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At the Root of Cancer?

Stem cells may be at the root of both cancer and cures for a variety of diseases. That is, if stem cells divide out of control in the body, they could cause cancer, but if those same cells divide under control in a dish, they have the potential to become specialized cells for transplant to treat disease. The relationship between malignant and pluripotent cells, some scientists suspect, may lie in so-called cancer stem cells.

A stem cell, explains Rick Jones, M.D., head director of the Johns Hopkins Bone Marrow Transplantation Program, is a progenitor cell that replicates (or self-renews) and differentiates into specialized cells. In the case of blood, for example, a stem cell makes more stem cells and yields white cells, red cells, and platelets.

Dr. Elias Zambidis Elias Zambidis, M.D., Ph.D.

A cancerous stem cell of the blood, however, would generate more and more of itself rather than specialized cells. The classic case with blood is leukemia, says Elias Zambidis, M.D., Ph.D., a member of  the Stem Cell Biology Program at Hopkins’ Institute for Cell Engineering and a pediatric oncologist specializing in treating blood disorders. While blood stem cells are very rare—there are probably less than 1 in 100, 000—a patient with leukemia has so many cells resembling blood stem cells that their bone marrow literally appears clogged.

Jones, Zambidis, and other researchers now believe that many cancers recur because current therapies target the byproduct of the cancerous stem cell rather than the cancerous stem cell itself. “Think of a dandelion,” Jones says. “You can mow down the part of the plant you can see, but that doesn’t get rid of the dandelion. You have to get rid of the root, the part of the plant you can’t see.” In this light, a cancer therapy that targets the source of the cancer, namely the cancer stem cells, probably would reduce the likelihood of recurrence.

Dr. Robert Brodsky Dr. Robert Brodsky

The irony, however, is that while doctors would like to eradicate these cancerous blood stem cells in patients, scientists in the lab would be thrilled to generate cells that behave like leukemia in a dish to learn more about the disease so they can devise a way to cure it. In vitro proliferation ability, says Robert Brodsky, M.D., chair of hematology at Johns Hopkins, might not only help treat patients with a host of blood diseases, but also help us understand the mechanisms underlying cancers of the blood. Zambidis agrees, noting that "malignancy and pluripotency are twins, one evil and one good.”

While scientists have made some headway in pushing blood stem cells to proliferate outside the body, particularly with induced pluripotent stem cells—adult cells that have been genetically engineered to resemble embryonic stem cells—they still can't generate enough blood to transfuse even a mouse, Brodsky says.

Zambidis says the key to getting blood cells to proliferate—or not, as the case may be —is to go back to the beginning, to our time in utero. The cancerous cells of patients with leukemia share at least one feature with cells on a dish, he says: Both exist in an immature, or embryonic, state. That's because, in their natural state, only embryonic stem cells have the ability to create more of themselves. In the case of leukemia, says Zambidis, we must ask: "How is it that a normal cell starts to behave like an embryonic stem cell?"

To answer this question, Zambidis is trying to push embryonic blood stem cells into adult blood stem cells. He says he’s about halfway there. “We’ve gotten them to be the type of blood that you find in the fetal liver. In other words, we’ve gotten them through steps A through F but we’re still working toward Z.” The bottom line, says Zambidis, is this: “If you understand how blood develops and occurs, you can understand how it goes wrong in cancer and you can understand how you can make more blood for therapies.”

--by Sujata Gupta