THE PRESENCE OF STEM CELLS in certain tissues, especially those with high cell turnover such as the gut and the skin, seems to be an overly complicated and inefficient system for replacing damaged or old cells. Would it not appear to make more sense for an organism if every cell could simply proliferate as needed to supply replacements for its injured neighbors? On the surface, perhaps—but that would make every cell in the body a potential cancer cell.
Malignancies are believed to arise when an accumulation of “oncogenic” changes to key genes within a cell leads to the abnormal growth and transformation of that cell. Gene mutations typically happen through a direct insult, such as the cell being exposed to radiation or chemicals, or simply through random error when the gene is improperly copied before cell division. Because the rare stem cells are the only long-lived cells in the organs where most cancers develop, they represent a much smaller potential reservoir for cumulative genetic damage that could eventually lead to cancer. Unfortunately, because stem cells are so long-lived, they also become the most likely repository for such damage.
Indeed, stem cells' longevity would explain why many cancers develop decades after tissues are subjected to radiation—the initial injury may be only the first in a series of mutations required to transform a healthy cell into a malignant one. In addition to accumulating and preserving these oncogenic scars, a stem cell's enormous proliferative capacity makes it an ideal target for malignancy. Because nature so strictly regulates self-renewal, a cell population already possessing that ability would need fewer additional mutations for malignant transformation than would cells lacking that capacity.
With these considerations in mind, several possible paths to malignancy become apparent. In one model, mutations occur in the stem cells themselves, and their resulting loss of control over self-renewal decisions produces a pool of stem cells predisposed to malignancy. Subsequent additional oncogenic events that trigger proliferation of the malignant cells into a tumor might happen in the stem cells or in their descendants, the committed progenitor cell population. A second model holds that oncogenic mutations initially occur in stem cells but that the final steps in transformation to cancer happen only in the committed progenitors. This scenario would require the progenitors' lost self-renewal capacity to be somehow reactivated.
Current evidence supports both models in different cancers. And at least one example exists of both processes playing a role in different stages of the same disease. Chronic myelogenous leukemia is a cancer of the white blood cells caused by the inappropriate fusion of two genes. Insertion of the resulting fused gene will transform a normal hematopoietic stem cell into a leukemia stem cell. Untreated, CML invariably progresses to an acute form known as CML blast crisis. Catriona Jamieson and Irving Weissman, both then at the Stanford University School of Medicine, demonstrated that in patients who progressed to CML blast crisis, the specific additional genetic events responsible for this more virulent version of the disease had conferred the ability to self-renew on certain progenitor cells.