Impact of inflammatory mechanisms on osteoblast-metastatic tumor cell interaction

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The issue of inflammation-driven progression of later tumor stages like bone metastasis has not yet been functionally dissected. In particular, the role of TNF, TRAIL, RANKL, IL-1 and IL-6 may be pathophysiologically relevant in this context. Recently, we observed that the TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 (TRAIL-R1/2) facilitate a novel, non-apoptotic function involving microRNA processing. Inhibition of TRAIL-R1/2 by siRNAs exhibited a clear impact on E-cadherin expression and strongly inhibited cell proliferation. Here, we will test the hypotheses I) that inflammatory cytokines contribute to epithelial-mesenchymal transition (EMT) in osteotropic tumor cells, and II) that TRAIL-R1/2-mediated mechanisms of EMT induction stimulate bone metastases. The impact of TNF, TRAIL, RANKL, IL-1 and IL-6 and their respective inhibitors on osteotropism of breast tumor cells will be studied in vitro using a fibroblast-invasion test as well as osteoblast-matrix based tests. Further in vitro studies will focus on TRAIL-R1/ R2-mediated EMT using knock-down strategies. In vivo, we will use three different breast cancer models, orthotopic, intra-cardial, and tumor resection/mastectomy to study anti-inflammatory combination therapies in human (xenotransplant) and murine (syngeneic) pre-clinical models using EMT-modulated cell systems. Tumor progress will be monitored using molecular imaging read-outs.