Stem cells, the prodigious precursors of all the tissues in our body, can make almost anything, given the right circumstances. Including, unfortunately, cancer. Now 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 precursor cells for blood, or hematopoietic stem cells, the work is the first to connect the death of such cells to a later susceptibility to tumors in mice. It also provides evidence of the potentially carcinogenic downside to stem cell treatments, and suggests that nature has sought to balance stem cells' regenerative power against their potentially lethal potency.
Research associate Maria Garcia-Fernandez, Hermann Steller, head of the Strang Laboratory of Apoptosis and Cancer Biology, and their colleagues explored the activity of a gene called Sept4, which encodes a protein, ARTS, that increases programmed cell death, or apoptosis, by antagonizing other proteins that prevent cell death. ARTS was originally discovered by Sarit Larisch, a visiting professor at Rockefeller, and is found to be lacking in human leukemia and other cancers, suggesting it suppresses tumors. To study the role of ARTS, the experimenters bred a line of mice genetically engineered to lack the Sept4 gene.
For several years, 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 and earlier in development, until finally she was comparing hematopoietic progenitor and stem cells. Here she found crucial differences, to be published in Genes and Development.
Newborn ARTS-deprived mice had about twice as many hematopoietic stem cells as their normal, ARTS-endowed peers, and those stem cells were extraordinary in their ability to survive experimentally induced mutations.
"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," says Garcia-Fernandez. "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 make 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," Steller says. "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. By inhibiting these inhibitors, under the right circumstances ARTS helps to take the brakes off the process of apoptosis, permitting the cell to die on schedule. Pharmaceutical companies are working to develop small molecule IAP antagonists, but this research is the first to show that inactivating a natural IAP antagonist actually causes tumors to grow, Steller says. It also suggests that the premature silencing of the Sept4/ARTS pathway at the stem cell level may herald cancer to come.
"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," said Marion Zatz, who oversees cell death grants, including Steller's, at the NIH's 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."
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