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Fox-Cat Connection Promotes Glioblastoma Via Brain Tumor Stem Cells

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Thumbnail image for cancer cell cover 10.2011.jpgA pair of proteins found to be overexpressed in a variety of cancers actually link to each other in glioblastoma multiforme. In the process, they support the survival and function of tumor-initiating cells in the most common and lethal form of brain tumor.

MD Anderson researchers report the connection between FoxM1 and beta-catenin in this week's edition of the journal Cancer Cell.

Their findings are the first to put FoxM1 in the Wnt signaling pathway, which normally regulates neural stem cells, says senior author Suyun Huang, M.D., Ph.D., associate professor in MD Anderson's Department of Neurosurgery.

"When FoxM1 binds to beta-catenin, we found that it also supports the self-renewal and differentiation of glioma-initiating cells, the cancer stem cells thought to drive glioblastoma multiforme," Huang says. Glioma-initiating cells are prime suspects in the disease's resistance to treatment and ability to reoccur."

Blocking FoxM1 reduced glioblastoma by 100% in mice
FoxM1 previously was known solely as a transcription factor -- a protein that binds to the DNA in a gene's promoter region to prompt the gene's expression. 

Structural analysis led Huang and her team to suspect FoxM1 might be a binding match for beta-catenin, a crucial protein in the Wnt signaling pathway, which regulates self-renewal and differentiation of neural stem cells.

When a normal cell divides, it produces two copies of itself. A neural stem cell produces one copy of itself (self-renewal) and a copy of a functional brain cell, such as a neuron or an astrocyte (differentiation).

The scientists established the relationship between FoxM1 and beta-catenin in a series of cell line experiments and confirmed their findings in mouse models and an analysis of human tumors.

In two mouse models of human glioblastoma, blocking FoxM1 with short hairpin RNA completely prevented development of brain tumors in 38 mice, while all 20 with unimpeded FoxM1 developed tumors.

Proteins' connection could be drug target

Drugs have not successfully targeted the two proteins. Huang and her team are focusing on the details of the connection between the proteins in search of small molecules that might block their binding. Much preclinical work remains before such a drug can be identified and brought to clinical trial.

The theme of the headline for this post was shamelessly borrowed from artwork by Huang's daughter Victoria Xie, a sophomore at Michael DeBakey High School for Health Professions in Houston. Cancer Cell chose the illustration for its cover art.

Resources
Researchers Find Coupling of Proteins Promotes Glioblastoma Development (news release)
Science Direct editorial
Science Direct article

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