Abstract
Malignant mesothelioma (MM), an incurable tumor, is reportedly an interleukin‐6 (IL‐6) secreting tumor. The pathological significance of IL‐6 overexpression in this tumor, however, has remained unclear. We investigated the biological functions of IL‐6 in mesotheliomas. Five mesothelioma cell lines were analyzed for IL‐6 production and IL‐6 receptor (IL‐6R) expression. Of them, 2 produced high levels of IL‐6, 2 produced intermediate levels and 1 cell line showed no secretion. All mesothelioma cell lines used in this study expressed very small amounts of IL‐6R mRNA. We compensated for this low level of IL‐6R expression in mesotheliomas by adding recombinant soluble IL‐6R (sIL‐6R) to mediate the IL‐6 signal. IL‐6 together with sIL‐6R was found to promote cell growth of H2052 and H226 MMs classified as high‐level IL‐6 producers in a dose‐dependent manner. Moreover, a humanized anti‐IL‐6R antibody (MRA) capable of blocking IL‐6 signaling suppressed the cell growth of mesotheliomas induced by IL‐6/sIL‐6R. These findings demonstrate that IL‐6 serves as an autocrine growth factor in the development of mesothelioma. In addition, IL‐6/sIL‐6R stimulation increased the expression of vascular endothelial growth factor (VEGF) in 4 out of 5 cell lines, and this induction was inhibited by MRA treatment. The involvement of the signal transducer and activator of transcription 3 (STAT3) pathway in both cell growth and VEGF induction by IL‐6/sIL‐6R was verified by dominant negative STAT3 transduction combined with adenovirus gene‐delivery methods. Although IL‐6 induces VEGF through the JAK2/STAT3 pathway, anti‐VEGF antibody could not inhibit the IL‐6‐induced cell growth observed in H2052 and H226. We concluded that IL‐6‐dependent growth does not occur via VEGF induction. These results suggest that treatment with anti‐IL‐6R antibody may constitute a potential molecular targeting therapy for MMs. © 2006 Wiley‐Liss, Inc.