Faculty of Veterinary Sciences, University of Sydney, Sydney, Australia.
PLoS One. 2012;7(8):e44085. doi: 10.1371/journal.pone.0044085. Epub 2012 Aug 29.
Devil Facial Tumour Disease (DFTD) is a unique clonal cancer that threatens the world's largest carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii) with extinction. This transmissible cancer is passed between individual devils by cell implantation during social interactions. The tumour arose in a Schwann cell of a single devil over 15 years ago and since then has expanded clonally, without showing signs of replicative senescence; in stark contrast to a somatic cell that displays a finite capacity for replication, known as the "Hayflick limit".
METHODOLOGY/PRINCIPAL FINDINGS: In the present study we investigate the role of telomere length, measured as Telomere Copy Number (TCN), and telomerase and shelterin gene expression, as well as telomerase activity in maintaining hyperproliferation of Devil Facial Tumour (DFT) cells. Our results show that DFT cells have short telomeres. DFTD TCN does not differ between geographic regions or between strains. However, TCN has increased over time. Unlimited cell proliferation is likely to have been achieved through the observed up-regulation of the catalytic subunit of telomerase (TERT) and concomitant activation of telomerase. Up-regulation of the central component of shelterin, the TRF1-intercating nuclear factor 2 (TINF2) provides DFT a mechanism for telomere length homeostasis. The higher expression of both TERT and TINF2 may also protect DFT cells from genomic instability and enhance tumour proliferation.
CONCLUSIONS/SIGNIFICANCE: DFT cells appear to monitor and regulate the length of individual telomeres: i.e. shorter telomeres are elongated by up-regulation of telomerase-related genes; longer telomeres are protected from further elongation by members of the shelterin complex, which may explain the lack of spatial and strain variation in DFT telomere copy number. The observed longitudinal increase in gene expression in DFT tissue samples and telomerase activity in DFT cell lines might indicate a selection for more stable tumours with higher proliferative potential.
恶魔面部肿瘤病（DFTD）是一种独特的克隆性癌症，它威胁着世界上最大的肉食有袋动物袋獾（Sarcophilus harrisii）的灭绝。这种可传播的癌症是通过个体恶魔之间的社会互动中的细胞植入传播的。这种肿瘤起源于 15 年前的一只恶魔的施万细胞，此后它一直以克隆的方式扩张，没有表现出复制衰老的迹象；这与体细胞形成鲜明对比，体细胞的复制能力有限，被称为“海弗利克极限”。
方法/主要发现：在本研究中，我们调查了端粒长度（以端粒拷贝数（TCN）表示）、端粒酶和庇护体基因表达以及端粒酶活性在维持恶魔面部肿瘤（DFT）细胞过度增殖中的作用。我们的结果表明，DFT 细胞的端粒较短。DFTD 的 TCN 在地理区域或菌株之间没有差异。然而，TCN 随时间增加。无限制的细胞增殖可能是通过观察到端粒酶催化亚基（TERT）的上调和端粒酶的激活来实现的。庇护体中心成分 TRF1 相互作用核因子 2（TINF2）的上调为 DFT 提供了一种端粒长度平衡的机制。TERT 和 TINF2 的更高表达也可能保护 DFT 细胞免受基因组不稳定性的影响，并增强肿瘤的增殖。
结论/意义：DFT 细胞似乎监测和调节单个端粒的长度：即通过上调与端粒酶相关的基因来延长较短的端粒；通过庇护体复合物的成员来保护较长的端粒免受进一步延伸，这可能解释了 DFT 端粒拷贝数在空间和菌株上没有差异。在 DFT 组织样本中观察到的基因表达的纵向增加和 DFT 细胞系中的端粒酶活性可能表明选择了更稳定、增殖潜力更高的肿瘤。
