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Stem Cells In Brain Linked To Formation Of Gliomas

University of Florida scientists report they have found the first evidence of a link between stem cells in the brain and the formation of gliomas, the most common type of brain tumors found in adults.

The researchers say the findings could lead to new treatments that would rehabilitate the errant cells by redirecting their normal growth into a more controlled pattern-rather than by killing the malignant cells, as current treatments are intended to do.

The Florida team's discovery is based on extensive laboratory studies of brain cells from malignant gliomas that were surgically removed from human patients, then cultured under conditions that enabled them to isolate the stem cells.

Results of the investigations -- in the laboratory of neuroscientist Dennis Steindler, Ph.D. -- appear in the current online version of the international journal GLIA. The printed journal is due for release in July.

"This is incredibly exciting research, which suggests a novel form of adjuvant therapy for patients with glioblastoma tumors, for which curative therapy is essentially nonexistent," said Stratford May Jr., M.D., Ph.D., program director for the campuswide UF Shands Cancer Center.

"The UF investigators have found that glioblastoma tumor cells derived from brain tumors of patients can maintain their stem cell properties and may be induced to differentiate (mature) at least in the test tube," May said. "This suggests that under appropriate therapeutic conditions, any brain tumor cells lurking after surgery and radiation therapy could be induced to turn into normal cells if the right conditions were identified and could be administered."

Malignant gliomas comprise about half of the 17,000 brain tumors diagnosed each year in the United States. Certain types of rapidly growing gliomas tend to resist standard treatments, particularly chemotherapy and radiation therapy.

"Our observations suggest it is possible that tumor formation occurs when stem cells originating in a particular part of the brain -- which continually divide and regenerate -- go too far in the process of reproduction," said Steindler, who co-authored the paper. He is affiliated with UF's McKnight Brain Institute and the UF Shands Cancer Center.

"In recent years, it has been theorized that there may be a connection between brain tumors and stem cells," Steindler said. "We believe we have the first evidence this is true, and that it starts with stem cells that may have been produced in the region we call the brain marrow -- near the brain's central core and the fluid-filled ventricles."

UF neuroscientists Tanya Ignatova and Valery Kukekov, senior authors on the article in GLIA, noted that when they grew the excised glioma cells in culture, they observed cells that behaved like stem cells but exhibited abnormal growth. Using an analytical method developed by Kukekov, they found the stem cells and their progeny also contained genes that were different from the genes found in normal brain tissue, and some of these genes did not turn on as they do in normal cells.

The researchers analyzed particular genes known to be involved in abnormal cell proliferation, cell survival, and cell differentiation or maturation into specific cell types.

"Our observations evoked the question: Is this good evidence that gliomas may be derived from abnormal stem cells, or could it be that the tumors were initiated by some other problem and then produced the abnormal stem cells?" Steindler said. "We believe we have shown that abnormal stem cells are the culprit, not the bystander.

"We believe our study gives rise to a hypothesis that there could be a link between some types of brain injuries that actually trigger brain marrow stem cells to move toward the problem area in an effort to fix it," Steindler said. "It appears that brain marrow stem cells home to an area where the brain is trying to repair itself, but while doing so -- because these cells have to repopulate themselves to carry out the healing mission -- may go too far and produce tumors.

"Currently, most brain tumor therapies focus on trying to kill the brain tumor cells with drugs or radiation, but if we're dealing with abnormal brain marrow stem cells, as in gliomas, such destruction (of tumor cells) is almost impossible because the stem cells are in the mode of trying to build and are highly resistant to most known drug therapies," Steindler said.

The UF team offers a maverick suggestion: Instead of trying to kill the abnormal brain tumor stem cells, why not try to rehabilitate them by controlling their growth?

"Our study may pave the way for a new generation of therapies to halt the growth of gliomas -- such as with the delivery of factors that would help control the growth of the stem cells," Steindler said. "In tissue cultures, we have done exactly that.

"Through molecular manipulation and changes in the growth medium, we were able to induce stem cells (from gliomas) to grow into what looked like normal nerve cells and glia," Steindler said.

UF researchers now are conducting follow-up studies in animal models.

Funding sources include the National Institute of Neurological Diseases and Stroke, UF's McKnight Brain Institute and the UF Shands Cancer Center. They aim to characterize the genes involved in gliomas and to determine how these genes are turned on and off.

Members of the research team also are involved with a Gainesville-based biotechnology start-up company called NeuroStem Inc., which may further explore the technologies developed in Steindler's laboratories. - By Arline Phillips-Han






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