Body size, longevity, and cancer resistance in animals

每次细胞分裂都有风险，无论是通过机会还是对DNA的化学损伤，细胞都会发生突变。当细胞的DNA发生足够的特定突变时，癌症就会发展。基于此，人们会期望大型动物和/或具有长寿命的动物将处于患癌症的高风险中，因为它们在其一生中有更多的细胞分裂和更多的细胞分裂-然而，情况并非总是如此。有史以来最大的动物，弓头鲸，蓝鲸和其他鲸鱼，寿命超过100年，但细胞比人类多1000倍，很少发生癌症。同样，非洲大象比人类重100倍，癌症发病率不到人类的一半。这种身体大小、寿命和癌症发病率之间缺乏联系的现象通常被称为佩托悖论。大象和一些鲸鱼有多个功能性的肿瘤抑制基因拷贝，一些长寿的蝙蝠也是如此。这些基因产生的蛋白质抵消了促进癌症发展的因素。我的研究项目的目标是探索大型和/或长寿动物癌症发病率低于预期的机制。我们已经收集了一系列独特而多样的肿瘤，这些肿瘤出现在从鲸鱼到鹦鹉到蝙蝠的大型和/或长寿动物中，在这项研究计划中，我们将比较这些动物中的肿瘤抑制基因拷贝数与那些没有长寿命的动物，如狗和小鼠。我们将测量基因的表达，通过去除特定基因来评估它们在细胞培养中的功能，测试每个物种的细胞对DNA损伤剂的反应，并测量细胞转化的容易程度。该计划中的研究旨在产生关于大体型和/或长寿命生物体如何抵抗癌症发展的基本新知识。我的长期目标是应用进化比较方法来测试长寿和肿瘤抑制基因拷贝数和表达之间的潜在关系。这将有助于我们理解在进化历史中重复的基因拷贝模式的重要性。

Every time a cell divides there is the risk that, either through chance or chemical damage to DNA, the cell will sustain a mutation. When enough specific mutations occur in a cell's DNA, cancer develops. Based on this, one would expect that large sized animals and/or animals with a long lifespan would be at high risk of developing cancer, since they have more cells dividing and more cell divisions over their lifetime - however, this is not always the case. The largest animals that have ever lived, the bowhead, blue and other whales, have lifespans that exceed 100 years, yet have 1000-fold more cells than a human and only rarely develop cancer. Likewise, African elephants, which are 100 times heavier than humans, have less than half the incidence of cancer. This lack of association between body size, longevity, and cancer incidence is often referred to as Peto's paradox. Elephants and some whales have multiple functional copies of tumour suppressor genes, as do some long-lived bats. The proteins produced by these genes counteract the factors that promote cancer development. The goal of my research program is to explore the mechanisms underlying the lower than expected cancer incidence in large and/or long-lived animals. We have assembled a unique and diverse collection of tumours that arose in large and/or long-lived animals ranging from whales to parrots to bats, and in this research program we will compare tumour suppressor gene copy numbers in these animals to those that do not have a long lifespan for their size, such as dogs and mice. We will measure expression of the genes, assess their function in cell culture by removing specific genes, test each species' cells response to DNA damaging agents, and measure how readily the cells are transformed. The research laid out in this program is designed to yield fundamental new knowledge of how organisms with large body size and/or long lifespan resist development of cancer. My long-term goals are to apply evolutionary comparative methods to test potential relationships between longevity and tumour suppressor gene copy number and expression. This will help us to understand the importance of patterns in gene copies that repeat during evolutionary history.