INTRODUCTION: Fibroblasts are key components of the tumor microenvironment. We clarified the role of transforming growth factor (TGF)-β and interleukin (IL)-6 in the interaction between fibroblasts and non-small-cell lung cancer (NSCLC) cells. METHODS: We used NSCLC cells (A549, NCI-H358) and normal human lung fibroblast (NHLF) cells to evaluate phenotypic changes in the presence of human IL-6, TGF-β1, and conditioned media (CM) from these cells. Possible pathways were evaluated with SB431542, a TGF-β receptor inhibitor, or an anti-human IL-6 receptor neutralizing antibody (IL-6R-Ab). RESULTS: A549 and NCI-H358 cells incubated with IL-6 (50 ng/mL) and TGF-β1 (2 ng/mL) showed significantly increased epithelial-mesenchymal transition (EMT) signaling compared to those treated with TGF-β1 alone. Furthermore, NHLF cells were synergistically activated by IL-6 and TGF-β1. IL-6 increased the expression of TGF-β type I receptors on the surface of A549, NCI-H358 and NHLF cells and enhanced TGF-β signaling. TGF-β1 induced phenotypic changes were attenuated by IL-6R-Ab. NHLF cells were activated and A549 cells showed induction of EMT in response to CM from the other cell type. These activities were attenuated by SB431542 or IL-6R-Ab, suggesting that interplay between NSCLC cells and NHLF may lead to increased EMT signaling in NSCLC cells and activation of NHLF cells through TGF-β and IL-6 signaling. Subcutaneous co-injection of A549 and NHLF cells into mice resulted in a high rate of tumor formation compared with injection of A549 cells without NHLF cells. SB431542 or IL-6R-Ab also attenuated the tumor formation enhanced by co-injection of the two cell types. CONCLUSION: IL-6 enhanced epithelial cell EMT and stimulated tumor progression by enhancing TGF-β signaling. IL-6 and TGF-β may play a contributing role in maintenance of the paracrine loop between these two cytokines in the communication between fibroblasts and NSCLC cells for tumor progression.
INTRODUCTION: Fibroblasts are key components of the tumor microenvironment. We clarified the role of transforming growth factor (TGF)-β and interleukin (IL)-6 in the interaction between fibroblasts and non-small-cell lung cancer (NSCLC) cells. METHODS: We used NSCLC cells (A549, NCI-H358) and normal human lung fibroblast (NHLF) cells to evaluate phenotypic changes in the presence of humanIL-6, TGF-β1, and conditioned media (CM) from these cells. Possible pathways were evaluated with SB431542, a TGF-β receptor inhibitor, or an anti-humanIL-6 receptor neutralizing antibody (IL-6R-Ab). RESULTS: A549 and NCI-H358 cells incubated with IL-6 (50 ng/mL) and TGF-β1 (2 ng/mL) showed significantly increased epithelial-mesenchymal transition (EMT) signaling compared to those treated with TGF-β1 alone. Furthermore, NHLF cells were synergistically activated by IL-6 and TGF-β1. IL-6 increased the expression of TGF-β type I receptors on the surface of A549, NCI-H358 and NHLF cells and enhanced TGF-β signaling. TGF-β1 induced phenotypic changes were attenuated by IL-6R-Ab. NHLF cells were activated and A549 cells showed induction of EMT in response to CM from the other cell type. These activities were attenuated by SB431542 or IL-6R-Ab, suggesting that interplay between NSCLC cells and NHLF may lead to increased EMT signaling in NSCLC cells and activation of NHLF cells through TGF-β and IL-6 signaling. Subcutaneous co-injection of A549 and NHLF cells into mice resulted in a high rate of tumor formation compared with injection of A549 cells without NHLF cells. SB431542 or IL-6R-Ab also attenuated the tumor formation enhanced by co-injection of the two cell types. CONCLUSION:IL-6 enhanced epithelial cell EMT and stimulated tumor progression by enhancing TGF-β signaling. IL-6 and TGF-β may play a contributing role in maintenance of the paracrine loop between these two cytokines in the communication between fibroblasts and NSCLC cells for tumor progression.
Authors: Kayla F Goliwas; Hannah M Ashraf; Anthony M Wood; Yong Wang; Kenneth P Hough; Sandeep Bodduluri; Mohammad Athar; Joel L Berry; Selvarangan Ponnazhagan; Victor J Thannickal; Jessy S Deshane Journal: Front Oncol Date: 2021-04-23 Impact factor: 6.244
Authors: Javier De Las Rivas; Anamaria Brozovic; Sivan Izraely; Alba Casas-Pais; Isaac P Witz; Angélica Figueroa Journal: Arch Toxicol Date: 2021-05-18 Impact factor: 5.153