Human Lung Fibroblasts Inhibit Non-Small Cell Lung Cancer Metastasis in Ex Vivo 4D Model

Abstract

We determined the effect of human lung fibroblasts (LFs) in metastatic lesion formation in a four-dimensional (4D) lung cancer model. Human cancer-associated fibroblasts (CAFs) were isolated from the primary tumor, and normal LFs were isolated from adjacent lung using fluorescence-activated cell sorting. The 4D metastatic lung cancer model was seeded with the human lung cancer cell lines (H460, A549, and H1299) alone or was seeded with CAFs or LFs. In addition, the 4D model seeded with human lung cancer cell lines was also treated with conditioned media of LFs or CAFs grown on the 4D model. We determined the number of metastatic tumor cells per high-power field on the model. There were significantly fewer metastatic lesions per high-power field in the 4D model seeded with the H460 cell line and LFs compared with H460 alone on day 15 (p= 0.008) or compared with H460 and CAFs (p= 0.002). This relationship was also seen with A549 and H1299 tumor cells. Moreover, the H460 cell line treated with conditioned media from the 4D model seeded with LFs had significantly fewer metastatic lesions than the 4D model seeded with CAFs. This was also seen with two other pairs of human fibroblasts obtained from patients. The secreted factor from LFs grown on the 4D model inhibits the formation of metastatic lesions. The 4D model may be used to determine the role of different components of the tumor's microenvironment in metastatic lesion formation, and this secreted factor may provide a novel therapy for treatment of cancer metastasis.