Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer
Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer
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DOI：
10.1007/s00262-004-0533-9
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发表时间：
2004-09-01
影响因子：
5.8
通讯作者：
Fujisawa, T
中科院分区：
文献类型：
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作者：
Yamaji, H;Iizasa, T;Fujisawa, T
白细胞介素6（IL-6）促进B细胞分化为免疫球蛋白分泌细胞，并且据报道是某些肿瘤中的增殖因子。在这项研究中，我们研究了IL-6的生产在非小细胞肺癌（NSCLC）和肿瘤细胞增殖后，IL-6治疗在体外和体内。采用逆转录聚合酶链反应（RT-PCR）和酶联免疫吸附试验（ELISA）检测了15株人肺癌细胞系（4株腺癌、5株鳞癌、2株大细胞癌和4株小细胞癌）中IL-6 mRNA和蛋白的表达。我们通过将人IL-6 cDNA转染到人非IL-6产生的NSCLC细胞系（ABC-1）中，建立了IL-6产生的细胞系（ABC-1#IL-6）。用这两种细胞系在体内和体外测定肿瘤细胞增殖，以阐明IL-6对肿瘤生长和转移的影响。用这两种细胞系皮下接种无胸腺裸鼠、SCID小鼠和BALB/c小鼠，并测量体重、肿瘤生长和肿瘤倍增时间。免疫组化染色检测肿瘤组织中IL-6和肿瘤浸润淋巴细胞（TIL）的存在。结果：15株肺癌细胞系中有8株（53%）同时表达IL-6 mRNA和蛋白。在裸鼠和SCID小鼠中，两种细胞系均出现肿瘤病变，但在BALB/c小鼠中，两种细胞系均未出现此类病变。在接种细胞系ABC-1#IL-6的小鼠中，裸鼠和SCID小鼠的肿瘤倍增时间分别为2.97 +/-1.22天和2.45 +/-1.32天。这些倍增时间在统计学上显著短于接种对照原始ABC-1细胞系的小鼠中明显的倍增时间（裸，p = 0.0337; SCID，p = 0.0119;非配对t检验）。ABC-1#IL-6和原始ABC-1细胞系的体外细胞增殖速率相当（p = 0.1441，非配对t检验）。免疫组织化学染色显示，在源自IL-6产生细胞系的肿瘤中，IL-6表达较强，但在源自原始ABC-1细胞系的肿瘤中，IL-6表达不强（在裸鼠和SCID小鼠中）。结论：53%的肺癌细胞系表达IL-6 mRNA和蛋白。尽管IL-6本身在体外不影响肿瘤细胞增殖，但在裸鼠和SCID小鼠体内发现IL-6表达与肿瘤增殖之间存在关联。抗IL-6试剂可为产生IL-6的肺肿瘤患者提供新的治疗策略。
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.