A set of researchers found that a breakdown in proper cell development would cause brain-specific stem cells to become starter seeds for aggressive brain tumours called glioblastoma multiforme. This finding was the result of experiments done in lab and animal studies by a team of researchers at National Cancer Institute (NCI) and National Institute of Neurological Disease and Stroke (NINDS). NCI and NINDS are parts of National Institutes of Health (NIH).
This developmental breakdown is caused by an error in methylation, one of the cell's primary methods of controlling the extent to which genes are expressed. In laboratory studies and animal models of brain cancer, reversing this error repaired the breakdown, restoring the normal neural cell development pathway. The findings, which appeared in "Cancer Cell", could increase basic understanding of brain tumor biology and lead to the development of targeted therapies for brain cancer.
"The discovery of a link between tumor stem-like cells and expression control is both novel and exciting," said John Niederhuber, M.D, director, NCI. "These results bring new clarity to how all aspects of the genome's function, regulation, and structure can be perturbed in the development of cancer."
Many researchers have come to believe that the activity of a small group of stem-like tumor starter cells, or tumor-initiating cells with stem-like properties (TICs) may be one of the main reasons that cancer develops. Like normal stem cells, TICs are able to self-renew; unlike stem cells , TICs give rise to cells that develop into tumours, instead of differentiating into normal tissue. TICs have been reportedly found in tumours in a number of organs, including the breast, colon, lung, and brain.
Because normal stem cells and TICs are similar in some ways and dissimilar in others, a research team led by Howard Fine, M.D., chief of the Neuro-Oncology Branch at NCI's Center for Cancer Research, set out to identify what biological pathways are altered in these starter cells that enable them to give rise to tumor cells. Harvesting TICs from glioblastoma multiforme patients, the Fine team developed a human cell called 0308 that did not respond normally to environmental cues -- specifically, exposure to two proteins, called bone morphogenetic protein-2 (BMP2) and ciliary neurotrophic factor (CNTF) -- that cause normal neuronal stem cells to begin differentiating. Rather, they responded to these cues much like very immature neuronal stem cells in that they grew in response to BMP2 and were unresponsive to CNTF, suggesting that the 0308 starter cells were somehow locked in a very early stage of development.
Because the response to BMP2 in normal stem cells is linked to the presence of particular BMP receptors, which are present during specific developmental stages, Fine and his colleagues compared the expression of genes for BMP receptors in 0308 with what occurs in normal neuronal stem cells. The researchers found that the gene for one receptor, BMPR1B, was almost completely silent in 0308 cells. Experimentally reactivating this gene in the 0308 line caused the cells to respond more normally to environmental cues and reduced their potential for tumor development.
Subsequently, the Fine group determined that BMPR1B expression in 0308 cells was blocked via methylation, a chemical modification used by the cell to control gene expression. A methylated gene cannot be expressed and is rendered silent. Methylation-associated silencing of tumor suppressor genes has been found in several cancers.
Methylation has also been identified as a key mechanism for the control of proper cellular development in the early brain, and particularly for the differentiation of neuronal stem cells. Experimentally demethylating 0308 cells caused them to behave more normally. The results mimicked those seen when early normal embryonic neuronal stem cells are demethylated, adding further weight to the argument that the 0308 cells were locked in a developmentally immature state.
To put these findings into clinical context, Fine and his group then examined a set of 54 glioblastoma multiforme tumours, finding that in about 20 per cent of tumours, BMPR1B expression was greatly reduced; in the majority of these tumors the gene for BMPR1B was heavily methylated. These tumours also displayed the same markers of stalled differentiation found in 0308 cells.
"This research highlights an example of a stem cell whose normal development has been blocked in such a way as to both prevent it from differentiating and force it to contribute to the development of an aggressive tumor," said Fine. "The results we have generated can help us better understand the biology of neuronal stem-like starter cells in glioblastoma multiforme and other cancers, and give us a strong rationale for investigating BMPR1B as a potential target for therapeutic development."
The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- is comprised of 27 institutes and centers and is a component of the US Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases.