David T. Scadden, MD’s recent discovery using bone-forming cells, called osteoblasts, are activated with a hormone that is used to treat osteoporosis, can increase the number of stem cells with dramatic improvements in survival after stem-cell transplantation.

Q&A: A Conversation with David T. Scadden, MD

Our bodies are composed of millions of cells, most of which have a very specific function—from ferrying oxygen in our blood or fighting foreign invaders to capturing light that enables us to see.

However varied their roles, all of these cells originated from stem cells, the first cells to form early in the development of an embryo. Stem cells have two signature characteristics: the potential to become almost any type of specialized cell and to renew themselves.

Stem cells also exist in adults, standing quietly by until they are called upon to replace or repair cells of the tissue or organ in which they reside.

While most of the recent public attention has focused on the potential of embryonic stem cells, adult stem cells have had an important role in cancer treatment for many years. As scientists at the Cancer Center and elsewhere learn more about adult stem cells, they are finding new ways to exploit them for the benefit of patients. In the process, they are also discovering that these cells may hold important clues to the disease itself.

David T. Scadden, MD, is a hematologist/oncologist and research scientist in the Cancer Center and director of the new Massachusetts General Hospital (MGH) Center for Regenerative Medicine and Technology. During a recent conversation, he discussed several areas of promising research involving adult stem cells that are under way in his laboratory.

Q. How are adult stem cells currently being used in the treatment of cancer patients?

A. Many people think of cell-based therapies as futuristic, but stem cells have been an important part of cancer therapy for almost five decades. For example, stem-cell transplantation [often referred to as bone marrow transplantation] is a treatment used virtually every day for selected patients with cancers such as lymphoma, Hodgkin’s disease, leukemia, or multiple myeloma.

Stem-cell transplantation involves killing cancer cells with very high doses of chemotherapy and/or radiation. This also destroys the patient’s bone marrow, the source of the blood and immune system, which must be replaced. The replacement comes from stem cells harvested from the patient’s own blood prior to treatment [an autologous transplant] or, if that is not possible, a donor’s blood [an allogeneic transplant]. For many patients, this approach results in a cure.

Q. What are some of the challenges of stem-cell transplantation that your research is currently addressing?

A. About 10 to 20 percent of cancer patients for whom autologous stem-cell transplantation could potentially be effective are unable to undergo this therapy because they lack sufficient numbers of stem cells in their blood.

Many other patients cannot be considered for stem-cell transplantation because we are unable to find someone among the existing donor pool whose immune system matches the patient’s closely enough to make this feasible.

For these patients another, larger potential source of stem cells exists—umbilical cord blood, which is typically discarded. However, even when a close match can be found, there are not sufficient numbers of stem cells in umbilical cord blood to be used for adult transplants.

Driven by these clinical challenges, our recent work has focused on ways to increase the number of stem cells so that more patients can have access to this potentially life-saving therapy.

Q. What strategies have you used to increase stem cell numbers?

A. We have taken a slightly different approach than other scientists. Rather than focusing on what fuels the proliferation of stem cells, we have been looking at what restricts their growth—the “brakes” on stem cell proliferation, if you will—and have tried to determine how to release those. As a result of this work, we have identified molecular brakes that restrict the proliferation of stem cells and, by manipulating them, we have been able to induce the expansion of stem cells.

We have also focused on trying to understand how the environment in which the stem cells reside influences their proliferation—the idea being that if we could understand this process, we could strategically manipulate the environment as a way of increasing the number of stem cells.

Q. Has this work on stem cell environments led to any discoveries that might benefit patients?

A. Our work in mouse models led to our recent discovery that bone-forming cells, called osteoblasts, are key players in controlling stem cell numbers in the blood [which forms within the bone].

By activating the osteoblasts with a hormone that is FDA approved to treat osteoporosis, we saw a marked increase in stem cells and dramatic improvements in survival after stem-cell transplantation, despite small numbers of transplanted cells.

We recently started a multi-center clinical research trial that will evaluate this approach in patients with lymphoma who lack sufficient stem cells for an autologous transplant. Subsequent clinical studies will look at whether we can improve the outcomes of stem-cell transplantation using small numbers of stem cells in umbilical cord blood. If successful, this would mean that umbilical cord blood could be a viable new source of stem cells for adults for whom we cannot find a closely matched donor among the donor population.

Q. You and other cancer researchers are also investigating cancer stem cells. What is the focus and potential impact of this work?

A. There is now a recognition that not all cancer cells are alike—that some function like cancer stem cells. For example, in animal models we can transplant a tumor by transplanting just a small number of these cancer stem cells, but we can’t if we transplant the other tumor cells.

Scientists have found and defined the characteristics of cancer stem cells in three human cancers: leukemia, brain tumors, and breast cancer, and are looking for more. It may be that cancer researchers should be focusing on understanding what controls these rare cancer stem cells, rather than all the cells in the tumor. We are actively pursuing this fairly new, but potentially very promising, area of research, which could have a major effect on the way we develop new cancer therapies.

Source; Synergy, Fall 2004. Volume 2