Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas

April 26, 2006

International Journal of Cancer. Published Online: 26 Apr 2006 [Link]

Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas

Yasuo Adachi1, Chieko Aoki1, Naoko Yoshio-Hoshino1, Koichi Takayama2, David T. Curiel 3, Norihiro Nishimoto1 *

1 Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

2 Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

3 Division of Human Gene Therapy, Department of Medicine, Surgery, and Pathology, UAB Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL email: Norihiro Nishimoto (norihiro@fbs.osaka-u.ac.jp)

*Correspondence to Norihiro Nishimoto, Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3, Yamadaoka, Suita City, Osaka Prefecture, Japan 565-0871 Fax:+81-6-6879-4437

Funded by:

  • The Osaka Foundation for Promotion of Clinical Immunology
  • The UAB Mesothelioma Center of the UAB Comprehensive Cancer Center
  • Chugai Pharmaceutical Co., Ltd (Roche Group, Tokyo, 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.

Keywords: interleukin-6 (IL-6), mesothelioma, vascular endothelial growth factor (VEGF), humanized antibody to human IL-6 receptor (tocilizumub, currently known as MRA), adenovirus

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