Enhancement of experimental metastasis by tumor necrosis factor.
Enhancement of experimental metastasis by tumor necrosis factor.
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DOI：
10.1084/jem.177.5.1391
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发表时间：
1993-05-01
期刊：
影响因子：
--
通讯作者：
Männel DN
中科院分区：
文献类型：
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作者：
Orosz P;Echtenacher B;Falk W;Rüschoff J;Weber D;Männel DN
在实验性纤维肉瘤转移模型中研究了内源性和外源性肿瘤坏死因子（TNF）对转移的影响。在静脉内接种甲基胆蒽诱导的纤维肉瘤细胞 (CFS1) 之前 5 小时，将重组人 (rh) TNF 或重组小鼠 (rm) TNF 单次腹腔注射到小鼠体内，可导致肺部转移瘤数量显着增加。 rmTNF 和 rhTNF 的剂量反应表明，与 rhTNF 相比，rmTNF 具有更强的转移增强作用。这种效应是时间依赖性的，因为在肿瘤细胞接种前5小时或1小时但不是24小时后给予rmTNF导致肺表面肿瘤细胞集落形成增加，表明TNF对肿瘤细胞的血管粘附和血细胞渗出有影响。由于与对照小鼠相比，荷瘤小鼠在注射内毒素后表现出增强的产生 TNF 的能力，因此用抗 mTNF 抗体治疗荷瘤小鼠。内源性肿瘤诱导的 TNF 的中和导致肺转移数量显着减少。第 5 天，通过对与核仁组织区相关的蛋白质进行银染色，对肺部微转移进行组织学分析，结果显示，在小鼠 rmTNF 预处理后，肿瘤细胞有更多的转移灶和增强的增殖活性。然而，在体外没有观察到rmTNF对肿瘤细胞增殖率的直接影响。这些发现表明，低剂量的内源性 TNF 或在细胞因子治疗期间施用 TNF 可能会增强循环肿瘤细胞的转移潜力。
The influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metastasis model. A single intraperitoneal injection of recombinant human (rh) TNF or recombinant mouse (rm) TNF into mice 5 h before intravenous inoculation of methylcholanthrene-induced fibrosarcoma cells (CFS1) induced a significant enhancement of the number of metastases in the lung. Dose responses of rmTNF and rhTNF demonstrated a stronger metastasis-augmenting effect by rmTNF compared with rhTNF. This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24 h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface, suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice, tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histological analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic foci and augmented proliferative activity of the tumor cells after rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of tumor cells was seen in vitro. These findings suggest that low doses of endogenous TNF or administered TNF during cytokine therapy might enhance the metastatic potential of circulating tumor cells.