Pulmonary Fibroblasts Induce Epithelial Mesenchymal Transition and Some Characteristics of Stem Cells in Non-Small Cell Lung Cancer

Abstract

Fibroblasts are key components of the tumor microenvironment. The purpose of this study was to clarify the role of fibroblasts in tumor progression in non-small cell lung cancer (NSCLC). Fibroblasts isolated from surgical exploration were co-cultured with human lung adenocarcinoma cell lines. We defined fibroblasts obtained from tumors as cancer associated fibroblasts (CAFs) and those from normal lung tissue as lung normal fibroblasts (LNFs). Expression levels of myofibroblast markers were higher in CAFs than LNFs within 5 passages in the absence of continuing interaction with carcinoma cells. Thus, we used at least 2 pairs of these CAFs and LNFs in the following experiments; conditioned medium (CM) from fibroblast-induced epithelial mesenchymal transition and acquisition of cancer stem cell-like qualities in lung cancer cells (A549 and NCI-H358), indicating that CM from fibroblasts was biologically active. Furthermore, the concentration of the transforming growth factor (TGF)-β1 was higher in CM from CAFs as compared with that from LNFs, and phenotypic changes of cancer cells by CM from CAFs were greater than those induced by CM from LNFs. These CAF-induced changes were inhibited by addition of the TGF-β inhibitor SB431542. Subcutaneous co-injection of lung cancer cells and CAFs in mice enhanced tumor growth when compared with cancer cells alone, which was attenuated by administration of SB431542. Fibroblasts were associated with increased malignant potential and the acquisition of stem cell-like properties in NSCLC tumors. Targeting CAFs as a therapeutic strategy against cancer is an intriguing concept that would benefit from further study.