Attacking the Root of the Problem

Stem cells, often associated with embryos and new life, have recently been implicated as one of the leading causes of death. A wave of papers published in the last five years suggest that renegade stem cells are the driving force behind many cancers. While non-stem cells are limited to a finite number of divisions before they reach programmed cell death, stem cells can undergo a virtually infinite number of cell divisions, making them potential sources of the unchecked proliferation that is characteristic of cancer. While the theory is not yet universally accepted in the scientific community, it is steadily gaining support through a series of recent discoveries. The cancer stem cell hypothesis is opening doors for drug therapies that specifically target stem cells, heralding a new era in cancer treatment.

Only a small minority of the body’s cells are stem cells (known as adult stem cells in a mature organism), but these specialized cells regenerate damaged tissues and dying cells in the body. They are “undifferentiated,” meaning that they have not fully developed into a specific functional cell type. Each time a stem cell divides, one of its daughter cells becomes a differentiated cell while the other becomes another stem cell. This unbalanced cell division, a process called self-renewal, allows stem cells to retain their immortality while simultaneously generating mortal descendents. (1)

Healthy cells have numerous checks that strictly regulate growth and division. According to the traditional paradigm of cancer, cells accumulate mutations throughout their life that can disable these regulating genes. Usually such mutations cause apoptosis, or cell suicide. In some cases however, a cell evades apoptosis, and continues to accumulate mutations that disable the brakes on growth and division. If it survives and mutates for long enough, the cell may become cancerous and proliferate uncontrollably. (2)

In the cancer stem cell hypothesis, the picture remains largely the same, except that the initiator is a stem cell. This seemingly minor detail substantially changes the scene. Stem cells can generate a diversity of differentiated cells, a trait that explains why many tumors are a conglomerate of several different cell types. The frequent heterogeneity in tumors may arise because they are composed of a few highly proliferative self-renewing stem cells as well as various differentiated derivatives with limited proliferative potential (1, 3).

Cancer stem cells were first identified in studies of leukemia, when John Dick and his colleagues at the University of Toronto found that there was a small chance that a given population of leukemia cells would proliferate extensively in vitro and in vivo. At the time, it was unknown whether all cells had the same small probability of aggressive proliferation, or whether different subtypes of tumor cells were predisposed towards enhanced growth. By affixing specific antibodies to separate the different types of cancer cells, Dick’s team discovered that while all cells expressed a leukemic phenotype, only those that expressed the CD34+/CD38- surface phenotype were able to initiate leukemia in mice (1, 4, 5). These CD34+/CD38- cells turned out to exhibit stem cell-like self-renewal, laying the foundations for cancer stem cell theory. Since Dick’s initial experiments, stem cells have been observed in numerous cancers, including breast, brain, prostate, colon, pancreatic and others (2).

The new paradigm offers clues as to how scientists can more effectively combat cancers. In order to cure a tumor, all the stem cell sources must first be destroyed. Treatments that only eliminate the mortal differentiated cells but not the stem cells essentially leave the underlying cause of the disease intact. These therapies are the medical equivalent of weeding a garden by cutting off the leaves of unwanted plants, but allowing their roots to quickly spawn full-fledged replacements. An untargeted approach to disable a tumor might wipe out 90 percent of the cancerous cells. But if there are a few cancerous stem cells among the survivors, the disease can easily return. Thus, scientists are now focusing on treatments that specifically target stem cells.

However, tailoring treatments to disable stem cells is no easy task. In fact, stem cells are frequently more resistant to treatments than their differentiated counterparts. In 2006, Jeremy Rich and his colleagues at Duke University demonstrated that in glioblastomas, a class of brain tumors, cancer stem cells are more likely to survive radiation therapy than other cells in the tumor because of enhanced DNA repair mechanisms (6). Thus, radiation therapy may reduce the size of the tumor but leave behind a subpopulation of stem cells that can restart proliferation.

Though these discoveries seem bleak, they are steering scientists toward more effective treatments that specifically target the stem cell roots of cancers. Already, this course of study is showing promise. Rich found that coupling radiation therapy with a drug that interferes with DNA repair caused the stem cells to become vulnerable. The drug, called debromohymenialdisine (DBH), inhibits the function of checkpoint kinases Chk1 and Chk2, enzymes that are crucial in DNA repair. This treatment effectively reversed the stem cells’ resistance to the radiation therapy. (6)

Similar techniques have already been extended to other cancers. Earlier this year, Jenny Chang and her team at Baylor College of Medicine analyzed human breast cancer cells that had received chemotherapy. They found that the chemotherapy had preferentially killed non-stem cells, leaving a high proportion of stem cells unharmed. The distribution was similar to the results that Rich had observed in glioblastoma radiation. When Chang’s team treated the cells with Tykerb, a drug that interferes with the HER2 growth pathway, the stem cells ceased to be chemotherapy resistant and died at the same rate as the other cells (2, 7).

Not all tumors contain stem cells however, or perhaps they are just too rare for scientists to detect in some cases. But stem cell presence may soon become a major factor in prescribing a course of treatment. Tumors can be biopsied to analyze the stem cell content, and based on these results, physicians can prescribe a more effective course of treatment. For example, patients with high stem cell content may receive dual treatment of radiation or chemotherapy coupled with DNA repair inhibitors.

Despite the abundance of scientific output linking stem cells with cancer, there are still many questions that remain unanswered. One puzzling development is the discovery that some tumor cells appear to be able to activate a dormant pathway that can give them properties of cancer stem cells (8). The process, known as the epithelial-mesenchymal transition (EMT), can transform immobile epithelial cancer cells into highly metastatic and proliferative mesenchymal cells (2). If tumors can generate stem cells spontaneously, then perhaps the current cancer stem cell model is an oversimplification. There may be other forces at work that initiate conversion into cancer stem cells. But these questions seem manageable given the promising results of the new paradigm.

In a way, the role of stem cells has come full circle, from the generator of new life to an orchestrator of a deadly disease. The challenge now is to both harness their power to heal and control their power to destroy. Already, cancer studies that specifically address the proliferative nature of stem cells are unlocking doors for effective new treatments. These ideas, and the consequences that they entail may usher in a new era for cancer treatment.

References
1. R. Pardal, M. F. Clarke, S. J. Morrison, Nature Reviews Cancer 3, 895-902 (2003).
2. The Economist, 13 September 2008, pp. 84-86.
3. J. E. Visvader, G. J. Lindeman, Nature Reviews Cancer 8, 755-768 (2008).
4. D. Bonnet, J. E. Dick, Nature Medicine 3, 730-737 (1997).
5. R. Bjerkvig, B. B. Tysnes, K. S. Aboody, J. Najbauer, A. J. A. Terzis, Nature Reviews Cancer 5, 899-904 (2005).
6. S. Bao et al., Nature 444, 756-760 (2006).
7. X. Li et al., J. Natl. Cancer Inst. 100, 672-679 (2008).
8. R. A. Weinberg, Nature Cell Biol. 10, 1021-1023 (2008).

Profiles in Drug Development at Dartmouth

Randolph Noelle
In 1991, Randolph Noelle, a professor of microbiology and immunology at Dartmouth Medical School, discovered a mechanism that if replicated in humans, had the potential to treat several autoimmune conditions. In these disorders, the immune system attacks the body’s own healthy cells. Noelle discovered that a particular ligand called CD40 interacts with helper T cells and other immune cells to cause the proliferation of antibodies that is characteristic of autoimmune disorders. He developed an antibody that would bind to and disable CD40, seemingly alleviating the symptoms in animal models. (9)

Noelle and his colleague Lloyd Kasper, who is also a professor at Dartmouth Medical School, licensed the drug to Idec Pharmaceuticals in San Diego, California. Since then, the drug has encountered a few political snags, but given its potential, researchers are still hopeful that it will be approved for treatment. If successful, Noelle’s research may greatly alleviate debilitating autoimmune conditions in many patients. Noelle is the co-founder and currently Chief Scientific Officer for ImmuRx, a biotechnology firm focused on cancer research. (9)

 Tillman Gerngross
Antibodies have long been used to treat infections in immunodeficient patients. But most antibodies are harvested from animals, and may be recognized as foreign substances and attacked by the human immune system. Tillman Gerngross of the Thayer School of Engineering began to investigate methods of genetically engineering antibodies that could be peacefully inducted into a human body.

In 2003, he founded GlycoFi, a company that uses yeast cells to synthesize antibodies with human-like sugar residues. Just three years later, GlycoFi was successful in creating monoclonal antibodies that resembled human proteins. The technique was not only more efficient than previous methods, but it also allowed scientists to custom tailor the sugar residues to optimize different treatments. GlycoFi was acquired by Merck in 2006, which is continuing to develop the procedure. (10)

 Gordon Gribble
Dartmouth chemistry professor Gordon Gribble is investigating a new class of cancer drugs that may be more effective in curtailing tumor growth than existing treatments. Many anticancer agents bind to DNA, which halts growth and induces apoptosis in cancer cells. But Gribble has improved upon the current drugs by synthesizing compounds that bind tighter to DNA, due to a mechanism called “bis-intercalation.” Bis-intertercalating agents double-bind to the DNA in a manner that has been compared to “molecular stapling” (11). The conformation is more rigid than the flexible tethers in typical DNA binding agents, making the reaction more energetically favorable (12).

PhytoMedical Technologies, Inc., a pharmaceutical company based in Princeton, New Jersey, has entered into a collaboration agreement with Gribble and his colleagues at Dartmouth to further develop the drug for treatment of prostate, lung, bladder, and brain cancer.