Every gardener knows the key to successful weeding; extract the entire root because even a small section can regenerate the whole plant. When treating cancer, doctors are faced with the same problem. Immature cancer stem cells often escape treatment and repopulate the tumor, despite its successful elimination by radio or chemotherapy. In a new take on an old idea, Ravindra Majeti and his team from Standford University weed out immature cells by forcing them to change lineages.
Current cancer treatments target rapidly proliferating cells but largely fail to tackle the root of the problem, cancer stem cells, which divide more slowly and pump out many drugs thrown at them. These cells lie in wait during the bombardment of cytotoxic compounds from conventional chemotherapy and replenish the tumor when the attack has subsided.
One alternative to killing immature cancer cells is to try to convert them to more differentiated cells. Leukemic cells in particular are blocked in an early stage of differentiation, but experiments in the early 1980s showed that cells from some leukemia patients can be made to differentiate when exposed to retinoic acid.
Some cancer cells however may not be able to differentiate along their normal lineage. Malignant B cells from patients with precursor B cell acute lymphoblastic leukemia (B-ALL) often lack important B cell transcription factors, which presumably contributes to differentiation block. However, normal B cells can be persuaded to differentiate into macrophages when forced to express macrophage transcription factors or cultured with macrophage cytokines in a phenomenon called transdifferentiation.
Taking a leaf from the book of transdifferentiation, Majeti and his team isolated primary malignant B cells from patients with B-ALL, cultured them with macrophage cytokines and looked at what the cells had grown into after 12 days:
- Cells from most (but not all) patients expressed macrophage markers, and looked like macrophages under a microscope.
- They also produced reactive oxygen species like normal macrophages and phagocytosed bacteria.
- The reprogrammed cells did not cause disease when grafted into immunodeficient mice.
Thus, malignant cells can be rendered into harmless white blood cells with the right supplements. This transdifferentiation process may even occur naturally in patients in vivo, suggesting that drugs that can speed it up may be a viable alternative to chemotherapy.
Get your green-fingered guide to cancer treatment over in PNAS, March 2015.