Research from Rockefeller University shows that having too many stem cells, or stem cells that live for too long, can increase the odds of developing cancer. By identifying a mechanism that regulates programmed cell death in hematopoietic stem cells, the work connects the death of such cells to a later susceptibility to tumors in mice.
The study, which appears in Genes and Development, also provides evidence of the potentially carcinogenic downside to stem cell treatments. It suggests that nature has sought to balance stem cells’ regenerative power against their potentially lethal potency.
Research associate Maria Garcia-Fernandez, Hermann Steller, Ph.D., head of the Strang laboratory of apoptosis and cancer biology, and their colleagues explored the activity of a gene called Sept4, which encodes the ARTS protein that increases programmed cell death by antagonizing other proteins that prevent cell death. ARTS is known to be lacking in human leukemia and other cancers, suggesting it suppresses tumors. The scientists bred a line of mice genetically engineered to lack the Sept4 gene.
Garcia-Fernandez studied cells that lacked ARTS, looking for signs of trouble relating to cell death. In mature B and T cells she could not find any, however, so she began to look at cells earlier in development, until finally she was comparing hematopoietic progenitor and stem cells.
Newborn ARTS-deprived mice had about twice as many hematopoietic stem cells as their normal, ARTS-endowed peers. Those stem cells were extraordinary in their ability to survive experimentally induced mutations, reports Garcia-Fernandez.
“The increase in the number of hematopoietic progenitor and stem cells in Sept4-deficient mice brings with it the possibility of accelerating the accumulation of mutations in stem cells,” she explains. “They have more stem cells with enhanced resistance to apoptosis. In the end, that leads to more cells accumulating mutations that cannot be eliminated.”
Indeed, the ARTS-deprived mice developed spontaneous tumors at about twice the rate of their controls. “We’ve made a connection between apoptosis, stem cells, and cancer that has not been made in this way before: this pathway is critically important in stem cell death and in reducing tumor risk,” Dr. Steller remarks. “The work supports the idea that the stem cell is the seed of the tumor and that the transition from a normal stem cell to a cancer stem cell involves increased resistance to apoptosis.”
ARTS interferes with molecules called inhibitor of apoptosis proteins (IAPs), which prevent cells from killing themselves. Under the right circumstances, ARTS thus helps to take the brakes off apoptosis, permitting the cell to die on schedule. Companies are working to develop small molecule IAP antagonists, but this research shows that inactivating a natural IAP antagonist actually causes tumors to grow, Dr. Steller points out. It also suggests that the premature silencing of the Sept4/ARTS pathway at the stem cell level may herald in cancer.
“This work not only defines the role of the ARTS gene in the underlying mechanism of mammalian tumor-cell resistance to programmed cell death but also links this gene to another hallmark of cancer, stem and progenitor cell proliferation,” states Marion Zatz, who oversees cell-death grants including Dr. Steller's at the National Institute of General Medical Sciences. “The identification of the ARTS gene and its role in cancer cell death provides a potential target for new therapeutic approaches.”