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 (Prok2) and its receptor, Prokr1, respectively. Finally, the administration of 5-FU after the resection of the primary tumor failed to augment lung metastasis in the mice receiving Prokr1-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. Mol Cancer Ther; 17(7); 1515–25. ©2018 AACR.

中文翻译：

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表达促动力素 2 的中性粒细胞浸润参与 5-氟尿嘧啶诱导的乳腺癌肺转移加重

辅助化疗用于人类乳腺癌患者，即使是在原发肿瘤的治愈性手术后，以防止主要作为转移形式的肿瘤复发。然而，抗癌药物可以加速几种小鼠转移模型的转移。因此，我们研究了术后使用 5-氟尿嘧啶 (5-FU)、多柔比星和环磷酰胺对肺转移过程的影响，该过程是在切除原发肿瘤后发生的，该过程是在原位注射小鼠三阴性乳腺引起的原发肿瘤后发生的。癌细胞系，4T1。只有 5-FU 显着增加了肺转移灶的数量和大小，增强了肿瘤细胞增殖和血管生成，分别通过 Ki67 阳性细胞数量和 CD31 阳性区域的增加来证明。5-FU 介导的肺转移增强与肺内中性粒细胞数量增加和肿瘤细胞中中性粒细胞趋化因子 Cxcl1 和 Cxcl2 的表达有关，对肺内 T 细胞或巨噬细胞数量几乎没有影响。5-FU 以 NFκB 依赖性方式增强 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 的给药显着减弱了 5-FU 介导的增强肺转移，并抑制了中性粒细胞浸润。此外，浸润的中性粒细胞和 4T1 细胞分别大量表达 prokineticin-2 (Prok2) 及其受体 Prokr1。最后，在切除原发肿瘤后施用 5-FU 未能增加接受 Prokr1 缺失的 4T1 细胞的小鼠的肺转移。总的来说，5-FU 可以通过诱导肿瘤细胞产生 Cxcl1 和 Cxcl2 来增强肺转移，从而诱导表达 Prok2 的中性粒细胞迁移，从而增强 4T1 细胞增殖。摩尔癌症治疗; 17(7); 1515-25。©2018 AACR。