Lethal signals: Physicians know abnormal stem cells can give rise to cancer cells (stained purple) in leukemia patients. But how common is this phenomenon? Image: Joaquin Carrillo-Farga Photo Researchers, Inc.
On a sweltering August evening in 2009 Pat Elliott noticed that her feet seemed swollen. Because she had been standing for hours while teaching a workshop in Phoenix, she was not surprised. “I thought it was the heat,” she says. But her feet hurt, too, so Elliott decided to play it safe and called her doctor, who suggested she come in for some tests. Days later the marketing professional learned that she had developed an uncommon form of blood cancer called chronic myelogenous leukemia (CML).
Elliott’s cancer is the result of a genetic change that arose in one or more stem cells in her bone marrow. (Normally these stem cells give rise to various blood cells in the body.) The defect caused the stem cells and their progeny to produce an abnormal enzyme known as Bcr-Abl. This enzyme signals the marrow to produce too many immature white blood cells and allows them to persist longer than they should. The proliferating blood cells then crowd out healthy cells, damage the bone marrow and allow infections to take hold. Once these abnormal cells enter the bloodstream, they can also cause the spleen to swell and damage other organs. The pain and swelling in Elliott’s feet most likely resulted from kidney problems caused by her disease. CML usually starts off being fairly innocuous, especially if treated. It can, however, become aggressive and lethal if left untreated.
To keep her disease in check, Elliott takes a bright yellow pill daily. The medication, called imatinib (sold under the brand name Gleevec), binds to the abnormal enzyme and shuts off the proliferation signal. Without this enzyme, the extra white blood cells mature normally and die as they should. Indeed, a recent study suggests that CML patients who live at least two years after starting imatinib treatment can look forward to a normal life span. But the pill is not a cure. A small number of long-lived cancer cells persist inside Elliott’s body. If she stops taking her medication, the cancer will return.
Although imatinib keeps Elliott—and some 22,000 other CML patients in the U.S.—alive and healthy, the drug’s inability to eradicate the cancer suggests that perhaps the standard model that most researchers use to visualize how tumors grow—and the treatments that have arisen from that model—is flawed. An alternative hypothesis has recently gained traction; if it proves to be more accurate, physicians may need to adjust their therapeutic approaches, targeting their treatments to destroy particular subsets of cells within the tumor.
Oncologists have long worked under the assumption that most tumors develop from a single cell. After a series of genetic mutations, which occur as a result of exposure to radiation, cigarette smoke, dietary choices or a genetic predisposition, this single cell begins to divide uncontrollably into more cells. Each succeeding generation of cells accumulates more genetic mistakes that make the tumor grow bigger, invade local tissues and eventually spread (metastasize) to other parts of the body. Under the standard model of cancer growth, once a tumor has gained the ability to spread, any one of the founding cell’s descendants can break off and form a new mass—which is why health authorities emphasize early diagnosis and the need to destroy all tumor cells to prevent a recurrence.
The alternative view proposes that only a handful of the cells in a tumor—known as cancer stem cells—have the ability to grow uncontrollably and spread. These cells renew themselves indefinitely (essentially making close duplicates of themselves) and also give rise to a mix of cells having different properties and a finite life span. In this way, cancer stem cells resemble the normal stem cells sprinkled throughout the body that replace old or damaged tissues, such as skin or the lining of the intestine. Unlike normal stem cells, however, cancer stem cells ignore any and all chemical signals that tell them to stop dividing. According to this alternative conception, most cells in the tumor will eventually die and so should be less dangerous. The few stem cells in the tumor, however, would be particularly deadly: if even a single cancer stem cell survived the initial therapy, it could give rise to a whole new tumor weeks, months or even years later.