Key Laboratory of Gene Engineering of Ministry of Education, Cooperative Innovation Center for High Performance Computing, College of Ecology and Evolution, Sun Yat-sen University, Guangzhou 510275, China.
1] Key Laboratory of Gene Engineering of Ministry of Education, Cooperative Innovation Center for High Performance Computing, College of Ecology and Evolution, Sun Yat-sen University, Guangzhou 510275, China [2] Key Laboratory of Biodiversity Dynamics and Conservation of Guangdong Higher Education Institutes, Sun Yat-Sen University, Guangzhou 510275, China.
Nat Commun. 2015 Mar 9;6:6367. doi: 10.1038/ncomms7367.
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 ~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.
理论推理表明，癌症可能是由于维持后生动物多细胞性的遗传限制被削弱而导致的。通过描述异种移植肿瘤的整个生命周期，我们在这里表明，转移是由与多细胞性相关基因的普遍功能丧失突变的正选择驱动的。表达分析显示，主要是下调与多细胞性相关的基因，并朝着类似于胚胎干细胞的表达谱进化，胚胎干细胞在其无限克隆增殖的能力上类似于单细胞生命。此外，后生动物多细胞性在大约 6 亿年前的出现伴随着癌症基因出生率的提高，而且在一个典型的肿瘤中，失活的肿瘤抑制基因比激活的癌基因多。这些数据共同表明，癌症代表了一种功能丧失驱动的反向进化，回到了单细胞的“基础状态”。这种癌症进化模型可以解释肿瘤内/间的遗传异质性，可以解释远处器官的转移，并对癌症治疗具有重要意义。
