Scientists Say Stem Cells May Trigger Bone Cancer

The researchers are the first to identify a population of cells with characteristics of adult and embryonic stem cells in cultures derived from biopsies of patients' bone tumors. They describe their findings in this month's issue of the medical journal Neoplasia.

"We're saying the cell of origin of these tumors may be very, very primitive," said C. Parker Gibbs, M.D., an associate professor of orthopaedic oncology and a member of the UF Shands Cancer Center. Gibbs collaborated with several UF scientists, including Dennis A. Steindler, Ph.D., director of UF's McKnight Brain Institute.

Researchers elsewhere already have implicated stem cells in the development of leukemia, and Steindler's lab previously discovered stem-like cells in brain cancer. Others have identified these same cells in some breast cancers.

The studies are laying the foundation for novel ideas about cancer and its development, and are opening new avenues of research that could someday lead to more effective treatments that target the mutant cells that grow into tumors.

The cancer stem cell theory holds that a small subpopulation of rogue stem cells exists within a tumor and has the ability to sustain itself. As these abnormal cells divide, they may generate the bulk of a malignant tumor, then help to spur on its growth.

"Most current chemotherapeutic regimens are developed against the bulk tumor and therefore may not affect the small number of malignant stem cells, allowing recurrence and even metastasis," Gibbs said.

Osteosarcoma is the most common bone malignancy in children, most of whom are 10 to 20 years old and in a period of rapid growth when the disease is diagnosed. Despite advances in surgery and chemotherapy, many patients do not survive long-term.

"Osteosarcoma is an extremely aggressive tumor that destroys bone and requires surgery and chemotherapy to cure," Gibbs said. "The current cure rate is approximately 65 percent with yearlong chemotherapy and radical surgery, but we still lose 30 to 40 percent of these kids despite that kind of aggressive therapy. So the thought was, 'Gee, what are we missing?'

"The existence of stem-like cells in bone sarcomas suggests that the study of stem cell biology may provide opportunities for targeted therapies that are markedly less toxic than current aggressive chemotherapy and surgical protocols," he added.

Stem cells are primed to multiply and divide in almost unlimited fashion, and develop into many kinds of organs. A bone stem cell, for example, develops into bone. Osteosarcoma resembles bone but looks abnormal. A stem cell "gone bad" could potentially multiply to produce an abnormal organ that is cancerous, Gibbs said.

"Osteosarcoma occurs right next to the most active centers of growth, the growth plates in long bones," Gibbs said. "These areas of the skeleton contain many stem cells undergoing rapid growth and developing into bone during the adolescent growth spurt. It makes sense that bone sarcomas occur in anatomic areas containing stimulated stem cells. A stimulated, abnormal stem cell might therefore be the cell of origin of osteosarcoma."

UF researchers studied two types of tumors - osteosarcomas common in childhood and adolescence, and chondrosarcomas, a form of adult bone cancer that requires aggressive surgery to treat because it does not respond to chemotherapy or radiation.

Using specialized cell culture techniques, they were able to isolate stem-like cells from bone tumors. About one in 1,000 cells in the samples they studied had features of embryonic stem cells. The researchers also found abundant levels in their samples of the two key factors that help maintain embryonic stem cells in a very primitive state.

"We found expression of these two transcription factors not only in culture but also in actual tumors," Gibbs said. "We were first to show these cancers expressed both of these embryonic stem cell markers.

"That these cells exist in bone sarcomas suggests osteosarcomas and chondrosarcomas might be stem cell diseases," he added. "This is pretty exciting stuff."

The discovery gives scientists new targets for treatment, he said.

"The next step, which is ongoing, is isolating and growing tumors from these cells in animals and then finding ways to interfere with that growth based on their stem cell biology," Gibbs said. "So the study of embryonic and adult stem cell biology may provide more effective ways to treat childhood sarcomas."

Still, the precise role stem-like cells play in the development of cancer is not entirely clear, said Eric C. Holland, M.D., Ph.D., an associate professor in the departments of neurosurgery, neurology, and cancer biology and genetics at Memorial Sloan-Kettering Cancer Center.

"Dr. Gibbs' identification of very early cells in these tumors has important implications for our understanding of cancer biology," Holland said. "But further work needs to be done to determine what the role of cells of this nature is in cancer biology - whether they are the cells of origin, the cause of cancer or the effect of the environment generated by a tumor. Clearly it's quite an exciting time for people who are interested in cells like this."