Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, 277-8577, Chiba, Japan.
Hum Cell. 2019 Oct;32(4):453-464. doi: 10.1007/s13577-019-00275-z. Epub 2019 Aug 22.
Regrowth of cancer cells following chemotherapy is a significant problem for cancer patients. This study examined whether cancer-associated fibroblasts (CAFs), a major component of a tumor microenvironment, promote cancer cell regrowth after chemotherapy. First, we treated human lung adenocarcinoma cell line A549 and CAFs from four patients with cisplatin. Cisplatin treatment inhibited the viable cell number of A549 cells and induced epithelial-mesenchymal transition. After cisplatin was removed, A549 cells continued to manifest the mesenchymal phenotype and proliferated 2.2-fold in 4 days (regrowth of A549 cells). Cisplatin treatment inhibited the viable cell number of CAFs from four patients also. The CM (derived from cisplatin-pretreated CAFs from two patients) significantly enhanced the regrowth of cisplatin-pretreated A549 cells, and the CM derived from cisplatin-naïve CAFs marginally enhanced A549 regrowth. By contrast, the CM derived from either cisplatin-pretreated CAFs or cisplatin-naïve CAFs failed to enhance the growth of cisplatin-naïve A549 cells. The CM derived from cisplatin-pretreated CAFs did not enhance the proliferation of A549 cells in which epithelial-mesenchymal transition was induced by TGFβ-1. Our findings indicate the possibility that humoral factors from cisplatin-pretreated CAFs promote the regrowth of cisplatin-pretreated A549 cells. These results suggest that interactions between cancer cells and CAFs may significantly enhance cancer cell regrowth within the tumor microenvironment after cisplatin treatment.
化疗后癌细胞的再生是癌症患者面临的一个重大问题。本研究探讨了肿瘤微环境的主要组成部分——癌症相关成纤维细胞（CAFs）是否促进化疗后癌细胞的再生。首先，我们用顺铂处理人肺腺癌细胞系 A549 和来自四位患者的 CAFs。顺铂处理抑制了 A549 细胞的活细胞数，并诱导上皮-间充质转化。顺铂去除后，A549 细胞继续表现出间充质表型，并在 4 天内增殖 2.2 倍（A549 细胞的再生）。顺铂处理也抑制了来自四位患者的 CAFs 的活细胞数。CM（来自两位患者经顺铂预处理的 CAFs）显著增强了经顺铂预处理的 A549 细胞的再生，而来自未经顺铂处理的 CAFs 的 CM 则轻微增强了 A549 细胞的再生。相比之下，来自经顺铂预处理的 CAFs 或未经顺铂处理的 CAFs 的 CM 均不能增强未经顺铂处理的 A549 细胞的生长。来自经顺铂预处理的 CAFs 的 CM 并不能增强 TGFβ-1 诱导的上皮-间充质转化后的 A549 细胞的增殖。我们的研究结果表明，来自经顺铂预处理的 CAFs 的体液因子可能促进经顺铂预处理的 A549 细胞的再生。这些结果表明，癌细胞与 CAFs 之间的相互作用可能会在顺铂治疗后显著增强肿瘤微环境中癌细胞的再生。
