Wednesday, April 26th, 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

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

immunology

(im-mune-ahl-o-jee) study of how the body resists infection and certain other diseases. Knowledge gained in this field is important to those cancer treatments based on the principles of immunology.

gene therapy

a new type of treatment in which defective genes are replaced with normal ones. The new genes are delivered into the cells by viruses or proteins. (Mesothelioma gene therapy treatment options.)

gene

a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

antibody

a protein in the blood that defends against foreign agents, such as bacteria. These agents contain certain substances called antigens. Each antibody works against a specific antigen. (See also antigen.)

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

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