, Cancer Research 2009). Here, we have identified Galectin-3 binding protein (Gal-3BP) as a soluble factor produced by neuroblastoma cells that upregulates IL-6. We observed that several neuroblastoma cell lines
express and secrete Gal-3BP, and that expression correlates see more with the ability of these cells to induce the production of IL-6 by BMSC. Expression of IL-6 by Gal-3BP seems to be mediated by Gal-3, a multifunctional glycoprotein that binds Gal-3BP and is present in BMSC. Signaling involves activation of the Raf-1/MEK/ERK1/2 pathway and can be blocked in the presence of the MEK inhibitor PD 98059 or in the presence of an anti Gal-3 antibody. We also observed that Gal-3BP can upregulate IL-6 in peripheral blood monocytes suggesting that it may contribute to tumor-associated inflammation. In primary neuroblastoma tumors, Gal-3BP is present in tumor cells and in the surrounding extracellular matrix, whereas IL-6 is present in stromal and inflammatory cells. Preliminary studies also suggest that higher levels of Gal-3BP are present in neuroblastoma tumors with an unfavorable histology and more severe clinical outcome. Thus the data provide a novel function
for Gal-3BP in the tumor microenvironment and cancer progression. O101 Tumor-Derived IL-4 Upregulates Cathepsin Activity in Tumor-Associated Macrophages to Promote Cancer Development and ��-Nicotinamide molecular weight Progression Hao-Wei Wang 1,2 , Vasilena Gocheva1,2, Bedrick Gadea1, Tanaya Shree1, Johanna Joyce1 1 Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 2 Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA While macrophages are a fundamental component of the host innate immune system, their presence within the tumor microenvironment has been found to facilitate tumor initiation and progression. Previously, we have shown that cysteine cathepsin proteases are upregulated as tumors develop in the RIP1-Tag2 (RT2) mouse model of pancreatic islet carcinogenesis and that tumor-associated
Avelestat (AZD9668) macrophages (TAMs) are the major source of cathepsin activity in tumors. Using pharmacological inhibition and genetic JQ1 ablation, we have further shown that specific cathepsins are critical in several steps of tumor progression, including tumor cell proliferation, angiogenesis and tumor invasion. Therefore, we set out to investigate the mechanisms whereby cathepsin activity is upregulated in TAMs. Using an activity-based probe for cathepsin proteases and a novel cell-based system, we have shown that tumor cell-conditioned media (TCM) upregulates cathepsin activity in bone marrow-derived macrophages. Cytokine protein expression arrays revealed enrichment of several candidate cytokines and growth factors in TCM.