Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Mol Cancer Ther. 2018 Jul;17(7):1515-1525. doi: 10.1158/1535-7163.MCT-17-0845. Epub 2018 Apr 11.
Adjuvant chemotherapy is used for human breast cancer patients, even after curative surgery of primary tumor, to prevent tumor recurrence primarily as a form of metastasis. However, anticancer drugs can accelerate metastasis in several mouse metastasis models. Hence, we examined the effects of postsurgical administration with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide, on lung metastasis process, which developed after the resection of the primary tumor arising from the orthotopic injection of a mouse triple-negative breast cancer cell line, 4T1. Only 5-FU markedly increased the numbers and sizes of lung metastasis foci, with enhanced tumor cell proliferation and angiogenesis as evidenced by increases in Ki67-positive cell numbers and CD31-positive areas, respectively. 5-FU-mediated augmented lung metastasis was associated with increases in intrapulmonary neutrophil numbers and expression of neutrophilic chemokines, Cxcl1 and Cxcl2 in tumor cells, with few effects on intrapulmonary T-cell or macrophage numbers. 5-FU enhanced Cxcl1 and Cxcl2 expression in 4T1 cells in a NFκB-dependent manner. Moreover, the administration of a neutrophil-depleting antibody or a Cxcr2 antagonist, SB225002, significantly attenuated 5-FU-mediated enhanced lung metastasis with depressed neutrophil infiltration. Furthermore, infiltrating neutrophils and 4T1 cells abundantly expressed prokineticin-2 () and its receptor, , respectively. Finally, the administration of 5-FU after the resection of the primary tumor failed to augment lung metastasis in the mice receiving -deleted 4T1 cells. Collectively, 5-FU can enhance lung metastasis by inducing tumor cells to produce Cxcl1 and Cxcl2, which induced the migration of neutrophils expressing Prok2 with a capacity to enhance 4T1 cell proliferation. .
辅助化疗用于人类乳腺癌患者，即使在原发性肿瘤的根治性手术后，也是为了预防肿瘤复发，主要是转移形式。然而，抗癌药物可以在几种小鼠转移模型中加速转移。因此，我们检查了术后给予氟尿嘧啶（5-FU）、阿霉素和环磷酰胺对肺转移过程的影响，该过程发生在从原位注射的原发性肿瘤切除后，源自小鼠三阴性乳腺癌细胞系 4T1。只有 5-FU 明显增加了肺转移灶的数量和大小，并分别通过增加 Ki67 阳性细胞数量和 CD31 阳性区域来增强肿瘤细胞增殖和血管生成。5-FU 介导的增强的肺转移与肺内中性粒细胞数量的增加以及肿瘤细胞中中性粒细胞趋化因子 Cxcl1 和 Cxcl2 的表达增加有关，对肺内 T 细胞或巨噬细胞数量的影响很小。5-FU 以 NFκB 依赖的方式增强了 4T1 细胞中 Cxcl1 和 Cxcl2 的表达。此外，中性粒细胞耗竭抗体或 Cxcr2 拮抗剂 SB225002 的给药可显著减弱 5-FU 介导的增强的肺转移，并抑制中性粒细胞浸润。此外，浸润的中性粒细胞和 4T1 细胞分别丰富地表达促动力蛋白 2 (Prok2) 和其受体 Prokr2。最后，在接受 -/- 4T1 细胞的小鼠中，在原发性肿瘤切除后给予 5-FU 未能增强肺转移。总之，5-FU 可以通过诱导肿瘤细胞产生 Cxcl1 和 Cxcl2 来增强肺转移，这诱导表达 Prok2 的中性粒细胞迁移，并增强 4T1 细胞增殖。
