Department of Biology, University of Rochester, Rochester, NY 14627, USA.
Department of Biology, University of Rochester, Rochester, NY 14627, USA
Philos Trans R Soc Lond B Biol Sci. 2018 Mar 5;373(1741). doi: 10.1098/rstb.2016.0443.
Mammalian species differ dramatically in telomere biology. Species larger than 5-10 kg repress somatic telomerase activity and have shorter telomeres, leading to replicative senescence. It has been proposed that evolution of replicative senescence in large-bodied species is an anti-tumour mechanism counteracting increased risk of cancer due to increased cell numbers. By contrast, small-bodied species express high telomerase activity and have longer telomeres. To counteract cancer risk due to longer lifespan, long-lived small-bodied species evolved additional telomere-independent tumour suppressor mechanisms. Here, we tested the connection between telomere biology and tumorigenesis by analysing the propensity of fibroblasts from 18 rodent species to form tumours. We found a negative correlation between species lifespan and anchorage-independent growth. Small-bodied species required inactivation of Rb and/or p53 and expression of oncogenic H-Ras to form tumours. Large-bodied species displayed a continuum of phenotypes requiring additional genetic 'hits' for malignant transformation. Based on these data we refine the model of the evolution of tumour suppressor mechanisms and telomeres. We propose that two different strategies evolved in small and large species because small-bodied species cannot tolerate small tumours that form prior to activation of the telomere barrier, and must instead use telomere-independent strategies that act earlier, at the hyperplasia stage.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.
哺乳动物物种在端粒生物学上有显著差异。体重超过 5-10 公斤的物种抑制体细胞端粒酶活性，并且端粒较短，导致复制性衰老。有人提出，大体积物种中复制性衰老的进化是一种抗肿瘤机制，可对抗因细胞数量增加而导致的癌症风险增加。相比之下，小体积物种表达高的端粒酶活性，并且端粒较长。为了对抗因寿命延长而导致的癌症风险，长寿的小体积物种进化出了额外的端粒非依赖性肿瘤抑制机制。在这里，我们通过分析来自 18 种啮齿动物物种的成纤维细胞形成肿瘤的倾向，来检验端粒生物学与肿瘤发生之间的联系。我们发现物种寿命与无锚定生长之间呈负相关。小体积物种需要失活 Rb 和/或 p53 以及表达致癌性 H-Ras 才能形成肿瘤。大体积物种表现出一种连续的表型，需要额外的遗传“打击”才能发生恶性转化。基于这些数据，我们改进了肿瘤抑制机制和端粒进化的模型。我们提出，小体型和大体型物种中进化出了两种不同的策略，因为小体型物种不能容忍在端粒屏障激活之前形成的小肿瘤，而必须转而使用更早起作用的端粒非依赖性策略，即在增生阶段发挥作用。本文是主题为“理解端粒动力学多样性”的特刊的一部分。
