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Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer

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Abstract

Interleukin 6 (IL-6) facilitates the differentiation of B cells to immunoglobulin-secreting cells and is reported to be a proliferative factor in some tumors. In this study, we examined IL-6 production in non-small cell lung carcinoma (NSCLC) and the proliferation of tumor cells following IL-6 treatment in vitro and in vivo. We analyzed the expression of IL-6 mRNA and protein in a series of 15 human lung cancer cell lines (four adenocarcinomas, five squamous cell carcinomas, two large cell carcinomas, and four small cell carcinomas) by reverse transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We established an IL-6-producing cell line (ABC-1#IL-6) by transfecting a human IL-6 cDNA into a human non-IL-6-producing NSCLC cell line (ABC-1). These two cell lines were used to determine tumor cell proliferation both in vivo and in vitro in order to clarify the effect of IL-6 on tumor growth and metastasis. Athymic nude mice, SCID mice, and BALB/c mice were subcutaneously inoculated with these two cell lines, and body weight, tumor growth, and tumor doubling time were measured. The presence of IL-6 and tumor-infiltrating lymphocytes (TILs) within tumor tissues was examined by immunohistochemical staining. Results: Eight of 15 (53%) lung cancer cell lines expressed both IL-6 mRNA and protein. Tumor lesions of both cell lines developed in nude and SCID mice, although no such lesions of either cell lines developed in BALB/c mice. The tumor doubling time in nude and SCID mice was 2.97±1.22 days and 2.45±1.32 days, respectively, in mice inoculated with the cell line ABC-1#IL-6. These doubling times were statistically significantly shorter than those evident in mice inoculated with the control original ABC-1 cell line (nude, p=0.0337; SCID, p=0.0119; unpaired t-test). The rates of cell proliferation in vitro of the ABC-1#IL-6 and original ABC-1 cells lines were comparable (p=0.1441, unpaired t-test). Immunohistochemical staining revealed strong IL-6 expression in tumors derived from the IL-6-producing cell line but not in tumors derived from the original ABC-1 cell line (both in nude and SCID mice). Conclusion: 53% of lung cancer cell lines produce IL-6 mRNA and protein. Although IL-6 itself does not influence tumor cell proliferation in vitro, an association between IL-6 expression and tumor proliferation was found in vivo in nude and SCID mice. An anti-IL-6 reagent could provide a novel therapeutic strategy in patients with IL-6-producing lung tumors.

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Authors and Affiliations

  1. Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Haruko Yamaji, Toshihiko Iizasa, Eitetsu Koh, Makoto Suzuki, Mizuto Otsuji, Hao Chang, Shinichiro Motohashi, Sana Yokoi & Takehiko Fujisawa

  2. Department of Clinical Pathology, Chiba University, Chiba, Japan

    Kenzo Hiroshima

  3. Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan

    Masatoshi Tagawa

  4. Department of Medical Immunology, Chiba University, Chiba, Japan

    Toshinori Nakayama

Authors
  1. Haruko Yamaji
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  2. Toshihiko Iizasa
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  3. Eitetsu Koh
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  4. Makoto Suzuki
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  5. Mizuto Otsuji
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  6. Hao Chang
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  7. Shinichiro Motohashi
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  8. Sana Yokoi
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  9. Kenzo Hiroshima
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  10. Masatoshi Tagawa
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  11. Toshinori Nakayama
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  12. Takehiko Fujisawa
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Correspondence to Takehiko Fujisawa.

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Yamaji, H., Iizasa, T., Koh, E. et al. Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer. Cancer Immunol Immunother 53, 786–792 (2004). https://doi.org/10.1007/s00262-004-0533-9

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  • DOI: https://doi.org/10.1007/s00262-004-0533-9

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