The role of paracrine IL-6 and IL-10 in neuroblastoma progression (49.9)

Abstract Tumor-associated inflammation may play a critical role in tumor progression but its mechanism is yet poorly understood. We have detected elevated levels of IL-6 (2.9 – 88.9 pg/ml) in serum from 10 patients with recurrent stage 4 neuroblastoma. Although none of 5 tested neuroblastoma cell lines produced either IL-6 or IL-10, their conditioned medium selectively induced both cytokines in short-term culture of normal PBMC in a time- and dose-dependent manner as determined by 9-plex Luminex® assay. Treatment with rhIL-6 enhanced neuroblastoma cell proliferation as measured by BrdU incorporation and was sufficient for their survival in a serum-free medium. IL-6 induced rapid STAT3 phosphorylation in neuroblastoma cells and production of yet unidentified soluble factors that inhibited dendritic cell maturation. Gene expression analysis with TaqMan® Low Density Arrays of primary metastatic tumors from 40 patients revealed that elevated expression of IL-6 or IL-10 was associated with a poor 5-year event-free survival: 35% +/−11% vs. 75 +/−10% when IL-6 or IL-10 expression was above and below median levels, respectively (P < 0.02). Thus, although neuroblastoma cells do not express IL-6 and IL-10, they can induce expression of these cytokines by inflammatory cells. These cytokines can then have a paracrine effect on tumor cells and other elements of tumor microenvironment that may promote tumor progression.