Abstract 3597: Malignancy of bladder cancer cells is enhanced by tumor associated fibroblasts through a cytokine-chemokine loop

Abstract

The tumor microenvironment plays an important role in cancer progression. In particular, stromal fibroblasts have profound influence on migration and invasiveness of tumor cells. We employ bladder carcinoma cell lines of different de-differentiation grade to pursue the hypothesis that tumor cell malignancy correlates with the cells' potential to recruit support by tumor associated fibroblasts (TAFs). Bladder cancer cell lines RT112 and Cal29 were used as models for tumor cells of low or high de-differentiation grade, respectively. They were grown separately or in co-culture with tumor-associated fibroblast isolated from kidney carcinomas. Migratory and invasive cell properties were quantified by Boyden chamber (Matrigel) and wound healing assays. Cytokine production of cells was measured by intracellular staining followed by cytometry, by semi-quantitative PCR, or by subjecting conditioned medium to ELISA and Western blot analysis. Migration and invasiveness of bladder cancer cell lines Cal29 and RT112 was enhanced by co-cultivation with TAFs. The low grade cell line RT112, however, was much more dependent on TAF-derived signals to increase the malignancy parameters. Conditioned medium from tumor cells induced the secretion of Matrix Metalloproteinases (MMPs) and the release of GM-CSF, HGF, and Monocyte Chemotactic Protein (MCP-1, CCL2) by TAFs. We could identify tumor cell-derived IL-1α and β as well as TGF-β as stimuli responsible for the upregulation of GM-CSF and MCP-1, respectively, in fibroblasts. MCP-1 is implicated in inflammatory disease states characterized by monocytic infiltrates and was shown to promote cell migration of both bladder cancer cell lines under investigation. Employing pathway-specific reporter gene constructs we are currently addressing signal transduction reactions in both tumor cells and fibroblasts underlying this crosstalk. Supported by: IZKF Jena, European Regional Development Fund ERDF. Citation Format: Susanne Grimm, Susanne Jennek, Jens Bratsch, Andreas Wohlmann, Vrinda Mohta, Kerstin Junker, Karlheinz Friedrich. Malignancy of bladder cancer cells is enhanced by tumor associated fibroblasts through a cytokine-chemokine loop. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3597. doi:10.1158/1538-7445.AM2014-3597