Target for cancer therapy: proliferating cells or stem cells.

Tumor stem cells are quiescent and, therefore, resistant to therapy, yet harbor the capacity to replenish a tumor after therapy. Therefore, it is tempting to explain all therapeutic failures by the persistence of tumor stem cells. Yet, this explanation is relevant only to initial stages of stem-cell-dependent tumors (such as chronic myeloid leukemia) that, actually, are well controlled by therapy. In advanced cancers that poorly respond to therapy, quiescent tumor stem cells play a negligible role. Instead, proliferating cells determine disease progression, prognosis, therapeutic failures, and resistance to therapy. And therapy fails not because it eliminates only proliferating tumor cells, but because it does not eliminate them. With noticeable exceptions, it is the proliferating cell that should be targeted, whereas resting cancer cells including stem and dormant cells need to be targeted only when they 'wake up'. Finally, I discuss a strategy of selectively killing dominant proliferating clones, including proliferating stem-like and drug-resistant cancer cells, while sparing normal cells.