The present work proposes a single-cell development model for cancer based on recent insights into protist germ and stem cell biology and the analogy of the two systems. Germ stem cells (GSCs) were produced in cancer by a germline of unicellular imprinting that performs reproductive aCLS cycles consisting of self-renewing progenitor cells, committed aCLS precursor cells, aCLS polyploid cells (mother cells) and daughter germ stem cells, inherits stemness from one cell generation to the next. The highlights of this theory are:
- The cell-of-origin of cancer activates an ancient silent single-cell genome, which can differentiate germ and soma of unicellular imprinting;
- Germline and soma cell have differential stress resistance (DSR);
- Hyperoxia damages the germline, which loses the ability to perform reproductive aCLS cycles and GSCs (loss-of-function), but not the proliferation capacity;
- DNA damage signalling cells of the defective germline induce an EMT like soma-to-germ cell transition (SGT) that increases the fitness of the CSC pool;
- The hyperoxic damaged genome must be repaired by multinucleated genome repair structures (MGRSs) better known as “pre-existing” PGCCs;
- Germline evolution occurs by alternating normoxic and hyperoxic damaged phenotypes; genome reorganization increases the fitness and invasiveness of CSCs;
- Genotoxically induced PGCCs are not identical to “pre-existing” PGCCs.