According to a study by researchers at the Ludwig Institute for Cancer Research, loss of a gene required for stem cells in the brain to turn into neurons may be the underling cause of the most severe forms of neuroblastoma, a deadly childhood cancer of the nervous system.

The study was published in Developmental Cell, the findings also provide clues about how to improve the treatment of this often-incurable tumor.

This research could lead to new ways to treat neuroblastoma.

Neuroblastoma can appear in nervous tissue in the abdomen, chest and spine, among other regions of the body, and can spawn body-wracking metastasis. About 70% of patients with neuroblastoma have metastatic disease at the time of their diagnosis. The most severe tumors respond poorly to treatment, and the disease accounts for 15% of cancer deaths in children.

Childhood cancer
Since 1975, a dramatic improvement in survival has been achieved for children and adolescents with cancer.[1] In this period, childhood cancer mortality has decreased by more than 50%. For neuroblastoma,the 5-year overall survival for all infants and children with the disease has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005. [1] However, experts feel that this data may be misleading due to the extremely heterogeneous prognosis based on the neuroblastoma patient’s age, stage, and biology.

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CHD5 tumor suppressor
Johan Holmberg, PhD, at the Ludwig Institute for Cancer Research Stockholm took a close look at the role of the CHD5 tumor suppressor during normal nervous system development. Previous studies had shown that the gene CHD5 is often inactivated in the most severe forms of neuroblastoma, but little was known about its function in healthy tissue or how it operates. The study, which was conducted in close collaboration with colleagues at Trinity College (formally known as the College of the Holy and Undivided Trinity of Queen Elizabeth, a sole constituent college of the University of Dublin), Dublin, Ireland, addressed these two key issues.

Cellular transition
The researchers found that the chromatin remodeler CHD5is required for the cellular transition from a stem cell to a mature neuron. In one experiment, the researchers knocked down the CHD5 gene by injecting a small RNA into the brains of fetal mice while in the womb.”The result was a complete absence of neurons,” explained Ludwig researcher Holmberg who is based at the Karolinska Institutet. “Instead of becoming neurons, the cells with CHD5 knocked down stayed in a limbo-like state between an actively-dividing stem cell and a mature nerve cell. It was a very robust effect,” Holmberg noted.

New insights
The researchers also dissected how CHD5 operates, showing that it sticks to certain modifications of histone proteins. These modifications help control how genes are turned on and off. In the absence of CHD5, key stem cell genes are not turned off, and genes required for neuronal maturation are not turned on. The findings highlight how the failure of a cell to properly mature into its terminal state can underlie cancer, a relatively understudied area of research. “It is necessary for cells in the healthy nervous tissue to be able to go from stem cells to neurons,” Holmberg said. “If you lose this capacity, these cells become locked in an immature state, which might yield quite dangerous tumor cells, especially in combination with additional cancer-promoting cellular events.”

Insensitive to treatment
The research could also lead to new ways to treat neuroblastoma, perhaps using currently approved drugs. One component of neuroblastoma treatment is retinoic acid, a drug that can drive neuronal maturation. Holmberg and his colleagues found that knocking down the expression of CHD5 in more benign neuroblastoma cells blocked their capacity to mature in response to retinoic acid treatment. “These cells were completely insensitive to treatment, no matter how much we gave them, mirroring the same unresponsiveness to retinoic acid in the more malignant CHD5-negative neuroblastoma cells,” noted Holmberg.

Increasing responsiveness to retinoic acid
Results of these cell-based experiments are consistent with clinical findings that retinoic acid is often unsuccessful in patients with severe forms of the disease. Holmberg reasons that if CHD5 could be re-activated in such hard-to-treat patients, it might increase responsiveness to retinoic acid. The findings may also have relevance for other types of tumors. For instance, CHD5 is often inactivated in glioblastoma multiforme, the most common and most aggressive form of brain cancer in adults.

For more information:
[1] Horner MJ, Ries LA, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2006. Bethesda, Md: National Cancer Institute, 2009. Available online. Last accessed August 12, 2013.
[2] Egan CM, Nyman U, Skotte J, Streubel G, Turner S, O?Connell DJ, Rraklli V, et al. CHD5 Is Required for Neurogenesis and Has a Dual Role in Facilitating Gene Expression and Polycomb Gene Repression. Developmental Cell, Volume 26, Issue 3, 223-236, 12 August 2013. doi:10.1016/j.devcel.2013.07.008 [Article]

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