Why Most Cancer Cells Cannot Form Tumors: Replicative Lifespan, Damage Partitioning and Stem Cell Induction.

Tumors grow because the total number of cancer cells increases without limit. The prevailing explanation is that each proliferating cancer cell has acquired unlimited replicative capacity, yet this does not explain why the overwhelming majority of cancer cells fail to initiate tumors on transplantation, why the cancer stem cell fraction of serially passaged cultures remains nearly constant, or why the measured cell loss factor of human tumors is so high. This review proposes an alternative reading of these observations. Non-stem cancer cells may possess a replicative lifespan that is set not by telomere attrition but by the progressive accumulation of damaged proteins, protein aggregates and dysfunctional mitochondria, so that each lineage eventually terminates in growth arrest or death. Persistent expansion would then depend on th e rate at which non-stem cancer cells are converted back into stem cells. Work on transforming growth factor-β associated molecules, including TMEPAI/PMEPA1, MAFK-GPNMB and THG-1, is reviewed in this light, together with evidence from budding yeast and mammalian stem cells that damage is partitioned asymmetrically at division. Established observations, reasonable inferences and untested assumptions are distinguished explicitly, and experimental tests are proposed.