Interleukin 10 suppresses tumor growth and metastasis of human melanoma cells: potential inhibition of angiogenesis.
Interleukin 10 suppresses tumor growth and metastasis of human melanoma cells: potential inhibition of angiogenesis.
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发表时间：
1996-12
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通讯作者：
Suyun Huang;K. Xie;C. Bucana;S. Ullrich;M. Bar‐eli
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作者：
Suyun Huang;K. Xie;C. Bucana;S. Ullrich;M. Bar‐eli
白细胞介素10 （IL-10）抑制各种细胞类型中多种细胞因子的产生。本研究的目的是确定IL-10基因的表达是否会影响人类黑色素瘤细胞的肿瘤生长和转移特性。将不产生内源性IL-10的人黑色素瘤细胞系A375P转染湿霉素表达载体（对照）或含有全长小鼠IL-10 cDNA的载体。将A375P亲本细胞、A375P- hygro和A375P- il -10阳性细胞经体外注射和静脉注射于裸鼠。与对照细胞相比，A375P-IL-10细胞产生的sc肿瘤生长明显减慢，肺转移较少。裸鼠s. c.注射前，A375P-IL-10对人黑色素瘤A375SM和小鼠黑色素瘤B16-BL6细胞的致瘤性也有明显的抑制作用，而A375P-Hygro则无明显的抑制作用。抑制肿瘤生长和转移与抗因子VIII免疫染色测定的新生血管减少直接相关。由于肿瘤相关巨噬细胞是黑色素瘤中血管生成分子的主要来源，我们使用逆转录- pcr证明IL-10下调血管内皮生长因子的产生，而血管内皮生长因子是活化巨噬细胞中最有效的血管生成因子。在活化的巨噬细胞中，A375P-IL-10细胞的上清液也抑制了其他参与血管生成的因子，如il -1 β、肿瘤坏死因子α、IL-6和蛋白酶基质金属蛋白酶-9。总的来说，这些数据表明肿瘤细胞产生IL-10抑制巨噬细胞衍生的血管生成因子，从而抑制肿瘤的生长和转移。
Interleukin 10 (IL-10) inhibits the production of a wide range of cytokines in various cell types. The purpose of this study was to determine whether the expression of the IL-10 gene can influence tumor growth and metastatic properties of human melanoma cells. The human melanoma cell line, A375P, which does not produce endogenous IL-10, was transfected with a hygromycin expression vector (control) or a vector containing full-length murine IL-10 cDNA. A375P parental cells, A375P-Hygro, and A375P-IL-10-positive cells were injected s.c. and i.v. into nude mice. A375P-IL-10 cells produced significantly slower growing s.c. tumors and fewer lung metastases than control cells. The tumorigenicity of the human melanoma A375SM and the murine melanoma B16-BL6 cells was also significantly inhibited when they were admixed with A375P-IL-10 but not with A375P-Hygro before s. c. injection into nude mice. The suppression of tumor growth and metastasis was directly correlated with a decrease in neovascularity determined by immunostaining with anti-factor VIII. Because tumor-associated macrophages are the major source of angiogenic molecules in melanoma, we used reverse transcription-PCR to demonstrate that IL-10 down-regulates the production of vascular endothelial growth factor, the most potent angiogenic factor in activated macrophages. Other factors involved in angiogenesis such as IL-1beta, tumor necrosis factor-alpha, IL-6, and the proteinase matrix metalloproteinase-9 were also inhibited in activated macrophages by supernatants from A375P-IL-10 cells. Collectively, these data suggest that the production of IL-10 by tumor cells inhibits macrophages-derived angiogenic factors, and hence, tumor growth and metastasis.