The reverse evolution from multicellularity to unicellularity during carcinogenesis.
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.
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.
Han
H
Chen
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.
Fangqin
F
Lin
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.
Ke
K
Xing
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.
Xionglei
X
He
D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D063646:Carcinogenesis / Q000473:pathology*; D055028:Comparative Genomic Hybridization; D059472:Exome / Q000235:genetics; D064593:Heterografts / Q000503:physiopathology*; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000503:physiopathology*; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology*; D017422:Sequence Analysis, DNA