Department of Cancer Biology, Institut Génétique de Biologie Moléculaire et Cellulaire (IGBMC), France.
Mol Cancer. 2011 Apr 4;10:34. doi: 10.1186/1476-4598-10-34.
Gene ablation studies have revealed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L, TNFSF10) plays a crucial role in tumor surveillance, as TRAIL-deficient mice exhibit an increased sensitivity to different types of tumorigenesis. In contrast, possible tumor-protective effect of increased levels of endogenous TRAIL expression in vivo has not been assessed yet. Such models will provide important information about the efficacy of TRAIL-based therapies and potential toxicity in specific tissues.
To this aim, we engineered transgenic mice selectively expressing TRAIL in the skin and subjected these mice to a two-step chemical carcinogenesis protocol that generated benign and preneoplastic lesions. We were therefore able to study the effect of increased TRAIL expression at the early steps of skin tumorigenesis.
Our results showed a delay of tumor appearance in TRAIL expressing mice compared to their wild-type littermates. More importantly, the number of tumors observed in transgenic animals was significantly lower than in the control animals, and the lesions observed were mostly benign. Interestingly, Wnt/β-catenin signaling differed between tumors of wild-type and TRAIL transgenics.
Altogether, these data reveal that, at least in this model, TRAIL is able on its own to act on pre-transformed cells, and reduce their tumorigenic potential.
基因敲除研究表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL，Apo2L，TNFSF10）在肿瘤监测中起着至关重要的作用，因为 TRAIL 缺陷小鼠对多种肿瘤形成的敏感性增加。相比之下，体内内源性 TRAIL 表达水平增加的可能的肿瘤保护作用尚未得到评估。这些模型将提供关于 TRAIL 为基础的治疗方法的功效和在特定组织中潜在毒性的重要信息。
为此，我们构建了在皮肤中特异性表达 TRAIL 的转基因小鼠，并对这些小鼠进行了两步化学致癌发生方案，该方案产生良性和癌前病变。因此，我们能够研究在皮肤肿瘤发生的早期阶段增加 TRAIL 表达的效果。
我们的结果表明，与野生型同窝仔相比，TRAIL 表达的小鼠肿瘤出现的时间延迟。更重要的是，转基因动物中观察到的肿瘤数量明显低于对照动物，并且观察到的病变主要是良性的。有趣的是，野生型和 TRAIL 转基因动物的肿瘤之间的 Wnt/β-catenin 信号传导不同。
总之，这些数据表明，至少在这种模型中，TRAIL 能够自行作用于前转化细胞，并降低其肿瘤发生潜能。
