Understanding how PTEN works in the brain also is expected to shed light on how stem cells in other parts of the body develop abnormally and may contribute to tumor development in other organs.
The findings are described in an article posted Nov. 1 in the journal Science as part of the journal’s Science Express Web site, http://www.sciencexpress.org.
Led by Drs. Hong Wu and Xin Liu, scientists at UCLA’s Jonsson Cancer Center and senior authors of the journal article, the research has demonstrated for the first time how the absence of the PTEN gene — a tumor suppressor gene that frequently is mutated in many forms of cancer — disrupts the growth, proliferation and death of normal brain stem cells. (Brain stem cells are immature cells that later develop into adult brain cells.) The disruption causes the stem cells to behave abnormally, which may contribute to the formation of brain tumors.
"This is the first evidence of PTEN’s critical role in the biology of brain stem cells, but overall, our findings could serve as a foundation for addressing any disease where stem-cell biology plays an integral role because PTEN is present in stem cells throughout the body," said Wu, who also is an assistant scientific investigator for the Howard Hughes Medical Institute and an assistant professor of molecular and medical pharmacology at the UCLA School of Medicine. "The cell-signaling pathways mapped through our research also show promise as clinical targets to attack some forms of brain cancer and may have applications for other types of cancers."
Liu, who also is an assistant professor of pathology and laboratory medicine at the UCLA School of Medicine, said that stem cells are an important area of investigation because they serve as precursors for all adult cells. Stem cells start out as blank slates, but by receiving signals from specific genes and proteins they become associated with certain parts of the body and responsible for specialized functions.
"We stand to learn a great deal from understanding how all stem cells receive and fulfill their specialized ‘assignments,’ and how these processes can be interrupted by factors such as the absence or mutation of the PTEN gene," Liu said.
Studying laboratory animal models, the researchers found that the number of brain stem cells produced doubled when the PTEN gene was absent in those cells. The researchers also noted that brain stem cells without PTEN grew to be significantly larger than normal brain stem cells and lived longer.
"When PTEN is operating normally, it helps regulate cell growth, proliferation and death by functioning as a brake. But when PTEN is absent in brain stem cells, these processes go out of control," Wu said. "The overproduction of abnormally large, longer-living brain cells caused by PTEN deletion suggests that PTEN is a very important gene in controlling the development and the life cycles of brain stem cells."
Without PTEN, the brain stem cells receive too many signals promoting their development through two kinases, or proteins, called PI3 and Akt, which are part of the cell-signaling pathways. The stem cells become over-stimulated and rapidly mature into brain cells whose growth and functions cannot be controlled. The unchecked cell development may initiate tumor formation, Wu said.
Previous research has established that 30 percent to 40 percent of some aggressive types of brain cancer called malignant gliomas lack the PTEN gene. The discovery of PTEN’s role in controlling brain stem-cell functions does not prove how lack of PTEN causes malignant gliomas, "but it does serve as a strong indication about the kinds of conditions that permit these tumors to form, grow and spread," Wu said.
In collaboration with other researchers at UCLA’s Jonsson Cancer Center, Wu also is investigating PTEN’s role in prostate and breast cancers.
Wu said further study of PTEN’s role in stem-cell processes also could provide valuable insight for research on embryo formation, brain development and in particular for Cowden’s disease, which is caused by an inherited mutation in the PTEN gene. Cowden’s disease causes patients’ brains to enlarge abnormally by 10 percent to 15 percent and can lead to mental retardation.
Other UCLA scientists involved in the brain stem-cell research and journal article were Drs. Jerome Zack, Harley Kornblum, and Matthias Groszer, and Rebecca Erickson and Deirdre Scripture-Adams.
Journal
Science