Suzuki E, et al. - The researchers recognized the robust humoral factors secreted from cancer-associated fibroblasts (CAFs) that induce the primary resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). 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) were assessed. In CAFs and NCAFs, 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 were calculated. Whether HGF neutralizing antibody could abolish the EGFR-TKI resistance induced by CM from CAFs was investigated. In five out of 18 cases, CM from CAFs raised the resistance of PC-9 cells to EGFR-TKI, in contrast to CM from NCAFs. In these five CAFs in comparison with others, the relative expression ratio of HGF messenger RNA was significantly greater, whereas other cytokines were not. The addition of HGF neutralizing antibody significantly reduced the survival ratio of PC-9 cells in four of these five cases. Hence, the secretion of higher amounts of HGF was concluded to be the robust characteristic of EGFR-TKI resistance-promoting CAFs.