCL2 诱导的结肠癌细胞体外增殖和迁移。腹腔内注射 CT-26 结肠癌细胞导致剖腹动物腹膜表面转移性结节广泛生长。剖腹术增加了切口线上 CXCL2 的基因表达。CXCR2 拮抗剂预处理可使转移性结节减少 70%。此外，CXCL2 刺激以 CXCR2 依赖的方式增加 CT-26 细胞对细胞外基质 (ECM) 蛋白的粘附。CT-26 细胞表达 αV、β1 和 β3 整合素亚基，免疫中和 αV 可消除 CXCL2 触发的 CT-26 与 vitronectin、纤连蛋白和纤维蛋白原的粘附。最后，αV 整合素的抑制显著减少了剖腹小鼠的癌转移结节数 69%。这些结果通过体外使用人结肠癌细胞系 HT-29 得到了验证。我们的数据表明，结肠癌细胞在腹膜伤口部位的粘附和生长是由 CXCL2-CXCR2 信号轴和 αV 整合素依赖的 ECM 蛋白粘附介导的。
