The receptor for advanced glycation end-products (RAGE) is highly expressed in lung tissue, especially at the site of the alveolar epithelium, but its expression is reduced in lung carcinomas. Because epithelial-mesenchymal interactions are suggested to contribute to cancer progression, we investigated the RAGE-dependent impact of fibroblasts on tumor cell growth. Co-cultivation of human lung cancer cells (H358) with lung fibroblasts (WI-38) improved their proliferation in monolayer and spheroid culture models along with an increased amount of H358 cells in the S/G2 cell cycle phase and less spontaneous cell death. Over-expression of full-length human RAGE reduced the proliferative stimulus of fibroblasts as seen in monolayers (cell number, cell cycle), spheroid cultures (spheroid size) and in a colony-forming assay compared with mock-transfected cells. Comparable results were observed culturing H358 cells with and without RAGE over-expression in the presence of conditioned medium taken from WI-38 cells or in response to selected growth factors like bFGF. Moreover, we clearly showed that the fibroblast-induced proliferation correlates with activation of the p42/44 mitogen-activated protein kinase but not with Akt kinase activation. On the basis of lung cancer as an age-related disease, we additionally proved the impact of senescent WI-38 fibroblasts. Here, we showed that senescent fibroblasts improve the H358 cell proliferation at the same extent than pre-senescent fibroblasts do. From our data we conclude, that re-expression of RAGE in lung cancer cells impairs the proliferative stimulus mediated by fibroblasts. Therefore, lung cancer progression might be enhanced by the RAGE down-regulation in human lung carcinomas.