Membrane versus soluble isoforms of TNF-α exert opposing effects on tumor growth and survival of tumor-associated myeloid cells.
Membrane versus soluble isoforms of TNF-α exert opposing effects on tumor growth and survival of tumor-associated myeloid cells.
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DOI：
10.1158/0008-5472.can-13-0002
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发表时间：
2013-07-01
期刊：
影响因子：
11.2
通讯作者：
Young PP
中科院分区：
文献类型：
--
作者：
Ardestani S;Li B;Deskins DL;Wu H;Massion PP;Young PP
大多数恶性细胞产生TNFα，协调恶性细胞和髓系细胞之间的相互作用，这与肿瘤的生长和转移有关。尽管TNFα可以作为两种亚型之一存在，即26kda的膜系结形式（mTNFα）或可溶性的17 kda细胞因子（sTNFα），但绝大多数已发表的研究只研究了可溶性形式的生物学效应。我们首次证明膜和可溶性异构体对肿瘤生长和髓质含量具有完全相反的影响。与各自的控制系或表达sTNFα的系相比，表达mTNFα的小鼠肺和黑色素瘤细胞系产生了缺乏单核细胞的小肿瘤。髓细胞的缺乏是由于mTNFα通过增加活性氧诱导细胞坏死对髓细胞存活的直接影响。人类非小细胞肺癌表达不同水平的可溶性和膜性TNFα，支持mTNFα的基因表达模式可预测肺癌生存率的提高。这些数据表明，不同的TNFα亚型在肿瘤进展中的作用存在显著差异，每种亚型的生物利用度可能明显调节肿瘤进展。这一发现对于利用可用的tnf - α抑制剂有效干预癌症治疗至关重要，这些抑制剂可以阻断两种tnf - α亚型。
TNFα, produced by most malignant cells, orchestrates the interplay between malignant cells and myeloid cells, which have been linked to tumor growth and metastasis. Although TNFα can exist as one of two isoforms, a 26-kDa membrane tethered form (mTNFα) or a soluble 17-kDa cytokine (sTNFα), the vast majority of published studies have only investigated the biological effects of the soluble form. We demonstrate for the first time that membrane and soluble isoforms have diametrically opposing effects on both tumor growth and myeloid content. Mouse lung and melanoma tumor lines expressing mTNFα, generated small tumors devoid of monocytes versus respective control lines or lines expressing sTNFα. The lack of myeloid cells was due to a direct effect of mTNFα on myeloid survival via induction of cell necrosis by increasing reactive oxygen species. Human NSCLCs expressed varying levels of both soluble and membrane TNFα, and gene expression patterns favoring mTNFα were predictive of improved lung cancer survival. These data suggest that there are significant differences in the role of different TNFα isoforms in tumor progression and the bioavailability of each isoform may distinctly regulate tumor progression. This insight is critical for effective intervention in cancer therapy with the available TNFα inhibitors, which can block both TNFα isoforms.