08 Jun 2009, Posted by christie in Living Bytes, 2 Comments

Study: New findings about glioblastoma, the most common brain cancer, may lead to earlier and better treatment

A small population of cancer-initiating cells (green cells in the large circle) arises from a small area of the adult brain marked by a circle that harbors neural stem cells.

 In an NIH funded study, scientists at University of Michigan Health System have found that a deficiency in a tumor suppressor gene in the brain leads to glioblastoma, the most common type of adult brain cancer. The study, appearing the June 2, 2009 issue of Cancer Cell was conducted in mice and showed that glioblastoma, the type of cancer that afflicts Ted Kennedy and is diagnosed in about 10,000 Americans each year, may originate in neural stem cells located in the subventricular zone of the brain (SVZ). In mice, neural stem cells that normally live in this region give rise to more specialized nerve cells that migrate out of the niche. Cancer could begin with a single genetic mutation in the p53 gene, which makes stem cells migrate out of the niche like their specialized progenies.

The finding of a specific zone of origin could lead to treatments that may improve the current median survival rate of 12 months for this type of brain cancer, says Yuan Zhu, Ph.D., the study’s senior author. “We have to pay more attention to the stem cell niche in both early detection and treatment,” says Zhu. He added that if glioblastoma originates in neural stem cells in the SVZ in humans as it does in mice, then doctors need to direct treatments there, at the source of the tumor as well as to the tumor itself. “Now, if we believe that the SVZ is the location of the cells of origin, with enhanced resolution we could detect tumor cells there,” says Zhu. If it’s possible to detect the cancer early, the chances of treatment success should improve.

Patients with neurodegenerative diseases such as Parkinson’s disease had always been full of hope for using neural stem cells to help regenerate lost nerve function, but Zhu noted that this link between neural stem cells and this aggressive type of cancer is a warning sign for scientists to proceed carefully with these new stem cell treatments. “Our results in mice show that these neural stem cells in the brain have high potential to accumulate genetic lesions and to become a cellular target for cancerous cells,” he says. “ To some degree, the cancerous cells in early stages are not much different from normal stem cells, but aberrantly combine the key features of neural stem cells (self-renewal) and specialized progenies (migration). We have to understand these stem cells more extensively before we can harness them to treat disease.”

In the last six years, studies have shown that stem cell-like cells are involved in a number of cancers, including glioblastoma. But the new study specifically reveals that glioblastoma begins in neural stem cells that have a p53 mutation. These cells then give rise to mutated, fast-multiplying cells down the line of cell differentiation – a class called transit-amplifying progenitor cells. “We found that the cells with p53 mutations are highly plastic. If a treatment blocks one path of action, they may learn other ways to grow,” Zhu says. That helps explain why glioblastoma continues to return even after treatment. Given the plasticity of these cancer-initiating cells, targeting a single signaling pathway may not be sufficient, says Zhu. This trait adds to the complexity of cancer therapy.

Zhu’s team conducted a series of experiments using mice engineered to have a p53 mutation in the central nervous system. They found that a majority developed malignant brain tumors, and that a mutant form of p53 was present in the tumor cells, a phenomenon that is commonly found in human glioblastoma.

“Then we asked, does mutant p53 have any role in tumor initiation and progression? If so, we can use this as a marker for brain cancer in brain cells,” says Yuan Wang, the study’s first author and a U-M Ph.D. student in cell and developmental biology. The team found that mutant p53 was detectable in a minority of highly proliferative neural stem cells of p53-deficient mice two months after birth, and that the expansion of the mutant-p53-expressing cell population with features of transit-amplifying cells underlies the tumor initiation. The evidence supports the idea that mutant p53 can be a useful marker to trace the glioma cells at all stages.

Zhu and his team plan to continue experiments in mice to see if p53 function can be restored in tumor cells. They are also examining whether inhibiting neural stem cells in the SVZ has promise as a potential therapy. Given the plasticity of these cancer-initiating cells, targeting a single signaling pathway may not be sufficient, says Zhu. This trait adds to the complexity of cancer therapy.

Reference: University of Michigan Health System News Room