  Theoretical reasoning suggests that human cancer may result from knocking
down the genetic constraints evolved for maintenance of the metazoan
multicellularity, which, however, requires a critical test. Using
xenograft-based experimental evolution we characterized for the first time the
full life history from initiation to metastasis of a tumor at the genomic and
transcriptomic levels, and observed metastasis-driving positive selection for
generally loss-of-function mutations on a set of multicellularity-related
genes, which is further supported by large-scale exome data of clinical tumor
samples. Subsequent expression analysis revealed mainly expression
down-regulation of multicellularity-related genes, which form an evolving
expression profile approaching that of embryonic stem cells, the cell type with
the most characteristics of unicellular life. The theoretical conjecture
predicts that genes born at the emergence of metazoan multicellularity tend to
be cancer drivers, which we validated using a rigorous phylostratigraphy
analysis on the birth rate of genes annotated by Cancer Gene Census. Also, the
number of loss-of-function tumor suppressors often predominates over activated
oncogenes in a typical tumor of human patients. These data collectively suggest
that, different from typical organismal evolution in which gain of new genes is
the mainstream, cancer represents a loss-of-function-driven degenerative
evolution back to the unicellular ground state. This cancer evolution model may
explain the enormous tumoral genetic heterogeneity in the clinic, underlie how
distant-organ metastases originate in primary tumors despite distinct
environmental requirements, and hold implications for designing effective
cancer therapy.
