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Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas
Yasuo Adachi1, Chieko Aoki, Naoko Yoshio-Hoshino
1Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
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.
Insights
Interleukin-6 (IL-6) acts as an autocrine growth factor in malignant mesothelioma (MM). Blocking IL-6 signaling with an anti-IL-6 receptor antibody suppressed MM cell growth, suggesting a potential targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Malignant mesothelioma (MM) is an aggressive, incurable cancer.
- Interleukin-6 (IL-6) is known to be secreted by MM tumors, but its role is unclear.
- Understanding IL-6's function is crucial for developing novel MM therapies.
Purpose of the Study:
- To investigate the biological functions of IL-6 in malignant mesothelioma.
- To determine if IL-6 acts as an autocrine growth factor in MM.
- To explore the potential of targeting the IL-6 pathway for MM treatment.
Main Methods:
- Analyzed IL-6 production and IL-6 receptor (IL-6R) expression in five MM cell lines.
- Used recombinant soluble IL-6R (sIL-6R) to mediate IL-6 signaling in low IL-6R expressing cells.
- Treated cells with IL-6/sIL-6R and an anti-IL-6R antibody (MRA); assessed cell growth and vascular endothelial growth factor (VEGF) expression.
- Investigated the involvement of the signal transducer and activator of transcription 3 (STAT3) pathway.
Main Results:
- IL-6, in combination with sIL-6R, promoted dose-dependent cell growth in high IL-6 producing MM cell lines (H2052, H226).
- Anti-IL-6R antibody (MRA) suppressed IL-6/sIL-6R-induced MM cell growth.
- IL-6/sIL-6R stimulation increased VEGF expression in most cell lines, an effect inhibited by MRA.
- The STAT3 pathway was involved in IL-6/sIL-6R-mediated cell growth and VEGF induction.
- Anti-VEGF antibodies did not inhibit IL-6-induced cell growth, indicating IL-6-dependent growth is independent of VEGF induction.
Conclusions:
- Interleukin-6 (IL-6) functions as an autocrine growth factor in malignant mesothelioma.
- Targeting the IL-6 receptor with antibodies (e.g., MRA) shows promise for MM therapy.
- IL-6 signaling contributes to MM progression through pathways independent of VEGF induction.
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