Edward A. Rose, M.D.
We all know what stem cells are. They are the pluripotential cells throughout the body that can differentiate into one of several different types of cells as needed by the body. Complex cytokine signals tell the stem cells that we need more fibroblasts over here or more platelets in there, and the stem cells oblige. There are stem cells throughout the body waiting to be pressed into service. While it was once thought that one was born with only a certain number of these cells, it is now thought that differentiated cells can de-differentiate back into stem cells. The propensity to be a stem cell is called stemness.
In cancers such as acute myeloid leukemia, most cancer cells are just cancer cells. Traditional treatments such as chemotherapy and radiation therapy work to destroy those cancer cells. But more recent work in immunotherapy has found that some of the cells in the body of a patient with leukemia have stemness. They lack the surface markers typical of leukemic cells and differentiate into cancer after some trigger occurs. It is thought that these cancer stem cells (CSCs) are responsible for recurrences, both locally and distant. This explains why no cancer is ever considered truly cured and epidemiologists use phrases such as “disease-free interval”. After definitive adjuvant therapy, the CSCs can start producing cancer cells again.
Recent works by scientists such as Schimmer1 and Seneviratne2 have focused on the mitochondria and mitochondrial biology as one source of the stemness trait. Mitochondria, the powerhouses of the cell, occurred as a result of a symbiotic relationship between mammals and a bacterium, and the biology of mitochondria is dynamic depending on the needs of the cell. Mitochondria respond to external signals such as cytokines, nitric oxide, and oxidative stress, fusing or dividing and changing shape as needed. Because of their own double phospholipid wall, what happens inside the mitochondrion is not always controlled by cellular systems. The mitochondria of CSCs is different from the mitochondria of normal cells. While it is not clear whether the propensity towards recurrent cancer arises from the mitochondria, there are clearly immune targets for immunotherapy. This removes the “beating heart” from the cancer.
The interested reader should look at a recent piece by Hans Clevers in Nature for an overall review of the field of stemness. This is the future of immunotherapy, not just for leukemias but for solid tumors as well.
1Schimmer AD. Mitochondrial Shapeshifting Impacts AML Stemness and Differentiation. Cell stem cell. 2018 Jul 5;23(1):3-4.
2Seneviratne AK, Xu M, Henao JJ, Fajardo VA, Hao Z, Voisin V, Xu GW, Hurren R, Kim S, MacLean N, Wang X. The mitochondrial transacylase, tafazzin, regulates AML stemness by modulating intracellular levels of phospholipids. Cell stem cell. 2019 Apr 4;24(4):621-36.