Further attempts are made to correlate radiosensitivity with DNA repair mechanisms. O13 Interleukin-6 and the Tumor Microenvironment Yves A. De Clerck 1 1 Pediatrics and Biochemistry & Molecular Biology, The Saban Research Institute of Childrens GW-572016 cost Hospital Los Angeles, University of
Southern California Keck School of Medicine, Los Angeles, CA, USA The contribution of cytokines to the tumor microenvironment and to inflammation in cancer has been the focus of much recent attention. Among the cytokines that play a pro-tumorigenic role in cancer is IL-6, a pleiotropic cytokine produced by stromal and inflammatory cells. In many cancers, like multiple myeloma and neuroblastoma, the expression of IL-6 is increased and higher levels are indicators of poorer clinical outcome. Tumor cells stimulate the expression of IL-6 by stromal cells through adhesion dependent Selleck AR-13324 and adhesion independent mechanisms. The latter seems to predominate in neuroblastoma. We
have shown that Cox-2 mediated production of PGE2 and the expression of Galectin-3 binding protein by neuroblastoma cells are potent mechanisms of IL-6 induction in bone marrow-derived mesenchymal cells and monocytes. IL-6 has multiple effects on cancer progression. In the bone marrow it stimulates the maturation and activation of osteoclast precursor cells and promotes eFT-508 osteolytic bone metastasis. IL-6 also has a paracrine effect on neuroblastoma cells which express the 2 subunits of the IL-6 receptor (IL-6R/gp80 and gp130) that are necessary for IL-6-mediated activation of ERK 1/2 and STAT-3. Signaling is potentiated by soluble IL-6R/gp80 that stabilizes IL-6 and acts as a potent agonist. IL-6 stimulates the proliferation of tumor cells and enhances their survival in the presence of cytotoxicity drugs like etoposide (an inducer of the mitochondrial apoptotic pathway) by increasing the expression of the anti-apoptotic proteins Bcl-2, Bcl-XL and survivin. This effect is dependent on STAT-3 activation. In neuroblastoma, IL-6 is rarely expressed by tumor cells and commonly
expressed by bone marrow-derived mesenchymal cells in the bone marrow and monocytes/macrophages in primary tumors, Adenylyl cyclase which are also a source of sIL-6R. Thus stromal expression of IL-6 contributes to the protective role that the bone marrow microenvironment has against the cytotoxic effect of chemotherapy on tumor cells. IL-6 or IL-6 mediated signaling could therefore represent valuable targets for therapeutic intervention. O14 Inflammatory Chemokines in Malignancy: Regulation by Microenvironmental and Intrinsic Factors Gali Soria1, Maya Ofri1, Tal Leibovich-Rivkin1, Marcelo Ehrlich1, Tsipi Meshel1, Neora Yaal-Hahoshen2, Leonor Trejo-Leider3, Adit Ben-Baruch 1 1 Department of Cell Research and Immunology, George S.