The reverse evolution from multicellularity to unicellularity during carcinogenesis
The reverse evolution from multicellularity to unicellularity during carcinogenesis
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DOI：
10.1038/ncomms7367
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发表时间：
2015-03-01
影响因子：
16.6
通讯作者：
He, Xionglei
中科院分区：
文献类型：
--
作者：
Chen, Han;Lin, Fangqin;He, Xionglei
理论推理表明，癌症可能是为了维持后生动物多细胞而进化出的基因约束被击倒的结果。通过描述异种移植瘤的整个生命史，我们发现转移是由多细胞相关基因功能丧失突变的阳性选择所驱动的。表达分析显示，主要是多细胞相关基因下调，并朝着胚胎干细胞的表达谱进化，胚胎干细胞的细胞类型类似于单细胞生命，具有无限克隆增殖的能力。此外，类似于600Myr AGO的后生动物多细胞的出现伴随着癌症基因出生率的上升，在典型的肿瘤中，功能丧失的肿瘤抑制基因比激活的癌基因更多。这些数据共同表明，癌症代表了一种由功能丧失驱动的反向进化，回到了单细胞的“基态”。这一肿瘤进化模型可能解释了肿瘤间/瘤内的遗传异质性，可以解释远处器官转移，并对癌症治疗具有指导意义。
Theoretical reasoning suggests that cancer may result from a knockdown of the genetic constraints that evolved for the maintenance of metazoan multicellularity. By characterizing the whole-life history of a xenograft tumour, here we show that metastasis is driven by positive selection for general loss-of-function mutations on multicellularity-related genes. Expression analyses reveal mainly downregulation of multicellularity-related genes and an evolving expression profile towards that of embryonic stem cells, the cell type resembling unicellular life in its capacity of unlimited clonal proliferation. Also, the emergence of metazoan multicellularity similar to 600 Myr ago is accompanied by an elevated birth rate of cancer genes, and there are more loss-of-function tumour suppressors than activated oncogenes in a typical tumour. These data collectively suggest that cancer represents a loss-of-function-driven reverse evolution back to the unicellular 'ground state'. This cancer evolution model may account for inter-/intratumoural genetic heterogeneity, could explain distant-organ metastases and hold implications for cancer therapy.