Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects.
Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects.
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DOI：
10.1172/jci15333
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发表时间：
2002-06
期刊：
影响因子：
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通讯作者：
Yu-an Yang;O. Dukhanina;Binwu Tang;M. Mamura;J. Letterio;Jennifer N Macgregor;S. C. Patel;S. Khozin;Zi-yao Liu;Jeffrey E. Green;M. Anver;G. Merlino;L. Wakefield
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文献类型：
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作者：
Yu-an Yang;O. Dukhanina;Binwu Tang;M. Mamura;J. Letterio;Jennifer N Macgregor;S. C. Patel;S. Khozin;Zi-yao Liu;Jeffrey E. Green;M. Anver;G. Merlino;L. Wakefield
TGF-β在许多生物学过程中发挥着不同而复杂的作用。在肿瘤发生中，它们可以作为肿瘤抑制因子或作为促癌因子发挥作用，这取决于疾病的阶段。我们已经开发了在乳腺选择性MMTV-LTR启动子/增强子的调控下表达可溶性II型TGF-β受体的TGF-β拮抗剂的转基因小鼠：Fc融合蛋白类。在该小鼠系的血清和大部分组织中可检测到生物学显著水平的拮抗剂。与野生型对照组相比，在使用同基因黑色素瘤细胞的尾静脉转移试验中以及与转移性乳腺癌的MMTV-neu转基因小鼠模型的杂交中，小鼠对多个器官部位的转移的发展具有抗性。重要的是，内源性乳腺肿瘤的转移受到抑制，而原发性肿瘤发生没有任何增强。此外，尽管终生暴露于拮抗剂，但老年转基因小鼠未表现出TGF-β缺失小鼠的严重病理学特征。这些数据表明，在体内拮抗剂可以选择性地中和与转移相关的不需要的TGF-β，同时保留TGF-β在正常组织中的调节作用。因此，这种可溶性TGF-β拮抗剂在预防转移中具有长期临床应用的潜力。
TGF-betas play diverse and complex roles in many biological processes. In tumorigenesis, they can function either as tumor suppressors or as pro-oncogenic factors, depending on the stage of the disease. We have developed transgenic mice expressing a TGF-beta antagonist of the soluble type II TGF-beta receptor:Fc fusion protein class, under the regulation of the mammary-selective MMTV-LTR promoter/enhancer. Biologically significant levels of antagonist were detectable in the serum and most tissues of this mouse line. The mice were resistant to the development of metastases at multiple organ sites when compared with wild-type controls, both in a tail vein metastasis assay using isogenic melanoma cells and in crosses with the MMTV-neu transgenic mouse model of metastatic breast cancer. Importantly, metastasis from endogenous mammary tumors was suppressed without any enhancement of primary tumorigenesis. Furthermore, aged transgenic mice did not exhibit the severe pathology characteristic of TGF-beta null mice, despite lifetime exposure to the antagonist. The data suggest that in vivo the antagonist may selectively neutralize the undesirable TGF-beta associated with metastasis, while sparing the regulatory roles of TGF-betas in normal tissues. Thus this soluble TGF-beta antagonist has potential for long-term clinical use in the prevention of metastasis.