Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8
Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8
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DOI：
10.1002/ijc.10775
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发表时间：
2003-01-20
影响因子：
6.4
通讯作者：
Herlyn, M
中科院分区：
文献类型：
--
作者：
Schaider, H;Oka, M;Herlyn, M
IL-8是中性粒细胞的强化学引诱剂，它是由许多肿瘤组成的，包括人类黑色素瘤。为了确定IL-8对原发性和转移性黑色素瘤细胞的生物学重要性，我们使用复制缺陷腺病毒载体转导了选择的具有IL-8 cDNA的组成性低水平IL-8的细胞系。非致瘤性SBc12原发性黑色素瘤细胞在每个细胞中增加斑块形成单位IL-8时形成肿瘤。然而，在高IL-8转导水平（48小时内100 ng/ml/10(5)个细胞）时，由于大量中性粒细胞浸润，肿瘤生长受到损害。在WM115原发性黑色素瘤中观察到类似的双期反应，这些黑色素瘤是致瘤性的，但不是转移性的。用一种抗体阻断炎症部位粒细胞的积累，使中性粒细胞耗损，使原发黑色素瘤分泌高水平的IL-8存活和生长。相比之下，高度致瘤性和转移性的451 Lu细胞在肺中显示肿瘤生长和转移灶数量的显著增加，这取决于IL-8的表达水平。细胞毒性试验与分离的中性粒细胞证实优先杀死原发性黑色素瘤细胞转移。IL-8刺激免疫缺陷小鼠的SBc12细胞形成肿瘤，诱导其产生VEGF，表明血管生成反应因生长因子产生增加而增强。我们的研究结果表明，非致瘤性原发性黑色素瘤依赖于体内IL-8刺激的生长，而肿瘤的生长依赖于中性粒细胞的浸润水平。转移性黑色素瘤在体内的增殖独立于中性粒细胞的浸润。(C) 2002 Wiley-Liss, Inc。
IL-8 is a strong chemoattractant for neutrophils, and it is constitutively produced by many tumors, including human melanomas. To determine the biologic importance of IL-8 for melanoma cells from primary and metastatic lesions, we transduced selected cell lines constitutively producing low levels of IL-8 with IL-8 cDNA using a replication-deficient adenoviral vector. Nontumorigenic SBc12 primary melanoma cells formed tumors when transduced with increasing plaque-forming units of IL-8 per cell. However, at high IL-8 transduction levels (100 ng/ml/10(5) cells in 48 hr), tumor growth was impaired due to massive neutrophil infiltration. A similar biphasic response was observed in WM115 primary melanomas, which are tumorigenic but not metastatic. Depletion of neutrophils with an antibody that blocks the accumulation of granulocytes at the site of inflammation enabled transduced primary melanomas secreting high levels of IL-8 to survive and grow. In contrast, highly tumorigenic and metastatic 451 Lu cells showed marked increases in tumor growth and number of metastatic foci in the lungs depending on the expression levels of IL-8. Cytotoxicity assays with isolated neutrophils confirmed the preferential killing of primary over metastatic melanoma cells. SBc12 cells stimulated by IL-8 to form tumors in immunodeficient mice were induced to produce VEGF, suggesting that the angiogenic response is enhanced due to increased growth factor production. Our results demonstrate that nontumorigenic primary melanomas depend on IL-8 stimulation in vivo for growth and that tumor growth depends on the level of neutrophil infiltration. Metastatic melanomas proliferate in vivo independently of infiltrating neutrophils. (C) 2002 Wiley-Liss, Inc.