Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
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DOI：
10.1001/jama.2015.13134
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发表时间：
2015-11-03
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影响因子：
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通讯作者：
Schiffman JD
中科院分区：
文献类型：
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作者：
Abegglen LM;Caulin AF;Chan A;Lee K;Robinson R;Campbell MS;Kiso WK;Schmitt DL;Waddell PJ;Bhaskara S;Jensen ST;Maley CC;Schiffman JD
进化医学可能提供对人类生理学和病理生理学的洞察，包括肿瘤生物学。为了确定大象抗癌的机制，并比较大象、健康人类对照组和易患癌症的Li-Fraumeni综合征(LFS)患者对DNA损伤的细胞反应。对36种哺乳动物的尸检数据进行了全面的调查，以验证大型和长寿生物的抗癌能力，包括大象(n=644)。对非洲和亚洲大象的基因组进行了分析，以寻找抗癌的潜在机制。来自大象、健康人类对照组和LFS患者的外周血淋巴细胞在实验室进行了体外DNA损伤反应测试。这项研究包括非洲和亚洲大象(n=8)、LFS患者(n=10)和年龄匹配的人类对照组(n=11)。2014年6月至2015年7月期间，犹他大学采集了人体样本。电离辐射和阿霉素。根据体型和寿命计算和比较不同物种的癌症死亡率。研究人员调查了大象基因组中与癌症相关的基因的变化。比较了大象和人类外周血淋巴细胞的DNA修复和凋亡。在哺乳动物中，癌症死亡率没有随着身体大小和/或最长寿命的增加而增加(例如，岩兔，1%[95%CI，0%-5%]；非洲野狗，8%[95%CI，0%-16%]；狮子，2%[95%CI，0%-7%])。尽管大象体型庞大，寿命长，但它们仍然对癌症具有抵抗力，估计癌症死亡率为4.81%(95%可信区间，3.14%-6.49%)，而人类的癌症死亡率为11%至25%。人类有1个TP53拷贝(2个等位基因)，而非洲大象至少有20个拷贝(40个等位基因)，包括19个逆转录基因(38个等位基因)，通过逆转录聚合酶链式反应检测到转录活性的证据。作为对DNA损伤的反应，大象淋巴细胞经历了与TP53状态成正比的P53介导的凋亡率(电离辐射暴露：LFS患者，2.71%[95%CI，1.93%-3.48%]vs人类对照组，7.17%[95%CI，5.91%-8.44%]vs大象，14.64%[95%CI，10.91%-18.37%]；P<；.001；阿霉素暴露：人类对照组，8.10%[95%CI，6.55%-9.66%]对大象，24.77%[95%CI，23.0%-26.53%]；P<；.001)。与其他哺乳动物物种相比，大象的癌症发病率似乎低于预期，这可能与TP53的多个副本有关。与人类细胞相比，大象细胞在DNA损伤后表现出更强的凋亡反应。如果这些发现被重复，可能代表着一种基于进化的方法来理解与癌症抑制相关的机制。
Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. Ionizing radiation and doxorubicin. Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95%CI, 0%–5%]; African wild dog, 8%[95%CI, 0%–16%]; lion, 2%[95%CI, 0% –7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95%CI, 3.14%–6.49%), compared with humans, who have 11% to 25%cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95%CI, 1.93%–3.48%] vs human controls, 7.17%[95%CI, 5.91%–8.44%] vs elephants, 14.64%[95%CI, 10.91%–18.37%]; P < .001; doxorubicin exposure: human controls, 8.10% [95%CI, 6.55%–9.66%] vs elephants, 24.77%[95%CI, 23.0%–26.53%]; P < .001). Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.