Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Pathol Int. 2019 Aug;69(8):472-480. doi: 10.1111/pin.12838. Epub 2019 Jul 24.
Humoral factors from cancer-associated fibroblasts (CAFs) reportedly affect epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance in cancer cells with EGFR mutations. The aim of this study was to identify the robust humoral factors secreted from CAFs that induce the primary resistance to EGFR-TKI. We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell line (PC-9) treated with condition media (CM) from 18 cases of CAFs and matched non-cancerous-tissue-associated fibroblasts (NCAFs). We measured the expression levels of hepatocyte growth factor (HGF), interleukin-6, fibroblast growth factor-2, insulin-like growth factor-1, and vascular endothelial growth factor-A in CAFs and NCAFs. We examined whether HGF neutralizing antibody could annul the EGFR-TKI resistance induced by CM from CAFs. Compared to CM from NCAFs, CM from CAFs increased the resistance of PC-9 cells to EGFR-TKI in five out of 18 cases. Relative expression ratio of HGF messenger RNA was significantly higher in these five CAFs compared to others (P = 0.0013), whereas other cytokines were not. In four of these five cases, the addition of HGF neutralizing antibody significantly decreased the survival ratio of PC-9 cells. This study suggests that the secretion of higher amounts of HGF is the robust feature of EGFR-TKI resistance-promoting CAFs.
据报道，源自癌症相关成纤维细胞（CAFs）的体液因子会影响具有 EGFR 突变的癌细胞对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的耐药性。本研究旨在鉴定源自 CAFs 的强大体液因子，这些因子可诱导对 EGFR-TKI 的原发性耐药。我们评估了条件培养基（CM）处理的 EGFR 突变型肺腺癌细胞系（PC-9）对 18 例 CAFs 和匹配的非癌组织相关成纤维细胞（NCAFs）的 EGFR-TKI 敏感性。我们测量了 CAFs 和 NCAFs 中肝细胞生长因子（HGF）、白细胞介素 6、成纤维细胞生长因子 2、胰岛素样生长因子 1 和血管内皮生长因子 A 的表达水平。我们检查了 HGF 中和抗体是否可以消除 CAFs 来源的 CM 诱导的 EGFR-TKI 耐药性。与 NCAFs 的 CM 相比，CM 来自 CAFs 增加了 18 例中的 5 例中 PC-9 细胞对 EGFR-TKI 的耐药性。与其他 CAFs 相比，这 5 例 CAFs 中 HGF 信使 RNA 的相对表达比值明显更高（P = 0.0013），而其他细胞因子则没有。在这 5 例中的 4 例中，添加 HGF 中和抗体可显著降低 PC-9 细胞的存活率。本研究表明，HGF 分泌量较高是促进 EGFR-TKI 耐药性的 CAFs 的主要特征。
